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Comprehensive characterization of neuroblastoma cell line subtypes reveals bilineage potential similar to neural crest stem cells | BMC Developmental Biology | Full Text
<!DOCTYPE html> <html lang="en" class="no-js"> <head> <meta charset="UTF-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width, initial-scale=1"> <title>Comprehensive characterization of neuroblastoma cell line subtypes reveals bilineage potential similar to neural crest stem cells | BMC Developmental Biology | Full Text</title> <meta name="citation_abstract" content="Neuroblastic tumors (NBT) derive from neural crest stem cells (NCSC). Histologically, NBT are composed by neuroblasts and Schwannian cells. In culture, neuroblastic (N-), substrate-adherent (S-) and intermediate phenotype (I-) cell subtypes arise spontaneously. Here, neuroblastoma (NB) cell line subtypes were characterized according to embryonic peripheral nervous system development markers (GAP43, Phox2b, Sox10, c-kit, GD2, NF68, vimentin, S100β, calcyclin and ABCG2), morphological features, gene expression and differentiation potential. I-type cells were investigated as a bipotential (neuronal and glial) differentiation stage. Positive immunostaining of NCSC (GAP43, c-kit, NF68, vimentin and Phox2b) and undifferentiated cell (ABCG2) markers was observed in all NB subtypes. N- and I-type cells displayed cytoplasmic membrane GD2 staining, while nuclear calcyclin was restricted to S-type. N- and I-type cells showed similar phenotype and immunoreactivity pattern. Differential gene expression was associated with each cell subtype. N- and I-type cells displayed similar differentiation capacity towards neuronal and glial lineage fates. S-type cells, upon induction, did not show a neuronal-like phenotype, despite gene expression changes. Results suggest that N- and I-type NB cell subtypes represent an immature bilineage stage, able to progress towards neuronal and glial fates upon induction of differentiation. S-type cells appear irreversibly committed to a glial lineage fate."/> <meta name="journal_id" content="12861"/> <meta name="dc.title" content="Comprehensive characterization of neuroblastoma cell line subtypes reveals bilineage potential similar to neural crest stem cells"/> <meta name="dc.source" content="BMC Developmental Biology 2009 9:1"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="BioMed Central"/> <meta name="dc.date" content="2009-02-12"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2009 Acosta et al; licensee BioMed Central Ltd."/> <meta name="dc.rights" content="http://creativecommons.org/licenses/by/2.0"/> <meta name="dc.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="dc.description" content="Neuroblastic tumors (NBT) derive from neural crest stem cells (NCSC). Histologically, NBT are composed by neuroblasts and Schwannian cells. In culture, neuroblastic (N-), substrate-adherent (S-) and intermediate phenotype (I-) cell subtypes arise spontaneously. Here, neuroblastoma (NB) cell line subtypes were characterized according to embryonic peripheral nervous system development markers (GAP43, Phox2b, Sox10, c-kit, GD2, NF68, vimentin, S100β, calcyclin and ABCG2), morphological features, gene expression and differentiation potential. I-type cells were investigated as a bipotential (neuronal and glial) differentiation stage. Positive immunostaining of NCSC (GAP43, c-kit, NF68, vimentin and Phox2b) and undifferentiated cell (ABCG2) markers was observed in all NB subtypes. N- and I-type cells displayed cytoplasmic membrane GD2 staining, while nuclear calcyclin was restricted to S-type. N- and I-type cells showed similar phenotype and immunoreactivity pattern. Differential gene expression was associated with each cell subtype. N- and I-type cells displayed similar differentiation capacity towards neuronal and glial lineage fates. S-type cells, upon induction, did not show a neuronal-like phenotype, despite gene expression changes. Results suggest that N- and I-type NB cell subtypes represent an immature bilineage stage, able to progress towards neuronal and glial fates upon induction of differentiation. S-type cells appear irreversibly committed to a glial lineage fate."/> <meta name="prism.issn" content="1471-213X"/> <meta name="prism.publicationName" content="BMC Developmental Biology"/> <meta name="prism.publicationDate" content="2009-02-12"/> <meta name="prism.volume" content="9"/> <meta name="prism.number" content="1"/> <meta name="prism.section" content="OriginalPaper"/> <meta name="prism.startingPage" content="1"/> <meta name="prism.endingPage" content="14"/> <meta name="prism.copyright" content="2009 Acosta et al; licensee BioMed Central Ltd."/> <meta name="prism.rightsAgent" content="reprints@biomedcentral.com"/> <meta name="prism.url" content="https://bmcdevbiol.biomedcentral.com/articles/10.1186/1471-213X-9-12"/> <meta name="prism.doi" content="doi:10.1186/1471-213X-9-12"/> <meta name="citation_pdf_url" content="https://bmcdevbiol.biomedcentral.com/counter/pdf/10.1186/1471-213X-9-12"/> <meta name="citation_fulltext_html_url" content="https://bmcdevbiol.biomedcentral.com/articles/10.1186/1471-213X-9-12"/> <meta name="citation_journal_title" content="BMC Developmental Biology"/> <meta name="citation_journal_abbrev" content="BMC Dev Biol"/> <meta name="citation_publisher" content="BioMed Central"/> <meta name="citation_issn" content="1471-213X"/> <meta name="citation_title" content="Comprehensive characterization of neuroblastoma cell line subtypes reveals bilineage potential similar to neural crest stem cells"/> <meta name="citation_volume" content="9"/> <meta name="citation_issue" content="1"/> <meta name="citation_publication_date" content="2009/12"/> <meta name="citation_online_date" content="2009/02/12"/> <meta name="citation_firstpage" content="1"/> <meta name="citation_lastpage" content="14"/> <meta name="citation_article_type" content="Research article"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1186/1471-213X-9-12"/> <meta name="DOI" content="10.1186/1471-213X-9-12"/> <meta name="size" content="179696"/> <meta name="citation_doi" content="10.1186/1471-213X-9-12"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1186/1471-213X-9-12&api_key="/> <meta name="description" content="Neuroblastic tumors (NBT) derive from neural crest stem cells (NCSC). Histologically, NBT are composed by neuroblasts and Schwannian cells. In culture, neuroblastic (N-), substrate-adherent (S-) and intermediate phenotype (I-) cell subtypes arise spontaneously. Here, neuroblastoma (NB) cell line subtypes were characterized according to embryonic peripheral nervous system development markers (GAP43, Phox2b, Sox10, c-kit, GD2, NF68, vimentin, S100β, calcyclin and ABCG2), morphological features, gene expression and differentiation potential. I-type cells were investigated as a bipotential (neuronal and glial) differentiation stage. Positive immunostaining of NCSC (GAP43, c-kit, NF68, vimentin and Phox2b) and undifferentiated cell (ABCG2) markers was observed in all NB subtypes. N- and I-type cells displayed cytoplasmic membrane GD2 staining, while nuclear calcyclin was restricted to S-type. N- and I-type cells showed similar phenotype and immunoreactivity pattern. Differential gene expression was associated with each cell subtype. N- and I-type cells displayed similar differentiation capacity towards neuronal and glial lineage fates. S-type cells, upon induction, did not show a neuronal-like phenotype, despite gene expression changes. Results suggest that N- and I-type NB cell subtypes represent an immature bilineage stage, able to progress towards neuronal and glial fates upon induction of differentiation. S-type cells appear irreversibly committed to a glial lineage fate."/> <meta name="dc.creator" content="Acosta, Sandra"/> <meta name="dc.creator" content="Lavarino, Cinzia"/> <meta name="dc.creator" content="Paris, Raquel"/> <meta name="dc.creator" content="Garcia, Idoia"/> <meta name="dc.creator" content="de Torres, Carmen"/> <meta name="dc.creator" content="Rodríguez, Eva"/> <meta name="dc.creator" content="Beleta, Helena"/> <meta name="dc.creator" content="Mora, Jaume"/> <meta name="dc.subject" content="Developmental Biology"/> <meta name="dc.subject" content="Animal Models"/> <meta name="dc.subject" content="Life Sciences, general"/> <meta name="citation_reference" content="citation_journal_title=Expert Rev Mol Diagn; citation_title=Origin of neuroblastic tumors: clues for future therapeutics; citation_author=J Mora, WL Gerald; citation_volume=4; citation_issue=3; citation_publication_date=2004; citation_pages=293-302; citation_doi=10.1586/14737159.4.3.293; citation_id=CR1"/> <meta name="citation_reference" content="citation_journal_title=Neoplasia; citation_title=Temporally regulated neural crest transcription factors distinguish neuroectodermal tumors of varying malignancy and differentiation; citation_author=TR Gershon, O Oppenheimer, SS Chin, WL Gerald; citation_volume=7; citation_issue=6; citation_publication_date=2005; citation_pages=575-584; citation_doi=10.1593/neo.04637; citation_id=CR2"/> <meta name="citation_reference" content="citation_journal_title=Cancer Genet Cytogenet; citation_title=Phenotypic and genotypic diversity of human neuroblastoma studied in three IGR cell line models derived from bone marrow metastases; citation_author=A Valent, J Benard, AM Venuat, J Silva, A Duverger, N Duarte, O Hartmann, BA Spengler, A Bernheim; citation_volume=112; citation_publication_date=1999; citation_pages=124-129; citation_doi=10.1016/S0165-4608(98)00264-7; citation_id=CR3"/> <meta name="citation_reference" content="citation_journal_title=Cancer Res; citation_title=Neuroblastic and Schwannian stromal cells of neuroblastoma are derived from a tumoral progenitor cell; citation_author=J Mora, NK Cheung, G Juan, P Illei, I Cheung, M Akram, S Chi, M Ladanyi, C Cordon-Cardo, WL Gerald; citation_volume=61; citation_publication_date=2001; citation_pages=6892-6898; citation_id=CR4"/> <meta name="citation_reference" content="citation_journal_title=J Pathol; citation_title=Genome analysis and gene expression profiling of neuroblastoma and ganglioneuroblastoma reveal differences between neuroblastic and Schwannian stromal cells; citation_author=S Coco, R Defferrari, P Scaruffi, A Cavazzana, C Di Cristofano, L Longo, K Mazzocco, P Perri, C Gambini, S Moretti, S Bonassi, GP Tonini; citation_volume=207; citation_publication_date=2005; citation_pages=346-357; citation_doi=10.1002/path.1843; citation_id=CR5"/> <meta name="citation_reference" content="citation_journal_title=N Engl J Med; citation_title=Role of ploidy, chromosome 1p, and Schwann cells in the maturation of neuroblastoma; citation_author=IM Ambros, A Zellner, B Roald, G Amann, R Ladenstein, D Printz, H Gadner, PF Ambros; citation_volume=334; citation_issue=23; citation_publication_date=1996; citation_pages=1505-11; citation_doi=10.1056/NEJM199606063342304; citation_id=CR6"/> <meta name="citation_reference" content="citation_journal_title=Oncogene; citation_title=In neuroblastic tumours, Schwann cells do not harbour the genetic alterations of neuroblasts but may nevertheless share the same clonal origin; citation_author=F Bourdeaut, A Ribeiro, R Paris, G Pierron, J Couturier, M Peuchmaur, O Delattre; citation_volume=27; citation_issue=21; citation_publication_date=2008; citation_pages=3066-71; citation_doi=10.1038/sj.onc.1210965; citation_id=CR7"/> <meta name="citation_reference" content="citation_journal_title=Nat Rev Neurosci; citation_title=Neural crest specification: migrating into genomics; citation_author=LS Gammill, M Bronner-Fraser; citation_volume=4; citation_publication_date=2003; citation_pages=795-805; citation_doi=10.1038/nrn1219; citation_id=CR8"/> <meta name="citation_reference" content="citation_journal_title=Bioessays; citation_title=Sorting out Sox10 functions in neural crest development; citation_author=RN Kelsh; citation_volume=28; citation_publication_date=2006; citation_pages=788-98; citation_doi=10.1002/bies.20445; citation_id=CR9"/> <meta name="citation_reference" content="citation_journal_title=Nat Rev Neurosci; citation_title=The origin and development of glial cells in peripheral nerves; citation_author=KR Jessen, R Mirsky; citation_volume=6; citation_publication_date=2005; citation_pages=671-682; citation_doi=10.1038/nrn1746; citation_id=CR10"/> <meta name="citation_reference" content="citation_journal_title=Neoplasia; citation_title=Characteristics of stem cells from human neuroblastoma cell lines and in tumors; citation_author=JD Walton, DR Kattan, SK Thomas, BA Spengler, HF Guo, JL Biedler, NK Cheung, RA Ross; citation_volume=6; citation_publication_date=2004; citation_pages=838-845; citation_doi=10.1593/neo.04310; citation_id=CR11"/> <meta name="citation_reference" content="citation_journal_title=J Pathol; citation_title=High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche; citation_author=A Pietras, D Gisselsson, I Ora, R Noguera, S Beckman, S Navarro, S Påhlman; citation_volume=214; citation_issue=4; citation_publication_date=2008; citation_pages=482-8; citation_doi=10.1002/path.2304; citation_id=CR12"/> <meta name="citation_reference" content="citation_journal_title=Int J Biochem Cell Biol; citation_title=S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles; citation_author=R Donato; citation_volume=33; citation_publication_date=2001; citation_pages=637-668; citation_doi=10.1016/S1357-2725(01)00046-2; citation_id=CR13"/> <meta name="citation_reference" content="citation_journal_title=Brain Res Dev Brain Res; citation_title=Differential expression of S100B and S100A6(1) in the human fetal and aged cerebral cortex; citation_author=SC Tiu, WY Chan, CW Heizmann, BW Schafer, SY Shu, DT Yew; citation_volume=119; citation_publication_date=2000; citation_pages=159-168; citation_doi=10.1016/S0165-3806(99)00151-0; citation_id=CR14"/> <meta name="citation_reference" content="citation_journal_title=J Biol Chem; citation_title=Calcium- and cell cycle-dependent association of annexin 11 with the nuclear envelope; citation_author=A Tomas, SE Moss; citation_volume=278; citation_publication_date=2003; citation_pages=20210-20216; citation_doi=10.1074/jbc.M212669200; citation_id=CR15"/> <meta name="citation_reference" content="citation_journal_title=Eur J Cancer; citation_title=Gene expression and protein localisation of calcyclin, a calcium-binding protein of the S-100 family in fresh neuroblastomas; citation_author=GP Tonini, G Fabretti, J Kuznicki, L Massimo, P Scaruffi, M Brisigotti, K Mazzocco; citation_volume=31A; citation_issue=4; citation_publication_date=1995; citation_pages=499-504; citation_doi=10.1016/0959-8049(95)00043-I; citation_id=CR16"/> <meta name="citation_reference" content="citation_title=Cellular heterogeneity; citation_inbook_title=Neuroblastoma; citation_publication_date=2005; citation_pages=55-60; citation_id=CR17; citation_author=RA Ross; citation_publisher=Springer-Verlag"/> <meta name="citation_reference" content="citation_journal_title=Oncol Res; citation_title=Cell lineage and differentiation state are primary determinants of MYCN gene expression and malignant potential in human neuroblastoma cells; citation_author=BA Spengler, DL Lazarova, RA Ross, JL Biedler; citation_volume=9; citation_publication_date=1997; citation_pages=467-476; citation_id=CR18"/> <meta name="citation_reference" content="citation_journal_title=J Histochem Cytochem; citation_title=Standardization of the immunocytochemical detection of neuroblastoma cells in bone marrow; citation_author=K Swerts, PF Ambros, C Brouzes, JM Navarro, N Gross, D Rampling, R Schumacher-Kuckelkorn, AR Sementa, R Ladenstein, K Beiske; citation_volume=53; citation_publication_date=2005; citation_pages=1433-1440; citation_doi=10.1369/jhc.5C6661.2005; citation_id=CR19"/> <meta name="citation_reference" content="citation_journal_title=J Cell Biol; citation_title=Disialogangliosides GD2 and GDI are involved in the attachment of human melanoma and neuroblastoma cells to extracellular matrix proteins; citation_author=DA Cheresh, MD Pierschbacher, MA Herzig, K Mujoo; citation_volume=102; citation_publication_date=1986; citation_pages=688-696; citation_doi=10.1083/jcb.102.3.688; citation_id=CR20"/> <meta name="citation_reference" content="citation_journal_title=Cancer Res; citation_title=Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture; citation_author=JL Biedler, L Helson, BA Spengler; citation_volume=33; citation_publication_date=1973; citation_pages=2643-2652; citation_id=CR21"/> <meta name="citation_reference" content="citation_journal_title=Cancer Res; citation_title=Phenotypic diversification in human neuroblastoma cells: expression of distinct neural crest lineages; citation_author=V Ciccarone, BA Spengler, MB Meyers, JL Biedler, RA Ross; citation_volume=49; citation_publication_date=1989; citation_pages=219-225; citation_id=CR22"/> <meta name="citation_reference" content="citation_journal_title=Cell Growth Differ; citation_title=Human neuroblastoma I-type cells are malignant neural crest stem cells; citation_author=RA Ross, BA Spengler, C Domenech, M Porubcin, WJ Rettig, JL Biedler; citation_volume=6; citation_publication_date=1995; citation_pages=449-456; citation_id=CR23"/> <meta name="citation_reference" content="citation_journal_title=Semin Cancer Biol; citation_title=Human neuroblastoma stem cells; citation_author=RA Ross, BA Spengler; citation_volume=17; citation_publication_date=2007; citation_pages=241-247; citation_doi=10.1016/j.semcancer.2006.04.006; citation_id=CR24"/> <meta name="citation_reference" content="citation_journal_title=J Neurobiol; citation_title=Role of all-trans retinoic acid in neurite outgrowth and axonal elongation; citation_author=M Clagett-Dame, EM McNeill, PD Muley; citation_volume=66; citation_issue=7; citation_publication_date=2006; citation_pages=739-56; citation_doi=10.1002/neu.20241; citation_id=CR25"/> <meta name="citation_reference" content="citation_journal_title=Cell Biol Int; citation_title=Human neuroblastoma GOTO cells express CD44 and localize it into lipid rafts upon differentiation into Schwannian cells; citation_author=G Hasegawa, N Minami, A Kushida, H Inuyama, M Koga, K Wakabayashi, Y Saito; citation_volume=29; citation_publication_date=2005; citation_pages=193-202; citation_doi=10.1016/j.cellbi.2004.09.011; citation_id=CR26"/> <meta name="citation_reference" content="citation_journal_title=Cancer Res; citation_title=Schwannian cell differentiation of human neuroblastoma cell lines in vitro induced by bromodeoxyuridine; citation_author=T Sugimoto, T Kato, T Sawada, Y Horii, JT Kemshead, T Hino, H Morioka, H Hosoi; citation_volume=48; citation_publication_date=1988; citation_pages=2531-2537; citation_id=CR27"/> <meta name="citation_reference" content="citation_journal_title=Genes Chromosomes Cancer; citation_title=Induction of senescence in MYCN amplified neuroblastoma cell lines by hydroxyurea; citation_author=R Narath, IM Ambros, A Kowalska, E Bozsaky, P Boukamp, PF Ambros; citation_volume=46; citation_publication_date=2007; citation_pages=130-42; citation_doi=10.1002/gcc.20393; citation_id=CR28"/> <meta name="citation_reference" content="citation_journal_title=J Neurobiol; citation_title=Immortalization and controlled in vitro differentiation of murine multipotent neural crest stem cells; citation_author=MS Rao, DJ Anderson; citation_volume=32; citation_publication_date=1997; citation_pages=722-746; citation_doi=10.1002/(SICI)1097-4695(19970620)32:7<722::AID-NEU7>3.0.CO;2-6; citation_id=CR29"/> <meta name="citation_reference" content="citation_journal_title=Cell; citation_title=Isolation of a stem cell for neurons and glia from the mammalian neural crest; citation_author=DL Stemple, DJ Anderson; citation_volume=71; citation_publication_date=1992; citation_pages=973-985; citation_doi=10.1016/0092-8674(92)90393-Q; citation_id=CR30"/> <meta name="citation_reference" content="citation_journal_title=Development; citation_title=Neural crest cell plasticity and its limits; citation_author=NM Le Douarin, S Creuzet, G Couly, E Dupin; citation_volume=131; citation_publication_date=2004; citation_pages=4637-4650; citation_doi=10.1242/dev.01350; citation_id=CR31"/> <meta name="citation_reference" content="citation_journal_title=J Cell Biochem; citation_title=Transdifferentiation – fact or artifact; citation_author=Y Liu, MS Rao; citation_volume=88; citation_publication_date=2003; citation_pages=29-40; citation_doi=10.1002/jcb.10281; citation_id=CR32"/> <meta name="citation_reference" content="citation_journal_title=Lab Invest; citation_title=The basic helix-loop-helix transcription factor dHAND, a marker gene for the developing human sympathetic nervous system, is expressed in both high- and low-stage neuroblastomas; citation_author=C Gestblom, A Grynfeld, I Ora, E Ortoft, C Larsson, H Axelson, B Sandstedt, P Cserjesi, EN Olson, S Pahlman; citation_volume=79; citation_publication_date=1999; citation_pages=67-79; citation_id=CR33"/> <meta name="citation_reference" content="citation_journal_title=Cancer Metastasis Rev; citation_title=Biology of pediatric peripheral neuroectodermal tumors; citation_author=CJ Thiele; citation_volume=10; citation_publication_date=1991; citation_pages=311-319; citation_doi=10.1007/BF00554793; citation_id=CR34"/> <meta name="citation_reference" content="citation_journal_title=Eur J Cancer; citation_title=Differentiation and survival influences of growth factors in human neuroblastoma; citation_author=S Pahlman, JC Hoehner, E Nanberg, F Hedborg, S Fagerstrom, C Gestblom, I Johansson, U Larsson, E Lavenius, E Ortoft, H Soderholm; citation_volume=31A; citation_issue=4; citation_publication_date=1995; citation_pages=453-458; citation_doi=10.1016/0959-8049(95)00033-F; citation_id=CR35"/> <meta name="citation_reference" content="citation_journal_title=Neuron; citation_title=SOX10 maintains multipotency and inhibits neuronal; citation_author=J Kim, L Lo, E Dormand, DJ Anderson; citation_volume=38; citation_issue=1; citation_publication_date=2003; citation_pages=17-31; citation_doi=10.1016/S0896-6273(03)00163-6; citation_id=CR36"/> <meta name="citation_reference" content="citation_journal_title=Cancer Cell; citation_title=Radial glia cells are candidate stem cells of ependymoma; citation_author=MD Taylor, H Poppleton, C Fuller, X Su, Y Liu, P Jensen, S Magdaleno, J Dalton, C Calabrese, J Board, T Macdonald, J Rutka, A Guha, A Gajjar, T Curran, R Gilbertson; citation_volume=8; citation_publication_date=2005; citation_pages=323-335; citation_doi=10.1016/j.ccr.2005.09.001; citation_id=CR37"/> <meta name="citation_reference" content="citation_journal_title=Stem Cells; citation_title=Multipotent cell fate of neural crest-like cells derived from embryonic stem cells; citation_author=T Motohashi, H Aoki, K Chiba, N Yoshimura, T Kunisada; citation_volume=25; citation_publication_date=2007; citation_pages=402-410; citation_doi=10.1634/stemcells.2006-0323; citation_id=CR38"/> <meta name="citation_reference" content="citation_title=Neuron-glial interactions; citation_inbook_title=Molecular and Cellular Approaches to neural development; citation_publication_date=1997; citation_pages=64-107; citation_id=CR39; citation_author=BA Barres; citation_publisher=New York"/> <meta name="citation_reference" content="citation_journal_title=PNAS; citation_title=Interactions between astrocytes and adult subventricular zone precursors stimulates neurogenesis; citation_author=DA Lim, A Alvarez-Buylla; citation_volume=96; citation_publication_date=1999; citation_pages=7526-7531; citation_doi=10.1073/pnas.96.13.7526; citation_id=CR40"/> <meta name="citation_reference" content="citation_journal_title=Am J Pathol; citation_title=Cross-talk between Schwann cells and neuroblasts influences the biology of neuroblastoma xenografts; citation_author=S Liu, Y Tian, A Chlenski, Q Yang, P Zage, HR Salwen, SE Crawford, SL Cohn; citation_volume=166; citation_publication_date=2005; citation_pages=891-900; citation_doi=10.1016/S0002-9440(10)62309-7; citation_id=CR41"/> <meta name="citation_reference" content="citation_journal_title=Proc Natl Acad Sci USA; citation_title=A biomarker that identifies senescent human cells in culture and in aging skin in vivo; citation_author=GP Dimri, X Lee, G Basile, M Acosta, G Scott, C Roskelley, EE Medrano, M Linskens, I Rubelj, O Pereira-Smith; citation_volume=92; citation_publication_date=1995; citation_pages=9363-7; citation_doi=10.1073/pnas.92.20.9363; citation_id=CR42"/> <meta name="citation_reference" content="citation_journal_title=Clin Cancer Res; citation_title=Quantitation of marrow disease in neuroblastoma by real-time reverse transcription-PCR; citation_author=IY Cheung, NK Cheung; citation_volume=7; citation_publication_date=2001; citation_pages=1698-1705; citation_id=CR43"/> <meta name="citation_reference" content="citation_journal_title=Genome Biol; citation_title=Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes; citation_author=J Vandesompele, K De Preter, F Pattyn, B Poppe, N Van Roy, A De Paepe, F Speleman; citation_volume=3; citation_issue=7; citation_publication_date=2002; citation_pages=RESEARCH0034; citation_doi=10.1186/gb-2002-3-7-research0034; citation_id=CR44"/> 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Histologically, NBT are composed by neuroblasts and Schwannian cells. In culture, neuroblastic (N-), substrate-adherent (S-) and intermediate phenotype (I-) cell subtypes arise spontaneously. Methods Here, neuroblastoma (NB) cell line subtypes were characterized according to embryonic peripheral nervous system development markers (GAP43, Phox2b, Sox10, c-kit, GD2, NF68, vimentin, S100β, calcyclin and ABCG2), morphological features, gene expression and differentiation potential. I-type cells were investigated as a bipotential (neuronal and glial) differentiation stage. Results Positive immunostaining of NCSC (GAP43, c-kit, NF68, vimentin and Phox2b) and undifferentiated cell (ABCG2) markers was observed in all NB subtypes. N- and I-type cells displayed cytoplasmic membrane GD2 staining, while nuclear calcyclin was restricted to S-type. N- and I-type cells showed similar phenotype and immunoreactivity pattern. Differential gene expression was associated with each cell subtype. N- and I-type cells displayed similar differentiation capacity towards neuronal and glial lineage fates. S-type cells, upon induction, did not show a neuronal-like phenotype, despite gene expression changes. Conclusion Results suggest that N- and I-type NB cell subtypes represent an immature bilineage stage, able to progress towards neuronal and glial fates upon induction of differentiation. S-type cells appear irreversibly committed to a glial lineage fate."/> <meta property="og:image" content="https://static-content.springer.com/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig1_HTML.jpg"/> <script type="application/ld+json">{"mainEntity":{"headline":"Comprehensive characterization of neuroblastoma cell line subtypes reveals bilineage potential similar to neural crest stem cells","description":"Neuroblastic tumors (NBT) derive from neural crest stem cells (NCSC). Histologically, NBT are composed by neuroblasts and Schwannian cells. In culture, neuroblastic (N-), substrate-adherent (S-) and intermediate phenotype (I-) cell subtypes arise spontaneously. Here, neuroblastoma (NB) cell line subtypes were characterized according to embryonic peripheral nervous system development markers (GAP43, Phox2b, Sox10, c-kit, GD2, NF68, vimentin, S100β, calcyclin and ABCG2), morphological features, gene expression and differentiation potential. I-type cells were investigated as a bipotential (neuronal and glial) differentiation stage. Positive immunostaining of NCSC (GAP43, c-kit, NF68, vimentin and Phox2b) and undifferentiated cell (ABCG2) markers was observed in all NB subtypes. N- and I-type cells displayed cytoplasmic membrane GD2 staining, while nuclear calcyclin was restricted to S-type. N- and I-type cells showed similar phenotype and immunoreactivity pattern. Differential gene expression was associated with each cell subtype. N- and I-type cells displayed similar differentiation capacity towards neuronal and glial lineage fates. S-type cells, upon induction, did not show a neuronal-like phenotype, despite gene expression changes. Results suggest that N- and I-type NB cell subtypes represent an immature bilineage stage, able to progress towards neuronal and glial fates upon induction of differentiation. 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characterization of neuroblastoma cell line subtypes reveals bilineage potential similar to neural crest stem cells </div> <div class="c-pdf-container"> <div class="c-pdf-download u-clear-both"> <a href="//bmcdevbiol.biomedcentral.com/counter/pdf/10.1186/1471-213X-9-12.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="pdf-link" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="link" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-download"/></svg> </a> </div> </div> </div> </div> <div class="c-pdf-button__container u-hide-at-lg js-context-bar-sticky-point-mobile"> <div class="c-pdf-container" data-track-context="article body"> <div class="c-pdf-download u-clear-both"> <a href="//bmcdevbiol.biomedcentral.com/counter/pdf/10.1186/1471-213X-9-12.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="pdf-link" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="link" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-download"/></svg> </a> </div> </div> </div> <article lang="en"> <div class="c-article-header"> <ul class="c-article-identifiers" data-test="article-identifier"> <li class="c-article-identifiers__item" data-test="article-category">Research article</li> <li class="c-article-identifiers__item"> <a href="https://www.springernature.com/gp/open-research/about/the-fundamentals-of-open-access-and-open-research" data-track="click" data-track-action="open access" data-track-label="link" class="u-color-open-access" data-test="open-access">Open access</a> </li> <li class="c-article-identifiers__item">Published: <time datetime="2009-02-12">12 February 2009</time></li> </ul> <h1 class="c-article-title" data-test="article-title" data-article-title="">Comprehensive characterization of neuroblastoma cell line subtypes reveals bilineage potential similar to neural crest stem cells</h1> <ul class="c-article-author-list c-article-author-list--short" data-test="authors-list" data-component-authors-activator="authors-list"><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Sandra-Acosta-Aff1" data-author-popup="auth-Sandra-Acosta-Aff1" data-author-search="Acosta, Sandra">Sandra Acosta</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Cinzia-Lavarino-Aff1" data-author-popup="auth-Cinzia-Lavarino-Aff1" data-author-search="Lavarino, Cinzia">Cinzia Lavarino</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Raquel-Paris-Aff1" data-author-popup="auth-Raquel-Paris-Aff1" data-author-search="Paris, Raquel">Raquel Paris</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Idoia-Garcia-Aff1" data-author-popup="auth-Idoia-Garcia-Aff1" data-author-search="Garcia, Idoia">Idoia Garcia</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Carmen-de_Torres-Aff1" data-author-popup="auth-Carmen-de_Torres-Aff1" data-author-search="de Torres, Carmen">Carmen de Torres</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Eva-Rodr_guez-Aff1" data-author-popup="auth-Eva-Rodr_guez-Aff1" data-author-search="Rodríguez, Eva">Eva Rodríguez</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item 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</li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <p class="c-article-info-details" data-container-section="info"> <a data-test="journal-link" href="/" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">BMC Developmental Biology</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 9</b>, Article number: <span data-test="article-number">12</span> (<span data-test="article-publication-year">2009</span>) <a href="#citeas" class="c-article-info-details__cite-as u-hide-print" data-track="click" data-track-action="cite this article" data-track-label="link">Cite this article</a> </p> <div class="c-article-metrics-bar__wrapper u-clear-both"> <ul class="c-article-metrics-bar u-list-reset"> <li class=" c-article-metrics-bar__item" data-test="access-count"> <p class="c-article-metrics-bar__count">19k <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="citation-count"> <p class="c-article-metrics-bar__count">42 <span class="c-article-metrics-bar__label">Citations</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/10.1186/1471-213X-9-12/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Metrics <span class="u-visually-hidden">details</span></a></p> </li> </ul> </div> </div> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Background</h3><p>Neuroblastic tumors (NBT) derive from neural crest stem cells (NCSC). Histologically, NBT are composed by neuroblasts and Schwannian cells. In culture, neuroblastic (N-), substrate-adherent (S-) and intermediate phenotype (I-) cell subtypes arise spontaneously.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Methods</h3><p>Here, neuroblastoma (NB) cell line subtypes were characterized according to embryonic peripheral nervous system development markers (GAP43, Phox2b, Sox10, c-kit, GD2, NF68, vimentin, S100β, calcyclin and ABCG2), morphological features, gene expression and differentiation potential. I-type cells were investigated as a bipotential (neuronal and glial) differentiation stage.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Results</h3><p>Positive immunostaining of NCSC (GAP43, c-kit, NF68, vimentin and Phox2b) and undifferentiated cell (ABCG2) markers was observed in all NB subtypes. N- and I-type cells displayed cytoplasmic membrane GD2 staining, while nuclear calcyclin was restricted to S-type. N- and I-type cells showed similar phenotype and immunoreactivity pattern. Differential gene expression was associated with each cell subtype. N- and I-type cells displayed similar differentiation capacity towards neuronal and glial lineage fates. S-type cells, upon induction, did not show a neuronal-like phenotype, despite gene expression changes.</p><h3 class="c-article__sub-heading" data-test="abstract-sub-heading">Conclusion</h3><p>Results suggest that N- and I-type NB cell subtypes represent an immature bilineage stage, able to progress towards neuronal and glial fates upon induction of differentiation. S-type cells appear irreversibly committed to a glial lineage fate.</p></div></div></section> <section data-title="Background"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Background</h2><div class="c-article-section__content" id="Sec1-content"><p>Neuroblastic tumors (NBT) are the most common extracranial solid tumors in children. NBTs derive from neural crest stem cells (NCSC) blocked at different stages of the sympathetic nervous system development [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Mora J, Gerald WL: Origin of neuroblastic tumors: clues for future therapeutics. Expert Rev Mol Diagn. 2004, 4 (3): 293-302." href="/articles/10.1186/1471-213X-9-12#ref-CR1" id="ref-link-section-d45557183e453">1</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Gershon TR, Oppenheimer O, Chin SS, Gerald WL: Temporally regulated neural crest transcription factors distinguish neuroectodermal tumors of varying malignancy and differentiation. Neoplasia. 2005, 7 (6): 575-584." href="/articles/10.1186/1471-213X-9-12#ref-CR2" id="ref-link-section-d45557183e456">2</a>]. Histologically, NBT are composed of variable proportion of neuroblasts (neuronal lineage) and Schwannian-like cells (glial lineage). Prior studies have reported that both cell types share chromosomal abnormalities, suggesting a common neoplastic precursor cell [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Valent A, Benard J, Venuat AM, Silva J, Duverger A, Duarte N, Hartmann O, Spengler BA, Bernheim A: Phenotypic and genotypic diversity of human neuroblastoma studied in three IGR cell line models derived from bone marrow metastases. Cancer Genet Cytogenet. 1999, 112: 124-129." href="/articles/10.1186/1471-213X-9-12#ref-CR3" id="ref-link-section-d45557183e459">3</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Coco S, Defferrari R, Scaruffi P, Cavazzana A, Di Cristofano C, Longo L, Mazzocco K, Perri P, Gambini C, Moretti S, Bonassi S, Tonini GP: Genome analysis and gene expression profiling of neuroblastoma and ganglioneuroblastoma reveal differences between neuroblastic and Schwannian stromal cells. J Pathol. 2005, 207: 346-357." href="/articles/10.1186/1471-213X-9-12#ref-CR5" id="ref-link-section-d45557183e462">5</a>] however; discrepant studies failed to detect genetic alterations in the Schwannian components of NBT [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Ambros IM, Zellner A, Roald B, Amann G, Ladenstein R, Printz D, Gadner H, Ambros PF: Role of ploidy, chromosome 1p, and Schwann cells in the maturation of neuroblastoma. N Engl J Med. 1996, 334 (23): 1505-11." href="/articles/10.1186/1471-213X-9-12#ref-CR6" id="ref-link-section-d45557183e465">6</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Bourdeaut F, Ribeiro A, Paris R, Pierron G, Couturier J, Peuchmaur M, Delattre O: In neuroblastic tumours, Schwann cells do not harbour the genetic alterations of neuroblasts but may nevertheless share the same clonal origin. Oncogene. 2008, 27 (21): 3066-71." href="/articles/10.1186/1471-213X-9-12#ref-CR7" id="ref-link-section-d45557183e469">7</a>].</p><p>The differentiation process of NCSC gives rise to peripheral nervous system (PNS), amongst other structures [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Gammill LS, Bronner-Fraser M: Neural crest specification: migrating into genomics. Nat Rev Neurosci. 2003, 4: 795-805." href="/articles/10.1186/1471-213X-9-12#ref-CR8" id="ref-link-section-d45557183e475">8</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Kelsh RN: Sorting out Sox10 functions in neural crest development. Bioessays. 2006, 28: 788-98." href="/articles/10.1186/1471-213X-9-12#ref-CR9" id="ref-link-section-d45557183e478">9</a>]. This process can be tracked by analyzing marker proteins sequentially expressed during embryonic cell development [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Jessen KR, Mirsky R: The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci. 2005, 6: 671-682." href="/articles/10.1186/1471-213X-9-12#ref-CR10" id="ref-link-section-d45557183e481">10</a>]. Likewise, the embryonic origin of neuroblastic tumor cells can be established using NCSC protein markers such as Phox2b and c-kit [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA: Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia. 2004, 6: 838-845." href="/articles/10.1186/1471-213X-9-12#ref-CR11" id="ref-link-section-d45557183e484">11</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Pietras A, Gisselsson D, Ora I, Noguera R, Beckman S, Navarro S, Påhlman S: High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. J Pathol. 2008, 214 (4): 482-8." href="/articles/10.1186/1471-213X-9-12#ref-CR12" id="ref-link-section-d45557183e487">12</a>] while embryonic glial-lineage markers such as SRY box 10 transcription factor (Sox10) and AP2α are expressed in immature glial cells in NBT [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Gershon TR, Oppenheimer O, Chin SS, Gerald WL: Temporally regulated neural crest transcription factors distinguish neuroectodermal tumors of varying malignancy and differentiation. Neoplasia. 2005, 7 (6): 575-584." href="/articles/10.1186/1471-213X-9-12#ref-CR2" id="ref-link-section-d45557183e491">2</a>].</p><p>NBT cell components may be identified using a variety of protein markers. The glial component may be identified by the expression of the calcium binding family protein S100. Specifically, S100A6 (Calcyclin), has been reported as a neural crest derived glial-cell lineage marker [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Donato R: S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol. 2001, 33: 637-668." href="/articles/10.1186/1471-213X-9-12#ref-CR13" id="ref-link-section-d45557183e497">13</a>], also expressed in the fetal CNS glia [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Tiu SC, Chan WY, Heizmann CW, Schafer BW, Shu SY, Yew DT: Differential expression of S100B and S100A6(1) in the human fetal and aged cerebral cortex. Brain Res Dev Brain Res. 2000, 119: 159-168." href="/articles/10.1186/1471-213X-9-12#ref-CR14" id="ref-link-section-d45557183e500">14</a>]. Calcyclin migrates to the nuclear membrane upon an increase of intracellular calcium concentration; its precise function remains unknown [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Tomas A, Moss SE: Calcium- and cell cycle-dependent association of annexin 11 with the nuclear envelope. J Biol Chem. 2003, 278: 20210-20216." href="/articles/10.1186/1471-213X-9-12#ref-CR15" id="ref-link-section-d45557183e503">15</a>]. In NBT, calcyclin expression is mostly found in Schwann-like cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Tonini GP, Fabretti G, Kuznicki J, Massimo L, Scaruffi P, Brisigotti M, Mazzocco K: Gene expression and protein localisation of calcyclin, a calcium-binding protein of the S-100 family in fresh neuroblastomas. Eur J Cancer. 1995, 31A (4): 499-504." href="/articles/10.1186/1471-213X-9-12#ref-CR16" id="ref-link-section-d45557183e506">16</a>].</p><p>The neuronal lineage compartment of NBT is characterized by the expression of proteins like neurofilament proteins and the membrane ganglioside GD2 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Ross RA: Cellular heterogeneity. Neuroblastoma. Edited by: Cheung NK, Cohn SL. 2005, Berlin: Springer-Verlag, 55-60." href="/articles/10.1186/1471-213X-9-12#ref-CR17" id="ref-link-section-d45557183e512">17</a>–<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Swerts K, Ambros PF, Brouzes C, Navarro JM, Gross N, Rampling D, Schumacher-Kuckelkorn R, Sementa AR, Ladenstein R, Beiske K: Standardization of the immunocytochemical detection of neuroblastoma cells in bone marrow. J Histochem Cytochem. 2005, 53: 1433-1440." href="/articles/10.1186/1471-213X-9-12#ref-CR19" id="ref-link-section-d45557183e515">19</a>]. GD2 is expressed in fetal brain neuroblasts and neuroectodermal derived tumors. Cell membrane GD2, synthesized by the GD2 synthase, is implicated in cell adhesion [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Cheresh DA, Pierschbacher MD, Herzig MA, Mujoo K: Disialogangliosides GD2 and GDI are involved in the attachment of human melanoma and neuroblastoma cells to extracellular matrix proteins. J Cell Biol. 1986, 102: 688-696." href="/articles/10.1186/1471-213X-9-12#ref-CR20" id="ref-link-section-d45557183e518">20</a>].</p><p>Biedler [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Biedler JL, Helson L, Spengler BA: Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture. Cancer Res. 1973, 33: 2643-2652." href="/articles/10.1186/1471-213X-9-12#ref-CR21" id="ref-link-section-d45557183e525">21</a>] described three cell subtypes spontaneously arising in NB cell line cultures, the N (neuroblastic), S (substrate adherent) and I (intermediate) subtypes. These three cell line subtypes were isolated and characterized on the basis of the different cell culture behavior and protein expression pattern [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Biedler JL, Helson L, Spengler BA: Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture. Cancer Res. 1973, 33: 2643-2652." href="/articles/10.1186/1471-213X-9-12#ref-CR21" id="ref-link-section-d45557183e528">21</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Ciccarone V, Spengler BA, Meyers MB, Biedler JL, Ross RA: Phenotypic diversification in human neuroblastoma cells: expression of distinct neural crest lineages. Cancer Res. 1989, 49: 219-225." href="/articles/10.1186/1471-213X-9-12#ref-CR22" id="ref-link-section-d45557183e531">22</a>]. I-type cell lines, reported to have a bipotential capacity to differentiate towards both neuronal and glial lineage when induced with retinoic acid and bromodeoxyuridine respectively, have recently been proposed as NBT stem cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Ross RA, Spengler BA, Domenech C, Porubcin M, Rettig WJ, Biedler JL: Human neuroblastoma I-type cells are malignant neural crest stem cells. Cell Growth Differ. 1995, 6: 449-456." href="/articles/10.1186/1471-213X-9-12#ref-CR23" id="ref-link-section-d45557183e534">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Ross RA, Spengler BA: Human neuroblastoma stem cells. Semin Cancer Biol. 2007, 17: 241-247." href="/articles/10.1186/1471-213X-9-12#ref-CR24" id="ref-link-section-d45557183e537">24</a>]. Retinoic acid is a vitamin A derived molecule, which plays an important role in the early development of the nervous system stimulating neuronal differentiation and inducing the expression of neuronal proteins [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Clagett-Dame M, McNeill EM, Muley PD: Role of all-trans retinoic acid in neurite outgrowth and axonal elongation. J Neurobiol. 2006, 66 (7): 739-56." href="/articles/10.1186/1471-213X-9-12#ref-CR25" id="ref-link-section-d45557183e541">25</a>]. Bromodeoxyuridine is a thymidine analog which incorporates into the newly synthesized DNA during the S phase of cell cycle. It has been used as a glial differentiation factor <i>in vitro</i> for NB, inducing cell flattening and increased substrate adhesiveness [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Ross RA, Spengler BA, Domenech C, Porubcin M, Rettig WJ, Biedler JL: Human neuroblastoma I-type cells are malignant neural crest stem cells. Cell Growth Differ. 1995, 6: 449-456." href="/articles/10.1186/1471-213X-9-12#ref-CR23" id="ref-link-section-d45557183e547">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Hasegawa G, Minami N, Kushida A, Inuyama H, Koga M, Wakabayashi K, Saito Y: Human neuroblastoma GOTO cells express CD44 and localize it into lipid rafts upon differentiation into Schwannian cells. Cell Biol Int. 2005, 29: 193-202." href="/articles/10.1186/1471-213X-9-12#ref-CR26" id="ref-link-section-d45557183e550">26</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Sugimoto T, Kato T, Sawada T, Horii Y, Kemshead JT, Hino T, Morioka H, Hosoi H: Schwannian cell differentiation of human neuroblastoma cell lines in vitro induced by bromodeoxyuridine. Cancer Res. 1988, 48: 2531-2537." href="/articles/10.1186/1471-213X-9-12#ref-CR27" id="ref-link-section-d45557183e553">27</a>].</p><p>In this study, we aimed to characterize each NB cell line subtype according to differential lineage markers from the embryonic development of PNS and test whether the intermediate subtype of NB derived cell lines reproduce a distinct and bipotential (neuronal and glial) stage of differentiation. A continuum process of differentiation between neuronal and glial lineage, which resemble the normal PNS development, was identified.</p></div></div></section><section data-title="Results"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Results</h2><div class="c-article-section__content" id="Sec2-content"><h3 class="c-article__sub-heading" id="Sec3">Cell lines characterization</h3><p>Eleven cell lines were investigated. In addition to morphological and <i>in vitro</i> behavior features, cell lines were characterized based on the differential expression of previously described markers [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA: Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia. 2004, 6: 838-845." href="/articles/10.1186/1471-213X-9-12#ref-CR11" id="ref-link-section-d45557183e574">11</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Ross RA, Spengler BA, Domenech C, Porubcin M, Rettig WJ, Biedler JL: Human neuroblastoma I-type cells are malignant neural crest stem cells. Cell Growth Differ. 1995, 6: 449-456." href="/articles/10.1186/1471-213X-9-12#ref-CR23" id="ref-link-section-d45557183e577">23</a>] using immunofluorescent staining (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/1471-213X-9-12#Tab1">1</a>) and qRT-PCR analysis.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Table 1 Immunophenotypical analysis of neuroblastoma cell lines</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/articles/10.1186/1471-213X-9-12/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Distinct morphological features were observed for S- and N-type cell lines, as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Biedler JL, Helson L, Spengler BA: Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture. Cancer Res. 1973, 33: 2643-2652." href="/articles/10.1186/1471-213X-9-12#ref-CR21" id="ref-link-section-d45557183e1371">21</a>]. S-type cell lines were morphologically characterized by large flat cytoplasms, relaxed chromatin and strong adherence to the flask surface. N- and I-type cell lines showed a very similar phenotype in culture, characterized by a low cytoplasm/nuclei ratio, poor adherence to the flask surface, growth in dense cell aggregates and neurite processes formation. Only one cell line displayed a clear intermediate phenotype, the I-type cell line SK-N-ER, characterized by a larger cytoplasm and greater adherence to the flask surface than the other I-type cell lines, features resembling those of the S-type cell lines.</p><p>Amongst the NBT cell line subtypes the intermediate neurofilaments and vimentin have been proposed as differentially expressed markers for neuronal and glial phenotypes, respectively [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA: Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia. 2004, 6: 838-845." href="/articles/10.1186/1471-213X-9-12#ref-CR11" id="ref-link-section-d45557183e1377">11</a>]. As shown in figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig1">1</a>, both proteins are expressed in the cytoplasm of the three cell subtypes. The neurofilament NF68 showed a higher cytoplasmic expression in the N- and I cell subtypes (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig1">1</a>). On the other hand, vimentin was detected with similar intensity, in the cytoplasm of all the cell lines analyzed (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig1">1</a>). In our hands, these markers were not helpful to distinguish amongst the cell lines subtypes.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Figure 1"><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 1</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig1_HTML.jpg?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig1_HTML.jpg" alt="figure 1" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p><b>Neuroblastic and glial immunophenotype in NB cell line subtypes</b>. Neurofilament NF68 cytoplasm expression intensity was higher in N-, I- than in S-type cell lines. Vimentin is expressed intensely in the cytoplasm of the three cell lines subtypes. GD2 cell membrane and intense nuclear membrane calcyclin staining allows to distinguish between the neuroblastic and the glial phenotype. Blue: DAPI, Green: FITC.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>N- and I-type were immunophenotypically distinguishable from S-type cell lines based on the differential staining of GD2 and calcyclin. Similar intense cytoplasm membrane GD2 immunostaining was observed in both N- and I-type cells, while intense nuclear membrane calcyclin was identified exclusively in the S-type. N- and I-type showed a faint diffuse cytoplasm staining for calcyclin (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig1">1</a>). Thus, among the markers tested, we found cytoplasm membrane-GD2 and nuclear-calcyclin immunolabelling as reliable NBT neuroblastic and glial lineage markers, respectively.</p><p>Of note, all but one of the S-type cell lines studied, the exception being LA1-5S, turned out not to be pure cultures since few morphologically N-type cells, which were GD2-membrane positive, were identified. S-like cells were also detected in the N-type cell lines Be2-M17V and SH-SY5Y (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/1471-213X-9-12#Tab1">1</a>).</p><p>Overall, the N- and I-type cell lines studied showed a very similar phenotype in culture, with equivalent adherence, cytoplasm/nuclei ratio, and similar neurite process formation. N- and I-type cell lines shared a similar immunoreactivity pattern, namely high membrane GD2 staining, absence of nuclear calcyclin and high neurofilament NF68 (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig1">1</a>).</p><p>Protein markers of undifferentiated neural crest derived cells, such as GAP43, c-kit and Phox2b, as well as the undifferentiated cell marker ABCG2, were positive in all the cell line subtypes tested (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/1471-213X-9-12#Tab1">1</a>). Intense GAP43 immunostaining was detected in the cytoplasm of N-type cell lines (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig2">2</a>) and two of the four I-type cell lines. S-type and the rest of I-type cell lines showed a lower intensity of GAP43 cytoplasmic staining (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/1471-213X-9-12#Tab1">1</a>). Similar results were observed for c-kit immunostaining (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/articles/10.1186/1471-213X-9-12#Tab1">1</a>). On the other hand, nuclear localization of Phox2b positivity was identified in the I-type cell lines, in some cells being very intense. A lower nuclear intensity was identified for the N- and S-type (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig2">2</a>). ABCG2 exhibited a moderate diffuse cytoplasmic immunoreactivity in most of the cell lines analyzed (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig2">2</a>).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Figure 2"><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 2</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig2_HTML.jpg?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig2_HTML.jpg" alt="figure 2" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p><b>Neural crest cell markers pattern in NB cell line subtypes</b>. All cell line subtypes exhibited positive protein expression for GAP43, c-kit, Phox2b and ABCG2 immunostaining. Differences in the intensity and localization of these proteins can be identified in some of the cell lines (see text). For Phox2b, small squares show non-merged nuclear cell images. Blue: DAPI, Green: FITC (ABCG2, GAP43). Red: Cy3 (Phox2b). c-kit (DAB staining).</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>To delve further into the differential expression among cell line subtypes, GD2-synthase and calcyclin mRNA expression were analyzed by qRT-PCR. GD2-synthase expression pattern showed differences among the 3 cell subtypes, being the N-type cells those with the highest expression followed by the I-type cells and, at lower level, the S-type cells (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig3">3A</a>). When calcyclin mRNA expression was quantified, different expression for S-type compared to N- and I-type was found (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig3">3B</a>). These results confirm those observed by immunofluorescence.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Figure 3"><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 3</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig3_HTML.jpg?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig3_HTML.jpg" alt="figure 3" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p><b>Gene expression pattern in the NB cell linesubtypes</b>. Results are displayed as mean expression levels of cell subtypes (N-, I- and S-type), obtained from three independent experiments. Quantification was performed relative to the cell line with the lowest amplification level. Error bars illustrate the variability amongst the cell lines of each subtype. <b>A</b>. GD2 synthase mean expression quantified in relation to LA1-5S. <b>B</b>. Calcyclin mean expression quantified in relation to LA1-55N. <b>C</b>. NF68 mean expression quantified in relation to SK-N-ER. <b>D</b>. Tuj1 mean expression quantified in relation to LA1-5S.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Additional gene expression analyses were performed in the cell subtypes by qRT-PCR. Neuronal lineage markers, NF68 and Tuj1, showed the highest expression in N-type cells. I-type cells showed higher expression than S-type for the NF68 marker (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig3">3C</a>), and lower for Tuj1 (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig3">3D</a>). Sox10, an immature neural crest marker also expressed in glial cells, did not show detectable expression by qRT-PCR in any of the cell lines analyzed, regardless of the cell type (data not shown).</p><p>Altogether, the observed gene expression patterns confirm the inmunofluorescent results underscoring the immature, yet distinct, nature of these NBT cell lines. Nonetheless, I-type cell lines share features closer to the N-type subgroup, namely immature neuronal lineage phenotype, whilst S-type cell lines embody a glial immature stage.</p></div></div></section><section data-title="Differentiation Studies"><div class="c-article-section" id="Sec4-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec4">Differentiation Studies</h2><div class="c-article-section__content" id="Sec4-content"><p>To investigate the behavior of the different cell subtypes during differentiation induction, LA1-55N (N-type), SK-N-Be2C, SK-N-LP and SK-N-ER (I-type), and LA1-5S (S-type) were chosen to represent each cell subtype.</p><h3 class="c-article__sub-heading" id="Sec5">I. Neuronal differentiation induced by all-<i>trans</i>retinoic acid (ATRA)</h3><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec6">I.a. Morphological and immunophenotypical changes</h4><p>When differentiation was induced towards neuronal lineage by treatment with ATRA, both N- and I-type cell lines changed their morphology. One week after treatment most cells showed a neuronal-like phenotype, displaying long and growing neurites. These cells proliferated forming large, dense interconnected cell clumps that were eventually released as floating spherical cell aggregates, neurospheres, with capacity to grow in suspension (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig4">4A</a> and <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig4">4B</a>). In the N-type, changes appeared early in the first week of treatment and persisted during all the differentiation induction experiment (60 days). All the I-type cells showed morphological changes, the most remarkable being in the SK-N-Be2C cell line. During the first week of treatment neurites grew significantly, and, after two weeks, floating neurospheres appeared. The I-type SK-N-LP cell line did not form neurospheres, but poorly adherent cell clusters. In the I-type SK-N-ER cell line, the morphological changes appeared later and around the 5<sup>th</sup> week of treatment they formed neurospheres. In all the N- and I-type cell lines, the morphological changes remained evident even when ATRA treatment was removed; however, the capacity to form neurospheres was clearly diminished. Overall, no significant change in the proliferation ratio was detected in the cell lines during treatment, however, an increase in cell mortality was observed after one week of treatment.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4" data-title="Figure 4"><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 4</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig4_HTML.jpg?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig4_HTML.jpg" alt="figure 4" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-4-desc"><p><b>Morphological, immunophenotypical and gene expression changes induced by ATRA</b>. Neuronal differentiation in the I-type cell line SK-N-Be2C: <b>A</b>. 60 days of ATRA treatment. Arrow: neurosphere in formation. <b>B</b>. not-treated negative control culture. <b>C</b>. GD2 expression in newly formed floating neurosphere at day 15 of ATRA treatment. <b>D</b>. Calcyclin expression at day 60 of ATRA treatment. White arrow: calcyclin positive cell that appear during neuronal differentiation induction treatment. Gene expression changes of calcyclin (<b>E</b>) and GD2 synthase (<b>F</b>) in LA1-55N, LA1-5S and SK-N-ER cell lines. q-RT-PCR analysis was performed by triplicate of two separate differentiation experiments (60 days induction and 30 days of treatment depletion (90). RA-IND: ATRA induction period.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/4" data-track-dest="link:Figure4 Full size image" aria-label="Full size image figure 4" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Both N- and I-type cell lines showed no variation of the membrane-GD2 immunostaining during ATRA treatment in comparison to non-treated control cell lines. GD2 cell membrane staining was observed in all the newly formed neurospheres (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig4">4C</a>). For S-type cells, no GD2 staining was observed during the entire neuronal induced differentiation experiment. No changes of ABCG2 and NF68 neurofilament immunostaining was detected in the cell lines.</p><p>In all the N- and I-type cell lines, some nuclear calcyclin positive cells were detected during ATRA induced neuronal differentiation. S-like cells were initially detected in the periphery of the adhered neuronal clusters (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig4">4D</a>). Throughout the induction of neuronal differentiation, these nuclear-calcyclin positive cells increased in number and acquired S-type morphology, enabling us to isolate them attached to the flask taking advantage of their greater capacity of adherence. However, when isolated from the neuronal cells, these potentially S-type cells stopped growing and died after 2–3 weeks. New aliquots of the cell lines tested were thawed and treated separately to verify whether the presence of nuclear-calcyclin positive cells was not due to cross contamination. Furthermore, non-treated control cell lines were studied in parallel and did not show any of the abovementioned changes observed during the ATRA treatment. Repeated experiments demonstrated that newly induced S-like cells arise in response to ATRA treatment.</p><p>The S-type cell line LA1-5S showed no apparent changes when treated with ATRA. It did not show changes in morphology, continued to be adherent to the flask and preserved a flat and large cytoplasm. However, calcyclin nuclear membrane staining decreased during treatment and was re-established upon ATRA removal.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec7">I.b. Calcyclin, GD2 synthase and SOX10 gene expression changes</h4><p>To further investigate changes induced during ATRA differentiation assays, mRNA levels of relevant genes like calcyclin, GD2 synthase and SOX10 were analyzed by qRT-PCR at different time points in the three cell subtypes (LA1-55N, SK-N-Be2C, SK-N-ER and LA1-5S).</p><p>ATRA treatment induced an increase of calcyclin transcript levels in the N-type LA1-55N cell line. The I-type cell line, SK-N-ER, displayed a peak of expression (more than 2-fold) at day 3 of treatment (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig4">4E</a>). The S-type cell line, LA1-5S, showed a slow decrease of the calcyclin expression level after 3 days of treatment, with a recover of expression detected at day 7 when ATRA was removed (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig4">4E</a>). In the I-type SK-N-Be2C cell line, calcyclin mRNA expression was undetectable by q-PCR until day 60, when an increase of expression was detected that decreased again to undetectable levels after ATRA depletion (data not shown).</p><p>GD2 synthase expression increased during ATRA treatment in N- and I-type cell lines, with a significant increase in the LA1-55N cells. However, LA1-5S showed a minor increase, with a 1.49–0.85 fold variation of expression levels with respect to non-treated controls (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig4">4F</a>).</p><p>SOX10 expression was studied in order to clarify the new appearance of S-like cells during neuronal-lineage induced differentiation experiments. SOX10 mRNA was undetectable by q-PCR in all the cell lines tested, both in the treated as well as in the non-treated controls cell lines (data not shown).</p><p>Taken together, these results show that I-type and N-type cells display a similar behavior when neuronal differentiation is induced, both showing the capacity to differentiate along the neuronal lineage. On the other hand, for S-type cells, no neuronal-like phenotype was observed, despite the gene expression changes detected. The S-like cells arising during neuronal lineage induced differentiation suggest the bipotential capacity of some of the neuroblastic cells in both N- and I-type cultures.</p><h3 class="c-article__sub-heading" id="Sec8">II. Bromodeoxyuridine (BrdU) induced glial differentiation</h3><p>In order to evaluate the capacity of each of the cell lines to differentiate towards glial lineage, BrdU was used as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA: Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia. 2004, 6: 838-845." href="/articles/10.1186/1471-213X-9-12#ref-CR11" id="ref-link-section-d45557183e1648">11</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Hasegawa G, Minami N, Kushida A, Inuyama H, Koga M, Wakabayashi K, Saito Y: Human neuroblastoma GOTO cells express CD44 and localize it into lipid rafts upon differentiation into Schwannian cells. Cell Biol Int. 2005, 29: 193-202." href="/articles/10.1186/1471-213X-9-12#ref-CR26" id="ref-link-section-d45557183e1651">26</a>].</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec9">II.a. Morphological and immunophenotypical changes</h4><p>After one week of BrdU treatment, morphological changes became apparent. N- and I-type cell lines acquired an S-like morphology, large flat cytoplasm, and augmented adherence to the flask surface (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig5">5A</a>). The S-type cell line did not show any apparent changes. Immunophenotypically, the N- and I-type cell lines showed a decrease of GD2 staining at day 7 of BrdU treatment in comparison to the non-treated control culture (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig5">5B</a>). Calcyclin staining in the nuclear membrane appeared in some cells one week after induction, corresponding with the occurrence of the above mentioned changes (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig5">5C</a>). Likewise, in all the cell lines subtypes, N, S and I, cytoplasmic Sox10 staining increased during treatment and at 3 weeks some nuclear positive cells appeared (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig5">5D</a>). Specifically, S100 staining showed a slight increase during BrdU differentiation, increasing the cytoplasmic staining and showing nuclear staining in some cells after 21 days of treatment (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig5">5E</a>). These changes were not detected in the non treated control cells.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-5" data-title="Figure 5"><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 5</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/5" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig5_HTML.jpg?as=webp"><img aria-describedby="Fig5" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig5_HTML.jpg" alt="figure 5" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-5-desc"><p><b>Morphological and immunophenotypical changes induced by BrdU glial differentiation treatment</b>. <b>A</b>. Morphological changes in SK-N-ER cells (Phase contrast microscopy; 100×). B. GD2 expression levels after 15 days of treatment in I-type cell line SK-N-Be2C. <b>C</b> Calcyclin, (<b>D</b>) Sox10 and (<b>E</b>) S100 expression after 21 days of BrdU treatment in N-type cell line LA1-55N. <b>F</b>. SA-β-GAL positive cells (arrow) after 21 days of BrdU treatment in the I-type SK-N-ER (Phase contrast; 100×). Control cell images are reported in the small squares. Scale bar: 50 μm.</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/5" data-track-dest="link:Figure5 Full size image" aria-label="Full size image figure 5" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>After 3–4 weeks of treatment, all N, I, and S cell lines showed a degenerated morphology, characterized by large cytoplasms, multinucleated cells and a moderate decrease of their growth rate. Narath et al. (2007) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Narath R, Ambros IM, Kowalska A, Bozsaky E, Boukamp P, Ambros PF: Induction of senescence in MYCN amplified neuroblastoma cell lines by hydroxyurea. Genes Chromosomes Cancer. 2007, 46: 130-42." href="/articles/10.1186/1471-213X-9-12#ref-CR28" id="ref-link-section-d45557183e1715">28</a>] have recently described this morphology associated to senescence in neuroblastoma cell lines. In order to test whether S-like induced cells were senescent, SA-β-galactosidase test was performed. A significant increase of senescent cells was observed only at day 21 of BrdU treatment. Specifically, after 15 days of treatment, less than 1% of cells were senescent (SA-β-GAL positive cells) in most of the cell lines studied; the same proportion was observed in non-treated control cells. However, after 21 days of treatment, 50–80% of cells were positive for SA-β-GAL (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig5">5F</a>) in LA1-55N, LA1-5S and SK-N-Be2C and, only 15% of senescent cells were detected in the I-type cell line SK-N-ER.</p><h4 class="c-article__sub-heading c-article__sub-heading--small" id="Sec10">II.b. Calcyclin, GD2 synthase and SOX10 gene expression changes</h4><p>Gene expression analyses of calcyclin, GD2 synthase and SOX10 (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig6">6</a>) were performed in all 3 cell lines subtypes. A 21-day time course was used for these experiments due to the state of cellular degeneration detected after three weeks of treatment. Days 1, 3, 5, 7, 15 and 21 were analyzed by qRT-PCR.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-6" data-title="Figure 6"><figure><figcaption><b id="Fig6" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 6</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/6" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig6_HTML.jpg?as=webp"><img aria-describedby="Fig6" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_Article_416_Fig6_HTML.jpg" alt="figure 6" loading="lazy"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-6-desc"><p><b>Quantitative RT-PCR analysis of gene expression changes induced by BrdU treatment in NB cell line subtypes</b>. Gene expression changes of GD2 synthase (<b>A</b>), calcyclin (<b>B</b>) and Sox10 (<b>C</b>) in LA1-55N, LA1-5S and SK-N-ER cells. q-RT-PCR was performed by triplicate of two separate differentiation experiments (21 days induction).</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/articles/10.1186/1471-213X-9-12/figures/6" data-track-dest="link:Figure6 Full size image" aria-label="Full size image figure 6" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>GD2 synthase expression showed a significant decrease in LA1-55N and LA1-5S, N- and S-type respectively. In, SK-N-ER (I-type), GD2 synthase mRNA level decreased after the 5<sup>th</sup> day of BrdU treatment, but not as dramatically as for the other cell subtypes (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig6">6A</a>). On the other hand, calcyclin gene expression showed a progressive increase in all the cell lines during treatment. The major increase was observed in the N-type cells. The I-type cell line, SK-N-ER, and the S-type, LA1-5S showed a progressive increase of calcyclin expression (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig6">6B</a>). However, SOX10 showed a great increase of mRNA levels within the first week of treatment, followed by a fast decrease in all the cell lines tested (Figure <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/articles/10.1186/1471-213X-9-12#Fig6">6C</a>).</p><p>Taken together, BrdU differentiation results suggest the capacity of N- and I-type cell lines to differentiate towards a glial lineage phenotype.</p></div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec11-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec11">Discussion</h2><div class="c-article-section__content" id="Sec11-content"><p>The neural-crest is a vertebrate-specific transient embryonic tissue that gives rise to several cell types [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Rao MS, Anderson DJ: Immortalization and controlled in vitro differentiation of murine multipotent neural crest stem cells. J Neurobiol. 1997, 32: 722-746." href="/articles/10.1186/1471-213X-9-12#ref-CR29" id="ref-link-section-d45557183e1788">29</a>]. It has been clearly established that early neural-crest cells are multipotent at the cellular level [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Stemple DL, Anderson DJ: Isolation of a stem cell for neurons and glia from the mammalian neural crest. Cell. 1992, 71: 973-985." href="/articles/10.1186/1471-213X-9-12#ref-CR30" id="ref-link-section-d45557183e1791">30</a>], and perhaps in reflection of the innate multipotency, neural-crest derived cells display long lasting plasticity during embryonic development [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Le Douarin NM, Creuzet S, Couly G, Dupin E: Neural crest cell plasticity and its limits. Development. 2004, 131: 4637-4650." href="/articles/10.1186/1471-213X-9-12#ref-CR31" id="ref-link-section-d45557183e1794">31</a>]. This plasticity is also reflected in the phenomenon of transdifferentiation, whereby cells change from one unique phenotype into another without going through a developmentally less mature stage [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Liu Y, Rao MS: Transdifferentiation – fact or artifact. J Cell Biochem. 2003, 88: 29-40." href="/articles/10.1186/1471-213X-9-12#ref-CR32" id="ref-link-section-d45557183e1797">32</a>]. Neural-crest derived tumors like NBT as well as NBT cell lines show many of the cell phenotypes characteristic of the developing neural crest cells: cellular heterogeneity, plasticity and transdifferentiation capacity [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Ross RA, Spengler BA: Human neuroblastoma stem cells. Semin Cancer Biol. 2007, 17: 241-247." href="/articles/10.1186/1471-213X-9-12#ref-CR24" id="ref-link-section-d45557183e1800">24</a>].</p><p>Normal embryogenesis of the PNS involves a bilineal stage of cell differentiation whereby early glial and neuronal markers can be found coexpressed [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Jessen KR, Mirsky R: The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci. 2005, 6: 671-682." href="/articles/10.1186/1471-213X-9-12#ref-CR10" id="ref-link-section-d45557183e1806">10</a>]. In neuroblastoma, I-type cells have been described to exhibit an intermediate morphological and <i>in vitro</i> behavior, sharing characteristics of both N- and S-type cells, and express neuronal as well as glial lineage markers, and to reproduce a distinct and bipotential (neuronal and glial) stage of differentiation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA: Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia. 2004, 6: 838-845." href="/articles/10.1186/1471-213X-9-12#ref-CR11" id="ref-link-section-d45557183e1812">11</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Ross RA, Spengler BA: Human neuroblastoma stem cells. Semin Cancer Biol. 2007, 17: 241-247." href="/articles/10.1186/1471-213X-9-12#ref-CR24" id="ref-link-section-d45557183e1815">24</a>].</p><p>Instead of neurofilaments and calcyclin, we found cytoplasm membrane-GD2 and nuclear-calcyclin as reliable NBT neuroblastic and glial lineage markers, respectively. By immunofluorescence, N- and I-type showed similar pattern of expression with high GD2 and undetectable calcyclin. On the other hand, S-type exhibited a high nuclear-membrane calcylin staining and no ganglioside GD2 expression. I-type cells represent thus, a distinct NB cell subpopulation, an intermediate state between the neuronal and glial lineages, however closer to neuroblastic lineage.</p><p>In this study, we aimed to characterize each NBT cell line subtype according to differential lineage markers from the embryonic development of PNS. Initially, lineage markers such as vimentin and GAP43 (glial and neuronal, respectively) were studied. In our hands, these proteins did not display differential expression between the different cell subtypes. An undifferentiated state of the cell lines was studied by using neural crest cells markers such as c-kit and Phox2b. These proteins displayed positive immunostaining in all the cell lines subtypes, suggesting a derivative from an immature state, comparable to neural crest cells.</p><p>NB cell lines can be induced to differentiate along many neural crest cell lineages like chromaffin cells, Schwann cells, melanocytes and neurons [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Gestblom C, Grynfeld A, Ora I, Ortoft E, Larsson C, Axelson H, Sandstedt B, Cserjesi P, Olson EN, Pahlman S: The basic helix-loop-helix transcription factor dHAND, a marker gene for the developing human sympathetic nervous system, is expressed in both high- and low-stage neuroblastomas. Lab Invest. 1999, 79: 67-79." href="/articles/10.1186/1471-213X-9-12#ref-CR33" id="ref-link-section-d45557183e1828">33</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Thiele CJ: Biology of pediatric peripheral neuroectodermal tumors. Cancer Metastasis Rev. 1991, 10: 311-319." href="/articles/10.1186/1471-213X-9-12#ref-CR34" id="ref-link-section-d45557183e1831">34</a>]. Differentiation inducers towards neuronal lineage like ATRA or glial lineage like BrdU have been thoroughly described in NBT [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Ciccarone V, Spengler BA, Meyers MB, Biedler JL, Ross RA: Phenotypic diversification in human neuroblastoma cells: expression of distinct neural crest lineages. Cancer Res. 1989, 49: 219-225." href="/articles/10.1186/1471-213X-9-12#ref-CR22" id="ref-link-section-d45557183e1834">22</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA: Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia. 2004, 6: 838-845." href="/articles/10.1186/1471-213X-9-12#ref-CR11" id="ref-link-section-d45557183e1837">11</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Pahlman S, Hoehner JC, Nanberg E, Hedborg F, Fagerstrom S, Gestblom C, Johansson I, Larsson U, Lavenius E, Ortoft E, Soderholm H: Differentiation and survival influences of growth factors in human neuroblastoma. Eur J Cancer. 1995, 31A (4): 453-458." href="/articles/10.1186/1471-213X-9-12#ref-CR35" id="ref-link-section-d45557183e1840">35</a>]. We showed that, upon ATRA treatment, both N- and I-type cell lines can be induced to differentiate towards a neuronal-like lineage, while, no neuronal-like phenotype was observed in the S-type cell line, despite the gene expression changes detected.</p><p>Furthermore, with BrdU treatment, our results for N- and I-type cell lines showed a similar shift towards a glial-like phenotype (S-type shape, reduced GD2 and increase of glial-lineage markers) for both cell subtypes. Recently, Narath et al. (2007) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Narath R, Ambros IM, Kowalska A, Bozsaky E, Boukamp P, Ambros PF: Induction of senescence in MYCN amplified neuroblastoma cell lines by hydroxyurea. Genes Chromosomes Cancer. 2007, 46: 130-42." href="/articles/10.1186/1471-213X-9-12#ref-CR28" id="ref-link-section-d45557183e1846">28</a>] described cellular senescence in MYCN amplified F-type NBT cells after 6 weeks of hydroxyurea treatment. F-type cells share some morphological features with the S-type cells. In our experiments, the abnormal aspect of BrdU treated cells and proliferation arrest after few weeks of treatment suggested that long exposition to BrdU might induce senescence. Our results, however, demonstrate that BrdU induced <i>bona fide</i> glial differentiation for the first two weeks of treatment. After longer exposure (3 weeks) to BrdU, senescence was induced.</p><p>In order to further correlate the embryonic development of the PNS and the <i>in vitro</i> model, we studied Sox10 induction. Sox10, which is expressed in NCSC and a subset of neural-crest derived lineages, plays a key role in maintaining pluripotency and inhibiting premature differentiation at the stem cell stage. <i>In vivo</i>, glial-lineage differentiation is a default program during the NCSC differentiation pathway towards a neuronal fate [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Jessen KR, Mirsky R: The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci. 2005, 6: 671-682." href="/articles/10.1186/1471-213X-9-12#ref-CR10" id="ref-link-section-d45557183e1861">10</a>]. Downregulation of SOX10 is a prerequisite for neuronal lineage differentiation and its expression is maintained in the terminally differentiated glial cell [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Kim J, Lo L, Dormand E, Anderson DJ: SOX10 maintains multipotency and inhibits neuronal. Neuron. 2003, 38 (1): 17-31." href="/articles/10.1186/1471-213X-9-12#ref-CR36" id="ref-link-section-d45557183e1864">36</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Jessen KR, Mirsky R: The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci. 2005, 6: 671-682." href="/articles/10.1186/1471-213X-9-12#ref-CR10" id="ref-link-section-d45557183e1867">10</a>]. Our results show that SOX10 is undetectable in all cell lines and ATRA treatment does not activate SOX10 expression. However, SOX10 expression is induced when glial differentiation is promoted by BrdU treatment with a fast increase of SOX10 expression in the S-type cell line and slower but significant increase in the N- and I-type cell lines.</p><p>Our results suggest that N- and I-type NB cells represent an immature bilineage stage, able to progress towards neuronal as well as glial fates upon induction of differentiation.</p><p>In addition to neurite elongation, neuron specific protein and gene expression induction, when N- and I-type cell lines were induced to differentiate with ATRA, two phenomena appeared concomitantly: clumps floating spheres similar to the previously described neurospheres [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA: Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia. 2004, 6: 838-845." href="/articles/10.1186/1471-213X-9-12#ref-CR11" id="ref-link-section-d45557183e1876">11</a>] and newly formed S-type cells. Neurospheres formation has been previously reported to occur spontaneously in N-type cell lines [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA: Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia. 2004, 6: 838-845." href="/articles/10.1186/1471-213X-9-12#ref-CR11" id="ref-link-section-d45557183e1879">11</a>]. The spontaneous or induced formation of neurospheres or big floating cell clusters has been described related to neural stemness [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, Jensen P, Magdaleno S, Dalton J, Calabrese C, Board J, Macdonald T, Rutka J, Guha A, Gajjar A, Curran T, Gilbertson R: Radial glia cells are candidate stem cells of ependymoma. Cancer Cell. 2005, 8: 323-335." href="/articles/10.1186/1471-213X-9-12#ref-CR37" id="ref-link-section-d45557183e1882">37</a>]. Ongoing experiments in our laboratory are investigating whether the differentiating neurospheres contain multipotent stem-like cells.</p><p>Concurrently to neuroblastic cells clustering, S-like cells appeared in the periphery of these cell clusters. Motohashi et al., (2007) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Motohashi T, Aoki H, Chiba K, Yoshimura N, Kunisada T: Multipotent cell fate of neural crest-like cells derived from embryonic stem cells. Stem Cells. 2007, 25: 402-410." href="/articles/10.1186/1471-213X-9-12#ref-CR38" id="ref-link-section-d45557183e1888">38</a>] have recently reported the presence of glial cells in ATRA treated NCSC cultures. Neuron-glia interactions control several processes in brain development, such as neurogenesis, myelination, synapse formations and neuronal migration, proliferation and differentiation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Barres BA: Neuron-glial interactions. Molecular and Cellular Approaches to neural development. Edited by: Cowan WM, Jessell TM, Zipursky SL. 1997, New York, Oxford University Press, 64-107." href="/articles/10.1186/1471-213X-9-12#ref-CR39" id="ref-link-section-d45557183e1891">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Lim DA, Alvarez-Buylla A: Interactions between astrocytes and adult subventricular zone precursors stimulates neurogenesis. PNAS. 1999, 96: 7526-7531." href="/articles/10.1186/1471-213X-9-12#ref-CR40" id="ref-link-section-d45557183e1894">40</a>]. During PNS development neuronal and glial differentiation are interdependent and the fates of these two types of cells are inextricably entangled. Moreover, in neuroblastoma, it has been hypothesized that Schwann cells release factors that could induce neuronal differentiation, providing better prognosis [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Liu S, Tian Y, Chlenski A, Yang Q, Zage P, Salwen HR, Crawford SE, Cohn SL: Cross-talk between Schwann cells and neuroblasts influences the biology of neuroblastoma xenografts. Am J Pathol. 2005, 166: 891-900." href="/articles/10.1186/1471-213X-9-12#ref-CR41" id="ref-link-section-d45557183e1897">41</a>]. Our results, first the appearance of S-like cells during induction of differentiation with ATRA in N- and I-type cells, and second the incapacity of these cells to survive devoid of N-/I-type cells, suggest a necessary cross-talk between immature neuron-glia in neuroblastoma tumor cells upon induced differentiation.</p><p>Overall, our findings highlight how N- and I-type cells possess a similar differentiation potential, and represent an uncommitted stage between neuronal and glial fates, whereas S-type cells seem to be committed towards a glial lineage fate. These comparable characteristics display, however, a degree of variability within and amongst the N- and I-cell line subtypes suggesting a continuum process in the differentiation program reproduced by the cell lines.</p></div></div></section><section data-title="Conclusion"><div class="c-article-section" id="Sec12-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec12">Conclusion</h2><div class="c-article-section__content" id="Sec12-content"><p>In summary, the characterization of each NB cell line subtype showed how all three cell lines represent an immature stage of the neural crest. However, both N- and I-type phenotypes are consistent with immature multilineage potential cells, since, upon induction, are able to progress towards neuronal as well as glial fates. By immunophenotype I-type cells did not show an intermediate pattern suggesting a distinct bipotential stage (neuronal and glial), although differential gene expression analysis revealed clear differences between the 3 subtypes. S-type cell lines, on the other hand, appear irreversibly committed towards glial lineage.</p></div></div></section><section data-title="Methods"><div class="c-article-section" id="Sec13-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec13">Methods</h2><div class="c-article-section__content" id="Sec13-content"><h3 class="c-article__sub-heading" id="Sec14">Tissue culture and cell lines</h3><p>Phenotype characterization studies were performed on four N-type human neuroblastoma cell lines (LAN-1, LA1-55N, Be2-M17V and SH-SY5Y), four I-type cell lines (SK-N-Be2C, SK-N-JD, SK-N-LP and SK-N-ER) and three S-type (LA1-5S, SH-EP1 and SK-N-AS). All cell lines except SK-N-AS (Sigma, US), were kindly provided by Dr. B. Spengler, Fordham University, New York, NY; and Dr. NK. V. Cheung, Memorial Sloan-Kettering Cancer Center, New York, NY.</p><p>Cell lines were grown in RPMI high glucose media supplemented with 10% FBS, 2 mM L-glutamine and penicillin (100 U/ml) and streptomycin (100 μg/ml) (Reactiva, Spain) at 37°C in 5% CO<sub>2</sub> atmosphere. Cell lines were never cultured more than 40 passages after thawing.</p><h3 class="c-article__sub-heading" id="Sec15">Immunofluorescence</h3><p>Cell lines were plated on round glass cover slips and incubated overnight at 37°C, then washed with PBS, fixed in 4% paraformaldehyde for 20 min, permeated with 0,1% Triton X-100 for 15 min, when required, and blocked for 30 min with 1% BSA. Primary antibodies, GD2 (BD, US), calcyclin (Sigma, US), NF68 (Zymed, US) Phox2b (Santa Cruz, US), GAP43 (Santa Cruz, US), ABCG2 (Alexis Biochemicals, Switzerland) and vimentin (Novocastra, UK) (Additional Table 1) were incubated for 1–3 h at room temperature or overnight (O/N) at 4°C and fluorochrome-linked secondary antibody was incubated for 45 min. Nuclear staining was obtained with 4'6-diamino-2-phenylindole (DAPI) 1:5000 in PBS (Sigma, US). Cells were mounted in Vectashield Mounting media (Vector Laboratories, US). Immunofluorescence was examined with a Leica epifluorescence DM5000B microscope (Leica Microsystems, US).</p><h3 class="c-article__sub-heading" id="Sec16">Immunocytochemistry</h3><p>Cell lines were cultured and fixed, permeated and blocked as explained above. Endogenous peroxidases were inhibited with H<sub>2</sub>O<sub>2</sub> for 20 min. Primary antibodies S100 (Novocastra, UK), Sox10 (R&D systems, US) and c-kit (Zymed, US)(Additional file <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/1471-213X-9-12#MOESM1">1</a>) were incubated for 15 min-O/N and chromogenically stained with Anti-mouse/rabbit Poly-HRP IHC detection kit (Chemicon, US).</p><h3 class="c-article__sub-heading" id="Sec17">Differentiation assays</h3><p>Differentiation experiments were performed as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA: Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia. 2004, 6: 838-845." href="/articles/10.1186/1471-213X-9-12#ref-CR11" id="ref-link-section-d45557183e1961">11</a>]. Briefly, 5·10<sup>5</sup>–10<sup>6</sup> cells were harvested in T.75 culture flasks and 1 μM all-<i>trans</i>-retinoic acid (ATRA) (Sigma, US) or 10 μM 5-Bromo-2'-deoxyuridine (BrdU) (Sigma, US) were added to cell culture media to induce neuronal and glial differentiation, respectively. Treatment was maintained for 60 days by renewing media containing the drug three times <i>per</i> week. After 60 days, drug treatment was removed and cell cultures were maintained for 30 more days in media without drug. When treated with ATRA, cells were trypsinized at least once per week. For the two initial weeks, we also harvested different amounts of cells for immunofluorescence studies (2.5·10<sup>5</sup>–10<sup>6</sup> cells) and mRNA extraction (2.5·10<sup>5</sup>–3·10<sup>6</sup> cells). For the rest of time points we obtained the cells directly from the T.75 flasks.</p><p>Cell samples were harvested at days 1, 3, 5, 7, 15, 30, 60 and 30 days after treatment removal to analyze target markers. Control cell cultures, maintained without drug treatment, were harvested in parallel with drug-cultured cells. The experiments were performed in duplicate. See Additional file <a data-track="click" data-track-label="link" data-track-action="supplementary material anchor" href="/articles/10.1186/1471-213X-9-12#MOESM2">2</a> for a flow-sheet diagram of differentiation experiments.</p><h3 class="c-article__sub-heading" id="Sec18">Senescence analysis</h3><p>Senescence of cells during differentiation experiments was analyzed by the senescence associated-β-galactosidase test kit (Sigma, US) based on Dimri protocol [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O: A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA. 1995, 92: 9363-7." href="/articles/10.1186/1471-213X-9-12#ref-CR42" id="ref-link-section-d45557183e1998">42</a>]. Briefly, cells were fixed in 2% glutaraldehyde/20% formaldehyde and then stained O/N with X-gal staining solution. Blue cells were considered positive. Non-treated cells cultured in parallel were used as control.</p><h3 class="c-article__sub-heading" id="Sec19">Quantitative RT-PCR (qRT-PCR)</h3><p>Quantification of transcript levels was performed for calcyclin, GD2 synthase, and SOX10. For GD2 synthase and calcyclin expression analyses all non-treated and differentiation induced cell lines LA1-55N, SK-N-ER and LA1-5S were used and, for SOX10 only the differentiation induced cell lines mentioned above were analyzed. RNA was isolated using Tri Reagent (Sigma, US), following manufacturers' protocols. cDNA was synthesized from 1 μg total RNA using random hexamers (Applied Biosystems, US) and M-MLV reverse transcriptase (Promega, US). q-PCR reactions (40 ng cDNA) and quantification, using the ΔΔC<sub>T</sub> relative quantification method, were performed on an ABI Prism 7000 Sequence Detection System using Assay-on-Demand Gene Expression products (Applied Biosystems, US). GD2 synthase primers and probes were described elsewhere [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Cheung IY, Cheung NK: Quantitation of marrow disease in neuroblastoma by real-time reverse transcription-PCR. Clin Cancer Res. 2001, 7: 1698-1705." href="/articles/10.1186/1471-213X-9-12#ref-CR43" id="ref-link-section-d45557183e2011">43</a>]. Transcript levels were normalized to TATA box binding protein (TBP) expression values [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002, 3 (7): RESEARCH0034-" href="/articles/10.1186/1471-213X-9-12#ref-CR44" id="ref-link-section-d45557183e2014">44</a>] and quantified relative to the cell line with the lowest amplification level or to each time course day non-treated control, in differentiation experiments. TBP coefficients of variation showed a low degree of variation amongst the cell lines and during the differentiation treatment (CV < 0.05). All experiments included no template controls and were performed in duplicate and repeated twice independently.</p></div></div></section> <div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1."><p class="c-article-references__text" id="ref-CR1">Mora J, Gerald WL: Origin of neuroblastic tumors: clues for future therapeutics. Expert Rev Mol Diagn. 2004, 4 (3): 293-302.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1586/14737159.4.3.293" data-track-item_id="10.1586/14737159.4.3.293" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1586%2F14737159.4.3.293" aria-label="Article reference 1" data-doi="10.1586/14737159.4.3.293">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2cXltFWrtrk%3D" aria-label="CAS reference 1">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15137897" aria-label="PubMed reference 1">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 1" href="http://scholar.google.com/scholar_lookup?&title=Origin%20of%20neuroblastic%20tumors%3A%20clues%20for%20future%20therapeutics&journal=Expert%20Rev%20Mol%20Diagn&doi=10.1586%2F14737159.4.3.293&volume=4&issue=3&pages=293-302&publication_year=2004&author=Mora%2CJ&author=Gerald%2CWL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="2."><p class="c-article-references__text" id="ref-CR2">Gershon TR, Oppenheimer O, Chin SS, Gerald WL: Temporally regulated neural crest transcription factors distinguish neuroectodermal tumors of varying malignancy and differentiation. Neoplasia. 2005, 7 (6): 575-584.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1593/neo.04637" data-track-item_id="10.1593/neo.04637" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1593%2Fneo.04637" aria-label="Article reference 2" data-doi="10.1593/neo.04637">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1501286" aria-label="PubMed Central reference 2">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2MXntVSjsr4%3D" aria-label="CAS reference 2">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16036108" aria-label="PubMed reference 2">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 2" href="http://scholar.google.com/scholar_lookup?&title=Temporally%20regulated%20neural%20crest%20transcription%20factors%20distinguish%20neuroectodermal%20tumors%20of%20varying%20malignancy%20and%20differentiation&journal=Neoplasia&doi=10.1593%2Fneo.04637&volume=7&issue=6&pages=575-584&publication_year=2005&author=Gershon%2CTR&author=Oppenheimer%2CO&author=Chin%2CSS&author=Gerald%2CWL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="3."><p class="c-article-references__text" id="ref-CR3">Valent A, Benard J, Venuat AM, Silva J, Duverger A, Duarte N, Hartmann O, Spengler BA, Bernheim A: Phenotypic and genotypic diversity of human neuroblastoma studied in three IGR cell line models derived from bone marrow metastases. Cancer Genet Cytogenet. 1999, 112: 124-129.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0165-4608(98)00264-7" data-track-item_id="10.1016/S0165-4608(98)00264-7" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0165-4608%2898%2900264-7" aria-label="Article reference 3" data-doi="10.1016/S0165-4608(98)00264-7">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DC%2BD3c7ltFGmtg%3D%3D" aria-label="CAS reference 3">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10686938" aria-label="PubMed reference 3">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 3" href="http://scholar.google.com/scholar_lookup?&title=Phenotypic%20and%20genotypic%20diversity%20of%20human%20neuroblastoma%20studied%20in%20three%20IGR%20cell%20line%20models%20derived%20from%20bone%20marrow%20metastases&journal=Cancer%20Genet%20Cytogenet&doi=10.1016%2FS0165-4608%2898%2900264-7&volume=112&pages=124-129&publication_year=1999&author=Valent%2CA&author=Benard%2CJ&author=Venuat%2CAM&author=Silva%2CJ&author=Duverger%2CA&author=Duarte%2CN&author=Hartmann%2CO&author=Spengler%2CBA&author=Bernheim%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="4."><p class="c-article-references__text" id="ref-CR4">Mora J, Cheung NK, Juan G, Illei P, Cheung I, Akram M, Chi S, Ladanyi M, Cordon-Cardo C, Gerald WL: Neuroblastic and Schwannian stromal cells of neuroblastoma are derived from a tumoral progenitor cell. Cancer Res. 2001, 61: 6892-6898.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3MXntFaitr0%3D" aria-label="CAS reference 4">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11559566" aria-label="PubMed reference 4">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 4" href="http://scholar.google.com/scholar_lookup?&title=Neuroblastic%20and%20Schwannian%20stromal%20cells%20of%20neuroblastoma%20are%20derived%20from%20a%20tumoral%20progenitor%20cell&journal=Cancer%20Res&volume=61&pages=6892-6898&publication_year=2001&author=Mora%2CJ&author=Cheung%2CNK&author=Juan%2CG&author=Illei%2CP&author=Cheung%2CI&author=Akram%2CM&author=Chi%2CS&author=Ladanyi%2CM&author=Cordon-Cardo%2CC&author=Gerald%2CWL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="5."><p class="c-article-references__text" id="ref-CR5">Coco S, Defferrari R, Scaruffi P, Cavazzana A, Di Cristofano C, Longo L, Mazzocco K, Perri P, Gambini C, Moretti S, Bonassi S, Tonini GP: Genome analysis and gene expression profiling of neuroblastoma and ganglioneuroblastoma reveal differences between neuroblastic and Schwannian stromal cells. J Pathol. 2005, 207: 346-357.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/path.1843" data-track-item_id="10.1002/path.1843" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fpath.1843" aria-label="Article reference 5" data-doi="10.1002/path.1843">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2MXht1agu7fP" aria-label="CAS reference 5">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16178058" aria-label="PubMed reference 5">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 5" href="http://scholar.google.com/scholar_lookup?&title=Genome%20analysis%20and%20gene%20expression%20profiling%20of%20neuroblastoma%20and%20ganglioneuroblastoma%20reveal%20differences%20between%20neuroblastic%20and%20Schwannian%20stromal%20cells&journal=J%20Pathol&doi=10.1002%2Fpath.1843&volume=207&pages=346-357&publication_year=2005&author=Coco%2CS&author=Defferrari%2CR&author=Scaruffi%2CP&author=Cavazzana%2CA&author=Di%20Cristofano%2CC&author=Longo%2CL&author=Mazzocco%2CK&author=Perri%2CP&author=Gambini%2CC&author=Moretti%2CS&author=Bonassi%2CS&author=Tonini%2CGP"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="6."><p class="c-article-references__text" id="ref-CR6">Ambros IM, Zellner A, Roald B, Amann G, Ladenstein R, Printz D, Gadner H, Ambros PF: Role of ploidy, chromosome 1p, and Schwann cells in the maturation of neuroblastoma. N Engl J Med. 1996, 334 (23): 1505-11.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1056/NEJM199606063342304" data-track-item_id="10.1056/NEJM199606063342304" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1056%2FNEJM199606063342304" aria-label="Article reference 6" data-doi="10.1056/NEJM199606063342304">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK283hsVKjtw%3D%3D" aria-label="CAS reference 6">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=8618605" aria-label="PubMed reference 6">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 6" href="http://scholar.google.com/scholar_lookup?&title=Role%20of%20ploidy%2C%20chromosome%201p%2C%20and%20Schwann%20cells%20in%20the%20maturation%20of%20neuroblastoma&journal=N%20Engl%20J%20Med&doi=10.1056%2FNEJM199606063342304&volume=334&issue=23&pages=1505-11&publication_year=1996&author=Ambros%2CIM&author=Zellner%2CA&author=Roald%2CB&author=Amann%2CG&author=Ladenstein%2CR&author=Printz%2CD&author=Gadner%2CH&author=Ambros%2CPF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="7."><p class="c-article-references__text" id="ref-CR7">Bourdeaut F, Ribeiro A, Paris R, Pierron G, Couturier J, Peuchmaur M, Delattre O: In neuroblastic tumours, Schwann cells do not harbour the genetic alterations of neuroblasts but may nevertheless share the same clonal origin. Oncogene. 2008, 27 (21): 3066-71.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/sj.onc.1210965" data-track-item_id="10.1038/sj.onc.1210965" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fsj.onc.1210965" aria-label="Article reference 7" data-doi="10.1038/sj.onc.1210965">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1cXlsFClt78%3D" aria-label="CAS reference 7">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=18071318" aria-label="PubMed reference 7">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 7" href="http://scholar.google.com/scholar_lookup?&title=In%20neuroblastic%20tumours%2C%20Schwann%20cells%20do%20not%20harbour%20the%20genetic%20alterations%20of%20neuroblasts%20but%20may%20nevertheless%20share%20the%20same%20clonal%20origin&journal=Oncogene&doi=10.1038%2Fsj.onc.1210965&volume=27&issue=21&pages=3066-71&publication_year=2008&author=Bourdeaut%2CF&author=Ribeiro%2CA&author=Paris%2CR&author=Pierron%2CG&author=Couturier%2CJ&author=Peuchmaur%2CM&author=Delattre%2CO"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="8."><p class="c-article-references__text" id="ref-CR8">Gammill LS, Bronner-Fraser M: Neural crest specification: migrating into genomics. Nat Rev Neurosci. 2003, 4: 795-805.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/nrn1219" data-track-item_id="10.1038/nrn1219" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fnrn1219" aria-label="Article reference 8" data-doi="10.1038/nrn1219">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXnslSitro%3D" aria-label="CAS reference 8">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=14523379" aria-label="PubMed reference 8">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 8" href="http://scholar.google.com/scholar_lookup?&title=Neural%20crest%20specification%3A%20migrating%20into%20genomics&journal=Nat%20Rev%20Neurosci&doi=10.1038%2Fnrn1219&volume=4&pages=795-805&publication_year=2003&author=Gammill%2CLS&author=Bronner-Fraser%2CM"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="9."><p class="c-article-references__text" id="ref-CR9">Kelsh RN: Sorting out Sox10 functions in neural crest development. Bioessays. 2006, 28: 788-98.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/bies.20445" data-track-item_id="10.1002/bies.20445" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fbies.20445" aria-label="Article reference 9" data-doi="10.1002/bies.20445">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16927299" aria-label="PubMed reference 9">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 9" href="http://scholar.google.com/scholar_lookup?&title=Sorting%20out%20Sox10%20functions%20in%20neural%20crest%20development&journal=Bioessays&doi=10.1002%2Fbies.20445&volume=28&pages=788-98&publication_year=2006&author=Kelsh%2CRN"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="10."><p class="c-article-references__text" id="ref-CR10">Jessen KR, Mirsky R: The origin and development of glial cells in peripheral nerves. Nat Rev Neurosci. 2005, 6: 671-682.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/nrn1746" data-track-item_id="10.1038/nrn1746" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fnrn1746" aria-label="Article reference 10" data-doi="10.1038/nrn1746">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2MXpslaksro%3D" aria-label="CAS reference 10">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16136171" aria-label="PubMed reference 10">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 10" href="http://scholar.google.com/scholar_lookup?&title=The%20origin%20and%20development%20of%20glial%20cells%20in%20peripheral%20nerves&journal=Nat%20Rev%20Neurosci&doi=10.1038%2Fnrn1746&volume=6&pages=671-682&publication_year=2005&author=Jessen%2CKR&author=Mirsky%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="11."><p class="c-article-references__text" id="ref-CR11">Walton JD, Kattan DR, Thomas SK, Spengler BA, Guo HF, Biedler JL, Cheung NK, Ross RA: Characteristics of stem cells from human neuroblastoma cell lines and in tumors. Neoplasia. 2004, 6: 838-845.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1593/neo.04310" data-track-item_id="10.1593/neo.04310" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1593%2Fneo.04310" aria-label="Article reference 11" data-doi="10.1593/neo.04310">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1531688" aria-label="PubMed Central reference 11">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15720811" aria-label="PubMed reference 11">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 11" href="http://scholar.google.com/scholar_lookup?&title=Characteristics%20of%20stem%20cells%20from%20human%20neuroblastoma%20cell%20lines%20and%20in%20tumors&journal=Neoplasia&doi=10.1593%2Fneo.04310&volume=6&pages=838-845&publication_year=2004&author=Walton%2CJD&author=Kattan%2CDR&author=Thomas%2CSK&author=Spengler%2CBA&author=Guo%2CHF&author=Biedler%2CJL&author=Cheung%2CNK&author=Ross%2CRA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="12."><p class="c-article-references__text" id="ref-CR12">Pietras A, Gisselsson D, Ora I, Noguera R, Beckman S, Navarro S, Påhlman S: High levels of HIF-2alpha highlight an immature neural crest-like neuroblastoma cell cohort located in a perivascular niche. J Pathol. 2008, 214 (4): 482-8.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/path.2304" data-track-item_id="10.1002/path.2304" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fpath.2304" aria-label="Article reference 12" data-doi="10.1002/path.2304">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD1cXktFelt7g%3D" aria-label="CAS reference 12">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=18189331" aria-label="PubMed reference 12">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 12" href="http://scholar.google.com/scholar_lookup?&title=High%20levels%20of%20HIF-2alpha%20highlight%20an%20immature%20neural%20crest-like%20neuroblastoma%20cell%20cohort%20located%20in%20a%20perivascular%20niche&journal=J%20Pathol&doi=10.1002%2Fpath.2304&volume=214&issue=4&pages=482-8&publication_year=2008&author=Pietras%2CA&author=Gisselsson%2CD&author=Ora%2CI&author=Noguera%2CR&author=Beckman%2CS&author=Navarro%2CS&author=P%C3%A5hlman%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="13."><p class="c-article-references__text" id="ref-CR13">Donato R: S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol. 2001, 33: 637-668.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S1357-2725(01)00046-2" data-track-item_id="10.1016/S1357-2725(01)00046-2" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS1357-2725%2801%2900046-2" aria-label="Article reference 13" data-doi="10.1016/S1357-2725(01)00046-2">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3MXktVKltro%3D" aria-label="CAS reference 13">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11390274" aria-label="PubMed reference 13">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 13" href="http://scholar.google.com/scholar_lookup?&title=S100%3A%20a%20multigenic%20family%20of%20calcium-modulated%20proteins%20of%20the%20EF-hand%20type%20with%20intracellular%20and%20extracellular%20functional%20roles&journal=Int%20J%20Biochem%20Cell%20Biol&doi=10.1016%2FS1357-2725%2801%2900046-2&volume=33&pages=637-668&publication_year=2001&author=Donato%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="14."><p class="c-article-references__text" id="ref-CR14">Tiu SC, Chan WY, Heizmann CW, Schafer BW, Shu SY, Yew DT: Differential expression of S100B and S100A6(1) in the human fetal and aged cerebral cortex. Brain Res Dev Brain Res. 2000, 119: 159-168.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0165-3806(99)00151-0" data-track-item_id="10.1016/S0165-3806(99)00151-0" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0165-3806%2899%2900151-0" aria-label="Article reference 14" data-doi="10.1016/S0165-3806(99)00151-0">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3cXhtFanu7k%3D" aria-label="CAS reference 14">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10675765" aria-label="PubMed reference 14">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 14" href="http://scholar.google.com/scholar_lookup?&title=Differential%20expression%20of%20S100B%20and%20S100A6%281%29%20in%20the%20human%20fetal%20and%20aged%20cerebral%20cortex&journal=Brain%20Res%20Dev%20Brain%20Res&doi=10.1016%2FS0165-3806%2899%2900151-0&volume=119&pages=159-168&publication_year=2000&author=Tiu%2CSC&author=Chan%2CWY&author=Heizmann%2CCW&author=Schafer%2CBW&author=Shu%2CSY&author=Yew%2CDT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="15."><p class="c-article-references__text" id="ref-CR15">Tomas A, Moss SE: Calcium- and cell cycle-dependent association of annexin 11 with the nuclear envelope. J Biol Chem. 2003, 278: 20210-20216.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1074/jbc.M212669200" data-track-item_id="10.1074/jbc.M212669200" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1074%2Fjbc.M212669200" aria-label="Article reference 15" data-doi="10.1074/jbc.M212669200">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXktVejsr0%3D" aria-label="CAS reference 15">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12601007" aria-label="PubMed reference 15">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 15" href="http://scholar.google.com/scholar_lookup?&title=Calcium-%20and%20cell%20cycle-dependent%20association%20of%20annexin%2011%20with%20the%20nuclear%20envelope&journal=J%20Biol%20Chem&doi=10.1074%2Fjbc.M212669200&volume=278&pages=20210-20216&publication_year=2003&author=Tomas%2CA&author=Moss%2CSE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="16."><p class="c-article-references__text" id="ref-CR16">Tonini GP, Fabretti G, Kuznicki J, Massimo L, Scaruffi P, Brisigotti M, Mazzocco K: Gene expression and protein localisation of calcyclin, a calcium-binding protein of the S-100 family in fresh neuroblastomas. Eur J Cancer. 1995, 31A (4): 499-504.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/0959-8049(95)00043-I" data-track-item_id="10.1016/0959-8049(95)00043-I" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2F0959-8049%2895%2900043-I" aria-label="Article reference 16" data-doi="10.1016/0959-8049(95)00043-I">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK2MXms12ksL8%3D" aria-label="CAS reference 16">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=7576953" aria-label="PubMed reference 16">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 16" href="http://scholar.google.com/scholar_lookup?&title=Gene%20expression%20and%20protein%20localisation%20of%20calcyclin%2C%20a%20calcium-binding%20protein%20of%20the%20S-100%20family%20in%20fresh%20neuroblastomas&journal=Eur%20J%20Cancer&doi=10.1016%2F0959-8049%2895%2900043-I&volume=31A&issue=4&pages=499-504&publication_year=1995&author=Tonini%2CGP&author=Fabretti%2CG&author=Kuznicki%2CJ&author=Massimo%2CL&author=Scaruffi%2CP&author=Brisigotti%2CM&author=Mazzocco%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="17."><p class="c-article-references__text" id="ref-CR17">Ross RA: Cellular heterogeneity. Neuroblastoma. Edited by: Cheung NK, Cohn SL. 2005, Berlin: Springer-Verlag, 55-60.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/3-540-26616-X_6" data-track-item_id="10.1007/3-540-26616-X_6" data-track-value="chapter reference" data-track-action="chapter reference" href="https://link.springer.com/doi/10.1007/3-540-26616-X_6" aria-label="Chapter reference 17" data-doi="10.1007/3-540-26616-X_6">Chapter</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 17" href="http://scholar.google.com/scholar_lookup?&title=Cellular%20heterogeneity&doi=10.1007%2F3-540-26616-X_6&pages=55-60&publication_year=2005&author=Ross%2CRA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="18."><p class="c-article-references__text" id="ref-CR18">Spengler BA, Lazarova DL, Ross RA, Biedler JL: Cell lineage and differentiation state are primary determinants of MYCN gene expression and malignant potential in human neuroblastoma cells. Oncol Res. 1997, 9: 467-476.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK1c7lsVynsg%3D%3D" aria-label="CAS reference 18">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=9495452" aria-label="PubMed reference 18">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 18" href="http://scholar.google.com/scholar_lookup?&title=Cell%20lineage%20and%20differentiation%20state%20are%20primary%20determinants%20of%20MYCN%20gene%20expression%20and%20malignant%20potential%20in%20human%20neuroblastoma%20cells&journal=Oncol%20Res&volume=9&pages=467-476&publication_year=1997&author=Spengler%2CBA&author=Lazarova%2CDL&author=Ross%2CRA&author=Biedler%2CJL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="19."><p class="c-article-references__text" id="ref-CR19">Swerts K, Ambros PF, Brouzes C, Navarro JM, Gross N, Rampling D, Schumacher-Kuckelkorn R, Sementa AR, Ladenstein R, Beiske K: Standardization of the immunocytochemical detection of neuroblastoma cells in bone marrow. J Histochem Cytochem. 2005, 53: 1433-1440.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1369/jhc.5C6661.2005" data-track-item_id="10.1369/jhc.5C6661.2005" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1369%2Fjhc.5C6661.2005" aria-label="Article reference 19" data-doi="10.1369/jhc.5C6661.2005">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3957549" aria-label="PubMed Central reference 19">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2MXht1OnsLrP" aria-label="CAS reference 19">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15956022" aria-label="PubMed reference 19">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 19" href="http://scholar.google.com/scholar_lookup?&title=Standardization%20of%20the%20immunocytochemical%20detection%20of%20neuroblastoma%20cells%20in%20bone%20marrow&journal=J%20Histochem%20Cytochem&doi=10.1369%2Fjhc.5C6661.2005&volume=53&pages=1433-1440&publication_year=2005&author=Swerts%2CK&author=Ambros%2CPF&author=Brouzes%2CC&author=Navarro%2CJM&author=Gross%2CN&author=Rampling%2CD&author=Schumacher-Kuckelkorn%2CR&author=Sementa%2CAR&author=Ladenstein%2CR&author=Beiske%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="20."><p class="c-article-references__text" id="ref-CR20">Cheresh DA, Pierschbacher MD, Herzig MA, Mujoo K: Disialogangliosides GD2 and GDI are involved in the attachment of human melanoma and neuroblastoma cells to extracellular matrix proteins. J Cell Biol. 1986, 102: 688-696.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1083/jcb.102.3.688" data-track-item_id="10.1083/jcb.102.3.688" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1083%2Fjcb.102.3.688" aria-label="Article reference 20" data-doi="10.1083/jcb.102.3.688">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaL28XhvVequr4%3D" aria-label="CAS reference 20">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=3005335" aria-label="PubMed reference 20">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 20" href="http://scholar.google.com/scholar_lookup?&title=Disialogangliosides%20GD2%20and%20GDI%20are%20involved%20in%20the%20attachment%20of%20human%20melanoma%20and%20neuroblastoma%20cells%20to%20extracellular%20matrix%20proteins&journal=J%20Cell%20Biol&doi=10.1083%2Fjcb.102.3.688&volume=102&pages=688-696&publication_year=1986&author=Cheresh%2CDA&author=Pierschbacher%2CMD&author=Herzig%2CMA&author=Mujoo%2CK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="21."><p class="c-article-references__text" id="ref-CR21">Biedler JL, Helson L, Spengler BA: Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture. Cancer Res. 1973, 33: 2643-2652.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaE2c%2FitFCluw%3D%3D" aria-label="CAS reference 21">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=4748425" aria-label="PubMed reference 21">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 21" href="http://scholar.google.com/scholar_lookup?&title=Morphology%20and%20growth%2C%20tumorigenicity%2C%20and%20cytogenetics%20of%20human%20neuroblastoma%20cells%20in%20continuous%20culture&journal=Cancer%20Res&volume=33&pages=2643-2652&publication_year=1973&author=Biedler%2CJL&author=Helson%2CL&author=Spengler%2CBA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="22."><p class="c-article-references__text" id="ref-CR22">Ciccarone V, Spengler BA, Meyers MB, Biedler JL, Ross RA: Phenotypic diversification in human neuroblastoma cells: expression of distinct neural crest lineages. Cancer Res. 1989, 49: 219-225.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaL1M%2Fmtlagsg%3D%3D" aria-label="CAS reference 22">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=2535691" aria-label="PubMed reference 22">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 22" href="http://scholar.google.com/scholar_lookup?&title=Phenotypic%20diversification%20in%20human%20neuroblastoma%20cells%3A%20expression%20of%20distinct%20neural%20crest%20lineages&journal=Cancer%20Res&volume=49&pages=219-225&publication_year=1989&author=Ciccarone%2CV&author=Spengler%2CBA&author=Meyers%2CMB&author=Biedler%2CJL&author=Ross%2CRA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="23."><p class="c-article-references__text" id="ref-CR23">Ross RA, Spengler BA, Domenech C, Porubcin M, Rettig WJ, Biedler JL: Human neuroblastoma I-type cells are malignant neural crest stem cells. Cell Growth Differ. 1995, 6: 449-456.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK2MXkvFWksrY%3D" aria-label="CAS reference 23">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=7794812" aria-label="PubMed reference 23">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 23" href="http://scholar.google.com/scholar_lookup?&title=Human%20neuroblastoma%20I-type%20cells%20are%20malignant%20neural%20crest%20stem%20cells&journal=Cell%20Growth%20Differ&volume=6&pages=449-456&publication_year=1995&author=Ross%2CRA&author=Spengler%2CBA&author=Domenech%2CC&author=Porubcin%2CM&author=Rettig%2CWJ&author=Biedler%2CJL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="24."><p class="c-article-references__text" id="ref-CR24">Ross RA, Spengler BA: Human neuroblastoma stem cells. Semin Cancer Biol. 2007, 17: 241-247.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.semcancer.2006.04.006" data-track-item_id="10.1016/j.semcancer.2006.04.006" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.semcancer.2006.04.006" aria-label="Article reference 24" data-doi="10.1016/j.semcancer.2006.04.006">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2sXjtVamsrw%3D" aria-label="CAS reference 24">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16839774" aria-label="PubMed reference 24">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 24" href="http://scholar.google.com/scholar_lookup?&title=Human%20neuroblastoma%20stem%20cells&journal=Semin%20Cancer%20Biol&doi=10.1016%2Fj.semcancer.2006.04.006&volume=17&pages=241-247&publication_year=2007&author=Ross%2CRA&author=Spengler%2CBA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="25."><p class="c-article-references__text" id="ref-CR25">Clagett-Dame M, McNeill EM, Muley PD: Role of all-trans retinoic acid in neurite outgrowth and axonal elongation. J Neurobiol. 2006, 66 (7): 739-56.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/neu.20241" data-track-item_id="10.1002/neu.20241" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fneu.20241" aria-label="Article reference 25" data-doi="10.1002/neu.20241">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD28XmsFWjsrg%3D" aria-label="CAS reference 25">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16688769" aria-label="PubMed reference 25">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 25" href="http://scholar.google.com/scholar_lookup?&title=Role%20of%20all-trans%20retinoic%20acid%20in%20neurite%20outgrowth%20and%20axonal%20elongation&journal=J%20Neurobiol&doi=10.1002%2Fneu.20241&volume=66&issue=7&pages=739-56&publication_year=2006&author=Clagett-Dame%2CM&author=McNeill%2CEM&author=Muley%2CPD"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="26."><p class="c-article-references__text" id="ref-CR26">Hasegawa G, Minami N, Kushida A, Inuyama H, Koga M, Wakabayashi K, Saito Y: Human neuroblastoma GOTO cells express CD44 and localize it into lipid rafts upon differentiation into Schwannian cells. Cell Biol Int. 2005, 29: 193-202.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.cellbi.2004.09.011" data-track-item_id="10.1016/j.cellbi.2004.09.011" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.cellbi.2004.09.011" aria-label="Article reference 26" data-doi="10.1016/j.cellbi.2004.09.011">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2MXks1akur4%3D" aria-label="CAS reference 26">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15878294" aria-label="PubMed reference 26">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 26" href="http://scholar.google.com/scholar_lookup?&title=Human%20neuroblastoma%20GOTO%20cells%20express%20CD44%20and%20localize%20it%20into%20lipid%20rafts%20upon%20differentiation%20into%20Schwannian%20cells&journal=Cell%20Biol%20Int&doi=10.1016%2Fj.cellbi.2004.09.011&volume=29&pages=193-202&publication_year=2005&author=Hasegawa%2CG&author=Minami%2CN&author=Kushida%2CA&author=Inuyama%2CH&author=Koga%2CM&author=Wakabayashi%2CK&author=Saito%2CY"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="27."><p class="c-article-references__text" id="ref-CR27">Sugimoto T, Kato T, Sawada T, Horii Y, Kemshead JT, Hino T, Morioka H, Hosoi H: Schwannian cell differentiation of human neuroblastoma cell lines in vitro induced by bromodeoxyuridine. Cancer Res. 1988, 48: 2531-2537.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaL1cXitFGqtLg%3D" aria-label="CAS reference 27">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=2833349" aria-label="PubMed reference 27">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 27" href="http://scholar.google.com/scholar_lookup?&title=Schwannian%20cell%20differentiation%20of%20human%20neuroblastoma%20cell%20lines%20in%20vitro%20induced%20by%20bromodeoxyuridine&journal=Cancer%20Res&volume=48&pages=2531-2537&publication_year=1988&author=Sugimoto%2CT&author=Kato%2CT&author=Sawada%2CT&author=Horii%2CY&author=Kemshead%2CJT&author=Hino%2CT&author=Morioka%2CH&author=Hosoi%2CH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="28."><p class="c-article-references__text" id="ref-CR28">Narath R, Ambros IM, Kowalska A, Bozsaky E, Boukamp P, Ambros PF: Induction of senescence in MYCN amplified neuroblastoma cell lines by hydroxyurea. Genes Chromosomes Cancer. 2007, 46: 130-42.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/gcc.20393" data-track-item_id="10.1002/gcc.20393" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fgcc.20393" aria-label="Article reference 28" data-doi="10.1002/gcc.20393">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2sXntFU%3D" aria-label="CAS reference 28">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=17106870" aria-label="PubMed reference 28">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 28" href="http://scholar.google.com/scholar_lookup?&title=Induction%20of%20senescence%20in%20MYCN%20amplified%20neuroblastoma%20cell%20lines%20by%20hydroxyurea&journal=Genes%20Chromosomes%20Cancer&doi=10.1002%2Fgcc.20393&volume=46&pages=130-42&publication_year=2007&author=Narath%2CR&author=Ambros%2CIM&author=Kowalska%2CA&author=Bozsaky%2CE&author=Boukamp%2CP&author=Ambros%2CPF"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="29."><p class="c-article-references__text" id="ref-CR29">Rao MS, Anderson DJ: Immortalization and controlled in vitro differentiation of murine multipotent neural crest stem cells. J Neurobiol. 1997, 32: 722-746.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/(SICI)1097-4695(19970620)32:7<722::AID-NEU7>3.0.CO;2-6" data-track-item_id="10.1002/(SICI)1097-4695(19970620)32:7<722::AID-NEU7>3.0.CO;2-6" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F%28SICI%291097-4695%2819970620%2932%3A7%3C722%3A%3AAID-NEU7%3E3.0.CO%3B2-6" aria-label="Article reference 29" data-doi="10.1002/(SICI)1097-4695(19970620)32:7<722::AID-NEU7>3.0.CO;2-6">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK2sXktFaqtLw%3D" aria-label="CAS reference 29">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=9183749" aria-label="PubMed reference 29">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 29" href="http://scholar.google.com/scholar_lookup?&title=Immortalization%20and%20controlled%20in%20vitro%20differentiation%20of%20murine%20multipotent%20neural%20crest%20stem%20cells&journal=J%20Neurobiol&doi=10.1002%2F%28SICI%291097-4695%2819970620%2932%3A7%3C722%3A%3AAID-NEU7%3E3.0.CO%3B2-6&volume=32&pages=722-746&publication_year=1997&author=Rao%2CMS&author=Anderson%2CDJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="30."><p class="c-article-references__text" id="ref-CR30">Stemple DL, Anderson DJ: Isolation of a stem cell for neurons and glia from the mammalian neural crest. Cell. 1992, 71: 973-985.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/0092-8674(92)90393-Q" data-track-item_id="10.1016/0092-8674(92)90393-Q" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2F0092-8674%2892%2990393-Q" aria-label="Article reference 30" data-doi="10.1016/0092-8674(92)90393-Q">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK3sXpslCnsQ%3D%3D" aria-label="CAS reference 30">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=1458542" aria-label="PubMed reference 30">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 30" href="http://scholar.google.com/scholar_lookup?&title=Isolation%20of%20a%20stem%20cell%20for%20neurons%20and%20glia%20from%20the%20mammalian%20neural%20crest&journal=Cell&doi=10.1016%2F0092-8674%2892%2990393-Q&volume=71&pages=973-985&publication_year=1992&author=Stemple%2CDL&author=Anderson%2CDJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="31."><p class="c-article-references__text" id="ref-CR31">Le Douarin NM, Creuzet S, Couly G, Dupin E: Neural crest cell plasticity and its limits. Development. 2004, 131: 4637-4650.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1242/dev.01350" data-track-item_id="10.1242/dev.01350" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1242%2Fdev.01350" aria-label="Article reference 31" data-doi="10.1242/dev.01350">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2cXptVOluro%3D" aria-label="CAS reference 31">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15358668" aria-label="PubMed reference 31">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 31" href="http://scholar.google.com/scholar_lookup?&title=Neural%20crest%20cell%20plasticity%20and%20its%20limits&journal=Development&doi=10.1242%2Fdev.01350&volume=131&pages=4637-4650&publication_year=2004&author=Le%20Douarin%2CNM&author=Creuzet%2CS&author=Couly%2CG&author=Dupin%2CE"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="32."><p class="c-article-references__text" id="ref-CR32">Liu Y, Rao MS: Transdifferentiation – fact or artifact. J Cell Biochem. 2003, 88: 29-40.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/jcb.10281" data-track-item_id="10.1002/jcb.10281" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fjcb.10281" aria-label="Article reference 32" data-doi="10.1002/jcb.10281">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXht1Cjsw%3D%3D" aria-label="CAS reference 32">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12461772" aria-label="PubMed reference 32">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 32" href="http://scholar.google.com/scholar_lookup?&title=Transdifferentiation%20%E2%80%93%20fact%20or%20artifact&journal=J%20Cell%20Biochem&doi=10.1002%2Fjcb.10281&volume=88&pages=29-40&publication_year=2003&author=Liu%2CY&author=Rao%2CMS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="33."><p class="c-article-references__text" id="ref-CR33">Gestblom C, Grynfeld A, Ora I, Ortoft E, Larsson C, Axelson H, Sandstedt B, Cserjesi P, Olson EN, Pahlman S: The basic helix-loop-helix transcription factor dHAND, a marker gene for the developing human sympathetic nervous system, is expressed in both high- and low-stage neuroblastomas. Lab Invest. 1999, 79: 67-79.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK1M7jsFGrsQ%3D%3D" aria-label="CAS reference 33">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=9952112" aria-label="PubMed reference 33">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 33" href="http://scholar.google.com/scholar_lookup?&title=The%20basic%20helix-loop-helix%20transcription%20factor%20dHAND%2C%20a%20marker%20gene%20for%20the%20developing%20human%20sympathetic%20nervous%20system%2C%20is%20expressed%20in%20both%20high-%20and%20low-stage%20neuroblastomas&journal=Lab%20Invest&volume=79&pages=67-79&publication_year=1999&author=Gestblom%2CC&author=Grynfeld%2CA&author=Ora%2CI&author=Ortoft%2CE&author=Larsson%2CC&author=Axelson%2CH&author=Sandstedt%2CB&author=Cserjesi%2CP&author=Olson%2CEN&author=Pahlman%2CS"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="34."><p class="c-article-references__text" id="ref-CR34">Thiele CJ: Biology of pediatric peripheral neuroectodermal tumors. Cancer Metastasis Rev. 1991, 10: 311-319.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1007/BF00554793" data-track-item_id="10.1007/BF00554793" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1007/BF00554793" aria-label="Article reference 34" data-doi="10.1007/BF00554793">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK387lsVOltA%3D%3D" aria-label="CAS reference 34">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=1786632" aria-label="PubMed reference 34">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 34" href="http://scholar.google.com/scholar_lookup?&title=Biology%20of%20pediatric%20peripheral%20neuroectodermal%20tumors&journal=Cancer%20Metastasis%20Rev&doi=10.1007%2FBF00554793&volume=10&pages=311-319&publication_year=1991&author=Thiele%2CCJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="35."><p class="c-article-references__text" id="ref-CR35">Pahlman S, Hoehner JC, Nanberg E, Hedborg F, Fagerstrom S, Gestblom C, Johansson I, Larsson U, Lavenius E, Ortoft E, Soderholm H: Differentiation and survival influences of growth factors in human neuroblastoma. Eur J Cancer. 1995, 31A (4): 453-458.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/0959-8049(95)00033-F" data-track-item_id="10.1016/0959-8049(95)00033-F" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2F0959-8049%2895%2900033-F" aria-label="Article reference 35" data-doi="10.1016/0959-8049(95)00033-F">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:STN:280:DyaK28%2FptFShsw%3D%3D" aria-label="CAS reference 35">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=7576944" aria-label="PubMed reference 35">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 35" href="http://scholar.google.com/scholar_lookup?&title=Differentiation%20and%20survival%20influences%20of%20growth%20factors%20in%20human%20neuroblastoma&journal=Eur%20J%20Cancer&doi=10.1016%2F0959-8049%2895%2900033-F&volume=31A&issue=4&pages=453-458&publication_year=1995&author=Pahlman%2CS&author=Hoehner%2CJC&author=Nanberg%2CE&author=Hedborg%2CF&author=Fagerstrom%2CS&author=Gestblom%2CC&author=Johansson%2CI&author=Larsson%2CU&author=Lavenius%2CE&author=Ortoft%2CE&author=Soderholm%2CH"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="36."><p class="c-article-references__text" id="ref-CR36">Kim J, Lo L, Dormand E, Anderson DJ: SOX10 maintains multipotency and inhibits neuronal. Neuron. 2003, 38 (1): 17-31.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0896-6273(03)00163-6" data-track-item_id="10.1016/S0896-6273(03)00163-6" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0896-6273%2803%2900163-6" aria-label="Article reference 36" data-doi="10.1016/S0896-6273(03)00163-6">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3sXjt1Gmsbo%3D" aria-label="CAS reference 36">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12691661" aria-label="PubMed reference 36">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 36" href="http://scholar.google.com/scholar_lookup?&title=SOX10%20maintains%20multipotency%20and%20inhibits%20neuronal&journal=Neuron&doi=10.1016%2FS0896-6273%2803%2900163-6&volume=38&issue=1&pages=17-31&publication_year=2003&author=Kim%2CJ&author=Lo%2CL&author=Dormand%2CE&author=Anderson%2CDJ"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="37."><p class="c-article-references__text" id="ref-CR37">Taylor MD, Poppleton H, Fuller C, Su X, Liu Y, Jensen P, Magdaleno S, Dalton J, Calabrese C, Board J, Macdonald T, Rutka J, Guha A, Gajjar A, Curran T, Gilbertson R: Radial glia cells are candidate stem cells of ependymoma. Cancer Cell. 2005, 8: 323-335.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/j.ccr.2005.09.001" data-track-item_id="10.1016/j.ccr.2005.09.001" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2Fj.ccr.2005.09.001" aria-label="Article reference 37" data-doi="10.1016/j.ccr.2005.09.001">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2MXhtFOrtLvN" aria-label="CAS reference 37">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=16226707" aria-label="PubMed reference 37">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 37" href="http://scholar.google.com/scholar_lookup?&title=Radial%20glia%20cells%20are%20candidate%20stem%20cells%20of%20ependymoma&journal=Cancer%20Cell&doi=10.1016%2Fj.ccr.2005.09.001&volume=8&pages=323-335&publication_year=2005&author=Taylor%2CMD&author=Poppleton%2CH&author=Fuller%2CC&author=Su%2CX&author=Liu%2CY&author=Jensen%2CP&author=Magdaleno%2CS&author=Dalton%2CJ&author=Calabrese%2CC&author=Board%2CJ&author=Macdonald%2CT&author=Rutka%2CJ&author=Guha%2CA&author=Gajjar%2CA&author=Curran%2CT&author=Gilbertson%2CR"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="38."><p class="c-article-references__text" id="ref-CR38">Motohashi T, Aoki H, Chiba K, Yoshimura N, Kunisada T: Multipotent cell fate of neural crest-like cells derived from embryonic stem cells. Stem Cells. 2007, 25: 402-410.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1634/stemcells.2006-0323" data-track-item_id="10.1634/stemcells.2006-0323" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1634%2Fstemcells.2006-0323" aria-label="Article reference 38" data-doi="10.1634/stemcells.2006-0323">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2sXivVOlt74%3D" aria-label="CAS reference 38">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=17038669" aria-label="PubMed reference 38">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 38" href="http://scholar.google.com/scholar_lookup?&title=Multipotent%20cell%20fate%20of%20neural%20crest-like%20cells%20derived%20from%20embryonic%20stem%20cells&journal=Stem%20Cells&doi=10.1634%2Fstemcells.2006-0323&volume=25&pages=402-410&publication_year=2007&author=Motohashi%2CT&author=Aoki%2CH&author=Chiba%2CK&author=Yoshimura%2CN&author=Kunisada%2CT"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="39."><p class="c-article-references__text" id="ref-CR39">Barres BA: Neuron-glial interactions. Molecular and Cellular Approaches to neural development. Edited by: Cowan WM, Jessell TM, Zipursky SL. 1997, New York, Oxford University Press, 64-107.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 39" href="http://scholar.google.com/scholar_lookup?&title=Neuron-glial%20interactions&pages=64-107&publication_year=1997&author=Barres%2CBA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="40."><p class="c-article-references__text" id="ref-CR40">Lim DA, Alvarez-Buylla A: Interactions between astrocytes and adult subventricular zone precursors stimulates neurogenesis. PNAS. 1999, 96: 7526-7531.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1073/pnas.96.13.7526" data-track-item_id="10.1073/pnas.96.13.7526" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1073%2Fpnas.96.13.7526" aria-label="Article reference 40" data-doi="10.1073/pnas.96.13.7526">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC22119" aria-label="PubMed Central reference 40">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK1MXltVOqsLg%3D" aria-label="CAS reference 40">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=10377448" aria-label="PubMed reference 40">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 40" href="http://scholar.google.com/scholar_lookup?&title=Interactions%20between%20astrocytes%20and%20adult%20subventricular%20zone%20precursors%20stimulates%20neurogenesis&journal=PNAS&doi=10.1073%2Fpnas.96.13.7526&volume=96&pages=7526-7531&publication_year=1999&author=Lim%2CDA&author=Alvarez-Buylla%2CA"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="41."><p class="c-article-references__text" id="ref-CR41">Liu S, Tian Y, Chlenski A, Yang Q, Zage P, Salwen HR, Crawford SE, Cohn SL: Cross-talk between Schwann cells and neuroblasts influences the biology of neuroblastoma xenografts. Am J Pathol. 2005, 166: 891-900.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0002-9440(10)62309-7" data-track-item_id="10.1016/S0002-9440(10)62309-7" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0002-9440%2810%2962309-7" aria-label="Article reference 41" data-doi="10.1016/S0002-9440(10)62309-7">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1602341" aria-label="PubMed Central reference 41">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD2MXivVOmsbs%3D" aria-label="CAS reference 41">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=15743800" aria-label="PubMed reference 41">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 41" href="http://scholar.google.com/scholar_lookup?&title=Cross-talk%20between%20Schwann%20cells%20and%20neuroblasts%20influences%20the%20biology%20of%20neuroblastoma%20xenografts&journal=Am%20J%20Pathol&doi=10.1016%2FS0002-9440%2810%2962309-7&volume=166&pages=891-900&publication_year=2005&author=Liu%2CS&author=Tian%2CY&author=Chlenski%2CA&author=Yang%2CQ&author=Zage%2CP&author=Salwen%2CHR&author=Crawford%2CSE&author=Cohn%2CSL"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="42."><p class="c-article-references__text" id="ref-CR42">Dimri GP, Lee X, Basile G, Acosta M, Scott G, Roskelley C, Medrano EE, Linskens M, Rubelj I, Pereira-Smith O: A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci USA. 1995, 92: 9363-7.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1073/pnas.92.20.9363" data-track-item_id="10.1073/pnas.92.20.9363" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1073%2Fpnas.92.20.9363" aria-label="Article reference 42" data-doi="10.1073/pnas.92.20.9363">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC40985" aria-label="PubMed Central reference 42">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DyaK2MXosVWlur0%3D" aria-label="CAS reference 42">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=7568133" aria-label="PubMed reference 42">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 42" href="http://scholar.google.com/scholar_lookup?&title=A%20biomarker%20that%20identifies%20senescent%20human%20cells%20in%20culture%20and%20in%20aging%20skin%20in%20vivo&journal=Proc%20Natl%20Acad%20Sci%20USA&doi=10.1073%2Fpnas.92.20.9363&volume=92&pages=9363-7&publication_year=1995&author=Dimri%2CGP&author=Lee%2CX&author=Basile%2CG&author=Acosta%2CM&author=Scott%2CG&author=Roskelley%2CC&author=Medrano%2CEE&author=Linskens%2CM&author=Rubelj%2CI&author=Pereira-Smith%2CO"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="43."><p class="c-article-references__text" id="ref-CR43">Cheung IY, Cheung NK: Quantitation of marrow disease in neuroblastoma by real-time reverse transcription-PCR. Clin Cancer Res. 2001, 7: 1698-1705.</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="cas reference" data-track-action="cas reference" href="/articles/cas-redirect/1:CAS:528:DC%2BD3MXltV2hs7o%3D" aria-label="CAS reference 43">CAS</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=11410509" aria-label="PubMed reference 43">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 43" href="http://scholar.google.com/scholar_lookup?&title=Quantitation%20of%20marrow%20disease%20in%20neuroblastoma%20by%20real-time%20reverse%20transcription-PCR&journal=Clin%20Cancer%20Res&volume=7&pages=1698-1705&publication_year=2001&author=Cheung%2CIY&author=Cheung%2CNK"> Google Scholar</a> </p></li><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="44."><p class="c-article-references__text" id="ref-CR44">Vandesompele J, De Preter K, Pattyn F, Poppe B, Van Roy N, De Paepe A, Speleman F: Accurate normalization of real-time quantitative RT-PCR data by geometric averaging of multiple internal control genes. Genome Biol. 2002, 3 (7): RESEARCH0034-</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="noopener" data-track-label="10.1186/gb-2002-3-7-research0034" data-track-item_id="10.1186/gb-2002-3-7-research0034" data-track-value="article reference" data-track-action="article reference" href="https://link.springer.com/doi/10.1186/gb-2002-3-7-research0034" aria-label="Article reference 44" data-doi="10.1186/gb-2002-3-7-research0034">Article</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed central reference" data-track-action="pubmed central reference" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC126239" aria-label="PubMed Central reference 44">PubMed Central</a> <a data-track="click_references" rel="nofollow noopener" data-track-label="link" data-track-item_id="link" data-track-value="pubmed reference" data-track-action="pubmed reference" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Abstract&list_uids=12184808" aria-label="PubMed reference 44">PubMed</a> <a data-track="click_references" data-track-action="google scholar reference" data-track-value="google scholar reference" data-track-label="link" data-track-item_id="link" rel="nofollow noopener" aria-label="Google Scholar reference 44" href="http://scholar.google.com/scholar_lookup?&title=Accurate%20normalization%20of%20real-time%20quantitative%20RT-PCR%20data%20by%20geometric%20averaging%20of%20multiple%20internal%20control%20genes&journal=Genome%20Biol&doi=10.1186%2Fgb-2002-3-7-research0034&volume=3&issue=7&publication_year=2002&author=Vandesompele%2CJ&author=De%20Preter%2CK&author=Pattyn%2CF&author=Poppe%2CB&author=Van%20Roy%2CN&author=De%20Paepe%2CA&author=Speleman%2CF"> Google Scholar</a> </p></li></ol><p class="c-article-references__download u-hide-print"><a data-track="click" data-track-action="download citation references" data-track-label="link" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1186/1471-213X-9-12?format=refman&flavour=references">Download references<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p></div></div></div></section></div><section data-title="Acknowledgements"><div class="c-article-section" id="Ack1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Ack1">Acknowledgements</h2><div class="c-article-section__content" id="Ack1-content"><p>This work was supported by: Career Development Award 2001 (to J. M.) from the American Society of Clinical Oncology (ASCO); grants from the Spanish Ministry of Health (Redes Temáticas de Investigación Cooperativa 2002;G03/089, FIS 2004/PI041259), the Catalan government (AGAUR, Generalitat de Catalunya, 2005SGR00605), and the generous gift from Fondo Margarita del Pozo to the laboratory.</p><p>Authors thank to Dr. R Ross, Dr. B. Spengler, Department of Biological Science, University of Fordham, NY; and Dr. NK Cheung, Pediatrics Department, Memorial Sloan Kettering Cancer Center, NY, for kindly providing the cell lines used for this study.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Developmental tumor biology laboratory, Hospital Sant Joan de Déu, Passeig Sant Joan de Déu, 2, Esplugues de Llobregat, 08950, Barcelona, Spain</p><p class="c-article-author-affiliation__authors-list">Sandra Acosta, Cinzia Lavarino, Raquel Paris, Idoia Garcia, Carmen de Torres, Eva Rodríguez, Helena Beleta & Jaume Mora</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Sandra-Acosta-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Sandra Acosta</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="https://www.biomedcentral.com/search?query=author%23Sandra%20Acosta" class="c-article-button" data-track="click" data-track-action="author link - 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publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Jaume%20Mora" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Jaume%20Mora%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li></ol></div><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:jmora@hsjdbcn.org">Jaume Mora</a>.</p></div></div></section><section data-title="Additional information"><div class="c-article-section" id="additional-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="additional-information">Additional information</h2><div class="c-article-section__content" id="additional-information-content"><h3 class="c-article__sub-heading">Competing interests</h3><p>The authors declare that they have no competing interests.</p><h3 class="c-article__sub-heading">Authors' contributions</h3><p>SA, CL and JM are responsible for the initial conception and overall hypothesis of this study. SA, CL and JM are responsible for the design of this manuscript, including the original draft and subsequent revisions and design of this manuscript. CdT assisted with the initial concept and was involved with the draft and revisions of this manuscript; provided guidance for many of the experiments. SA and RP are responsible for the differentiation experiments design and immunocytochemical characterization of cell lines. SA and IG are responsible for the qPCR analyses, immunocytochemical characterization of differentiated cell lines. IG, ER and HB assisted with valuable technical assistance for experiments associated with this manuscript. All were also involved in the drafting and revisions for this manuscript. All authors read and approved the final manuscript.</p></div></div></section><section data-title="Electronic supplementary material"><div class="c-article-section" id="Sec20-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec20">Electronic supplementary material</h2><div class="c-article-section__content" id="Sec20-content"><div data-test="supplementary-info"><div id="figshareContainer" class="c-article-figshare-container" data-test="figshare-container"></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM1"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="additional file 1: flowsheet of differentiation in" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_416_MOESM1_ESM.ppt" data-supp-info-image="">Additional file 1: Flowsheet of differentiation induction protocol.(PPT 66 KB)</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM2"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="additional file 2: primary antibodies used. list o" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_416_MOESM2_ESM.ppt" data-supp-info-image="">Additional file 2: Primary antibodies used. List of antibodies used for the immunostaining. (PPT 124 KB)</a></h3></div></div></div></div></section><section data-title="Authors’ original submitted files for images"><div class="c-article-section" id="Sec21-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec21">Authors’ original submitted files for images</h2><div class="c-article-section__content" id="Sec21-content"><div data-test="supplementary-info"><p>Below are the links to the authors’ original submitted files for images.</p><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM3"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="authors’ original file for figure 1" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_416_MOESM3_ESM.pdf" data-supp-info-image="">Authors’ original file for figure 1</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM4"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="authors’ original file for figure 2" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_416_MOESM4_ESM.pdf" data-supp-info-image="">Authors’ original file for figure 2</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM5"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="authors’ original file for figure 3" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_416_MOESM5_ESM.pdf" data-supp-info-image="">Authors’ original file for figure 3</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM6"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="authors’ original file for figure 4" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_416_MOESM6_ESM.pdf" data-supp-info-image="">Authors’ original file for figure 4</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM7"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="authors’ original file for figure 5" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_416_MOESM7_ESM.pdf" data-supp-info-image="">Authors’ original file for figure 5</a></h3></div><div class="c-article-supplementary__item" data-test="supp-item" id="MOESM8"><h3 class="c-article-supplementary__title u-h3"><a class="print-link" data-track="click" data-track-action="view supplementary info" data-test="supp-info-link" data-track-label="authors’ original file for figure 6" href="https://static-content.springer.com/esm/art%3A10.1186%2F1471-213X-9-12/MediaObjects/12861_2008_416_MOESM8_ESM.pdf" data-supp-info-image="">Authors’ original file for figure 6</a></h3></div></div></div></div></section><section data-title="Rights and permissions"><div class="c-article-section" id="rightslink-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="rightslink">Rights and permissions</h2><div class="c-article-section__content" id="rightslink-content"> <p> <b>Open Access</b> This article is published under license to BioMed Central Ltd. 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