VEGF-D promotes the metastatic spread of tumor cells via the lymphatics

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To investigate the molecular mechanisms underlying the spread of cancer by the lymphatics, we examined the ability of vascular endothelial growth factor (VEGF)-D, a ligand for the lymphatic growth factor receptor VEGFR-3/Flt-4, to induce formation of lymphatics in a mouse tumor model. Staining with markers specific for lymphatic endothelium demonstrated that VEGF-D induced the formation of lymphatics within tumors. Moreover, expression of VEGF-D in tumor cells led to spread of the tumor to lymph nodes, whereas expression of VEGF, an angiogenic growth factor which activates VEGFR-2 but not VEGFR-3, did not. VEGF-D also promoted tumor angiogenesis and growth. Lymphatic spread induced by VEGF-D could be blocked with an antibody specific for VEGF-D. 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To investigate the molecular mechanisms underlying the spread of cancer by the lymphatics, we examined the ability of vascular endothelial growth factor (VEGF)-D, a ligand for the lymphatic growth factor receptor VEGFR-3/Flt-4, to induce formation of lymphatics in a mouse tumor model. Staining with markers specific for lymphatic endothelium demonstrated that VEGF-D induced the formation of lymphatics within tumors. Moreover, expression of VEGF-D in tumor cells led to spread of the tumor to lymph nodes, whereas expression of VEGF, an angiogenic growth factor which activates VEGFR-2 but not VEGFR-3, did not. VEGF-D also promoted tumor angiogenesis and growth. Lymphatic spread induced by VEGF-D could be blocked with an antibody specific for VEGF-D. This study demonstrates that lymphatics can be established in solid tumors and implicates VEGF family members in determining the route of metastatic spread."/> <meta name="dc.creator" content="Stacker, Steven A."/> <meta name="dc.creator" content="Caesar, Carol"/> <meta name="dc.creator" content="Baldwin, Megan E."/> <meta name="dc.creator" content="Thornton, Gillian E."/> <meta name="dc.creator" content="Williams, Richard A."/> <meta name="dc.creator" content="Prevo, Remko"/> <meta name="dc.creator" content="Jackson, David G."/> <meta name="dc.creator" content="Nishikawa, Shin-ichi"/> <meta name="dc.creator" content="Kubo, Hajime"/> <meta name="dc.creator" content="Achen, Marc G."/> <meta name="dc.subject" content="Biomedicine, general"/> <meta name="dc.subject" content="Cancer Research"/> <meta name="dc.subject" content="Metabolic Diseases"/> <meta name="dc.subject" content="Infectious Diseases"/> <meta name="dc.subject" content="Molecular Medicine"/> <meta name="dc.subject" content="Neurosciences"/> <meta name="citation_reference" content="citation_journal_title=Sci. 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Pathol.; citation_title=The classification of cancer of the rectum; citation_author=CE Dukes; citation_volume=35; citation_publication_date=1932; citation_pages=323-332; citation_doi=10.1002/path.1700350303; citation_id=CR12"/> <meta name="citation_reference" content="citation_journal_title=Cancer; citation_title=Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. 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Chem.; citation_title=Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers; citation_author=SA Stacker; citation_volume=274; citation_publication_date=1999; citation_pages=32127-32136; citation_doi=10.1074/jbc.274.45.32127; citation_id=CR15"/> <meta name="citation_reference" content="citation_journal_title=Eur.J.Biochem.; citation_title=Monoclonal antibodies to vascular endothelial growth factor-D block interactions with both VEGF receptor-2 and VEGF receptor-3; citation_author=MG Achen; citation_volume=267; citation_publication_date=2000; citation_pages=2505-2515; citation_doi=10.1046/j.1432-1327.2000.01257.x; citation_id=CR16"/> <meta name="citation_reference" content="citation_journal_title=Am. J. Pathol.; citation_title=VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer; citation_author=R Valtola; citation_volume=154; citation_publication_date=1999; citation_pages=1381-1390; citation_doi=10.1016/S0002-9440(10)65392-8; citation_id=CR17"/> <meta name="citation_reference" content="citation_journal_title=J. Cell Biol.; citation_title=LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan; citation_author=S Banerji; citation_volume=144; citation_publication_date=1999; citation_pages=789-801; citation_doi=10.1083/jcb.144.4.789; citation_id=CR18"/> <meta name="citation_reference" content="citation_journal_title=Am. J. Pathol.; citation_title=Lack of lymphangiogenesis in human primary cutaneous melanoma. Consequences for the mechanism of lymphatic dissemination; citation_author=RMW de Waal; citation_volume=150; citation_publication_date=1997; citation_pages=1951-1957; citation_id=CR19"/> <meta name="citation_reference" content="citation_journal_title=Cancer Res.; citation_title=Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors; citation_author=M Prewett; citation_volume=59; citation_publication_date=1999; citation_pages=5209-5218; citation_id=CR20"/> <meta name="citation_reference" content="citation_journal_title=Curr. Opin. Immunol.; citation_title=The role of natural killer cells in immune surveillance of cancer; citation_author=TL Whiteside, RB Herberman; citation_volume=7; citation_publication_date=1995; citation_pages=704-710; citation_doi=10.1016/0952-7915(95)80080-8; citation_id=CR21"/> <meta name="citation_reference" content="citation_journal_title=Methods; citation_title=Antitumor functions of natural killer cells and control of metastases; citation_author=NL Vujanovic, P Basse, RB Herberman, TL Whiteside; citation_volume=9; citation_publication_date=1996; citation_pages=394-408; citation_doi=10.1006/meth.1996.0044; citation_id=CR22"/> <meta name="citation_reference" content="citation_journal_title=J. Immunol.; citation_title=Host NK cells are required for the growth of the human filarial parasite Brugia malayi in mice; citation_author=S Babu, P Porte, TR Klei, LD Shultz, TV Rajan; citation_volume=161; citation_publication_date=1998; citation_pages=1428-1432; citation_id=CR23"/> <meta name="citation_reference" content="citation_journal_title=Cancer; citation_title=Identification of sentinel lymph nodes in vulvar carcinoma patients with the aid of a Patent Blue V injection: a multicenter study; citation_author=AC Ansink; citation_volume=86; citation_publication_date=1999; citation_pages=652-656; citation_doi=10.1002/(SICI)1097-0142(19990815)86:4<652::AID-CNCR14>3.0.CO;2-R; citation_id=CR24"/> <meta name="citation_reference" content="citation_journal_title=Ann. Surg.; citation_title=Anti-angiogenesis: new concepts of therapy of solid tumors; citation_author=J Folkman; citation_volume=175; citation_publication_date=1972; citation_pages=409-416; citation_doi=10.1097/00000658-197203000-00014; citation_id=CR25"/> <meta name="citation_reference" content="citation_journal_title=Science; citation_title=Angiogenic factors; citation_author=J Folkman, M Klagsburn; citation_volume=235; citation_publication_date=1987; citation_pages=442-447; citation_doi=10.1126/science.2432664; citation_id=CR26"/> <meta name="citation_reference" content="citation_journal_title=J. Natl. Cancer Inst.; citation_title=What is the evidence that tumors are angiogenesis dependent?; citation_author=J Folkman; citation_volume=82; citation_publication_date=1990; citation_pages=4-6; citation_doi=10.1093/jnci/82.1.4; citation_id=CR27"/> <meta name="citation_reference" content="citation_journal_title=Cell; citation_title=Blood vessel formation:what is its molecular basis?; citation_author=J Folkman, PA D'Amore; citation_volume=87; citation_publication_date=1996; citation_pages=1153-1155; citation_doi=10.1016/S0092-8674(00)81810-3; citation_id=CR28"/> <meta name="citation_reference" content="citation_journal_title=Cancer Res.; citation_title=PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration; citation_author=JM Wood; citation_volume=60; citation_publication_date=2000; citation_pages=2178-2189; citation_id=CR29"/> <meta name="citation_reference" content="citation_journal_title=Cancer Res.; citation_title=Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model; citation_author=J Drevs; citation_volume=60; citation_publication_date=2000; citation_pages=4819-4824; citation_id=CR30"/> <meta name="citation_reference" content="citation_journal_title=Curr. Top. Microbiol. Immunol.; citation_title=Growth factors regulating lymphatic vessels; citation_author=A Lymboussaki, MG Achen, SA Stacker, K Alitalo; citation_volume=251; citation_publication_date=2000; citation_pages=75-82; citation_id=CR31"/> <meta name="citation_reference" content="citation_journal_title=Cancer Res.; citation_title=Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation; citation_author=AJ Leu, DA Berk, A Lymboussaki, K Alitalo, RK Jain; citation_volume=60; citation_publication_date=2000; citation_pages=4324-4327; citation_id=CR32"/> <meta name="citation_reference" content="citation_journal_title=Am. J. Pathol.; citation_title=Expression of the vascular endothelial growth factor C receptor VEGFR-3 in lymphatic endothelium of the skin and in vascular tumors; citation_author=A Lymboussaki; citation_volume=153; citation_publication_date=1998; citation_pages=395-403; citation_doi=10.1016/S0002-9440(10)65583-6; citation_id=CR33"/> <meta name="citation_reference" content="citation_journal_title=EMBO J.; citation_title=A novel vascular endothelial growth factor, VEGF-C, Is a ligand for the Flt-4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases; citation_author=V Joukov; citation_volume=15; citation_publication_date=1996; citation_pages=290-298; citation_doi=10.1002/j.1460-2075.1996.tb00359.x; citation_id=CR34"/> <meta name="citation_reference" content="citation_journal_title=Blood; citation_title=Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis; citation_author=H Kubo; citation_volume=96; citation_publication_date=2000; citation_pages=546-553; citation_id=CR35"/> <meta name="citation_reference" content="citation_journal_title=Am. J. Pathol.; citation_title=Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors; citation_author=P Salven; citation_volume=153; citation_publication_date=1998; citation_pages=103-108; citation_doi=10.1016/S0002-9440(10)65550-2; citation_id=CR36"/> <meta name="citation_reference" content="Achen, M.G. et al. Localisation of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumour angiogenesis J. Pathol. (in the press)."/> <meta name="citation_reference" content="citation_journal_title=Cancer Res.; citation_title=Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis; citation_author=KH Plate, G Breier, B Millauer, A Ullrich, W Risau; citation_volume=53; citation_publication_date=1993; citation_pages=5822-5827; citation_id=CR38"/> <meta name="citation_reference" content="citation_journal_title=Clin. Cancer Res.; citation_title=Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma; citation_author=T Niki; citation_volume=6; citation_publication_date=2000; citation_pages=2431-2439; citation_id=CR39"/> <meta name="citation_reference" content="Mandriota, S.J. et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumor metastasis. 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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-Steven_A_-Stacker-Aff1" data-author-popup="auth-Steven_A_-Stacker-Aff1" data-author-search="Stacker, Steven A." data-corresp-id="c1">Steven A. Stacker<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-mail-medium"></use></svg></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-Carol-Caesar-Aff1" data-author-popup="auth-Carol-Caesar-Aff1" data-author-search="Caesar, Carol">Carol Caesar</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-Megan_E_-Baldwin-Aff1" data-author-popup="auth-Megan_E_-Baldwin-Aff1" data-author-search="Baldwin, Megan E.">Megan E. Baldwin</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-Gillian_E_-Thornton-Aff1" data-author-popup="auth-Gillian_E_-Thornton-Aff1" data-author-search="Thornton, Gillian E.">Gillian E. Thornton</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-Richard_A_-Williams-Aff2" data-author-popup="auth-Richard_A_-Williams-Aff2" data-author-search="Williams, Richard A.">Richard A. Williams</a><sup class="u-js-hide"><a href="#Aff2">2</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-Remko-Prevo-Aff3" data-author-popup="auth-Remko-Prevo-Aff3" data-author-search="Prevo, Remko">Remko Prevo</a><sup class="u-js-hide"><a href="#Aff3">3</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-David_G_-Jackson-Aff3" data-author-popup="auth-David_G_-Jackson-Aff3" data-author-search="Jackson, David G.">David G. Jackson</a><sup class="u-js-hide"><a href="#Aff3">3</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-Shin_ichi-Nishikawa-Aff4" data-author-popup="auth-Shin_ichi-Nishikawa-Aff4" data-author-search="Nishikawa, Shin-ichi">Shin-ichi Nishikawa</a><sup class="u-js-hide"><a href="#Aff4">4</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-Hajime-Kubo-Aff4-Aff5" data-author-popup="auth-Hajime-Kubo-Aff4-Aff5" data-author-search="Kubo, Hajime">Hajime Kubo</a><sup class="u-js-hide"><a href="#Aff4">4</a>,<a href="#Aff5">5</a></sup> & </li><li class="c-article-author-list__show-more" aria-label="Show all 10 authors for this article" title="Show all 10 authors for this article">…</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-Marc_G_-Achen-Aff1" data-author-popup="auth-Marc_G_-Achen-Aff1" data-author-search="Achen, Marc G.">Marc G. Achen</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> </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="/nm" data-track="click" data-track-action="journal homepage" data-track-category="article body" data-track-label="link"><i data-test="journal-title">Nature Medicine</i></a> <b data-test="journal-volume"><span class="u-visually-hidden">volume</span> 7</b>, <span class="u-visually-hidden">pages </span>186–191 (<span data-test="article-publication-year">2001</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">3032 <span class="c-article-metrics-bar__label">Accesses</span></p> </li> <li class="c-article-metrics-bar__item" data-test="altmetric-score"> <p class="c-article-metrics-bar__count">9 <span class="c-article-metrics-bar__label">Altmetric</span></p> </li> <li class="c-article-metrics-bar__item"> <p class="c-article-metrics-bar__details"><a href="/articles/nm0201_186/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> </header> </div> <div class="c-article-body"> <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"><p>Metastasis to local lymph nodes via the lymphatic vessels is a common step in the spread of solid tumors. To investigate the molecular mechanisms underlying the spread of cancer by the lymphatics, we examined the ability of vascular endothelial growth factor (VEGF)-D, a ligand for the lymphatic growth factor receptor VEGFR-3/Flt-4, to induce formation of lymphatics in a mouse tumor model. Staining with markers specific for lymphatic endothelium demonstrated that VEGF-D induced the formation of lymphatics within tumors. Moreover, expression of VEGF-D in tumor cells led to spread of the tumor to lymph nodes, whereas expression of VEGF, an angiogenic growth factor which activates VEGFR-2 but not VEGFR-3, did not. VEGF-D also promoted tumor angiogenesis and growth. Lymphatic spread induced by VEGF-D could be blocked with an antibody specific for VEGF-D. 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srcset="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2F84635/MediaObjects/41591_2001_Article_BFnm0201_186_Fig2_HTML.jpg?as=webp"><img src="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2F84635/MediaObjects/41591_2001_Article_BFnm0201_186_Fig2_HTML.jpg" alt="" loading="lazy" width="114" height="312"></picture></div></div></figure></div><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3"><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Figure 3: Immunohistochemical staining of tumors with vascular markers.</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><picture><source type="image/webp" srcset="//media.springernature.com/m312/springer-static/image/art%3A10.1038%2F84635/MediaObjects/41591_2001_Article_BFnm0201_186_Fig3_HTML.jpg?as=webp"><img 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Cancer cell invasion and metastasis. <i>Sci. Am.</i> <b>266</b>, 34–41 (1992).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/scientificamerican0292-54" data-track-item_id="10.1038/scientificamerican0292-54" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2Fscientificamerican0292-54" aria-label="Article reference 1" data-doi="10.1038/scientificamerican0292-54">Article</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=Cancer%20cell%20invasion%20and%20metastasis&journal=Sci.%20Am.&doi=10.1038%2Fscientificamerican0292-54&volume=266&pages=34-41&publication_year=1992&author=Liotta%2CLA"> 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">O'Reilly, M.S. et al. Angiostatin: a novel angiogenesis inhibitor that mediates the supression of metastases by a lewis lung carcinoma. <i>Cell</i> <b>79</b>, 315–328 (1994).</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(94)90200-3" data-track-item_id="10.1016/0092-8674(94)90200-3" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2F0092-8674%2894%2990200-3" aria-label="Article reference 2" data-doi="10.1016/0092-8674(94)90200-3">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:DyaK2MXhvFWrsbY%3D" aria-label="CAS reference 2">CAS</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=Angiostatin%3A%20a%20novel%20angiogenesis%20inhibitor%20that%20mediates%20the%20supression%20of%20metastases%20by%20a%20lewis%20lung%20carcinoma&journal=Cell&doi=10.1016%2F0092-8674%2894%2990200-3&volume=79&pages=315-328&publication_year=1994&author=O%27Reilly%2CMS"> 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">O'Reilly, M.S. et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. <i>Cell</i> <b>88</b>, 277–285 (1997).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0092-8674(00)81848-6" data-track-item_id="10.1016/S0092-8674(00)81848-6" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0092-8674%2800%2981848-6" aria-label="Article reference 3" data-doi="10.1016/S0092-8674(00)81848-6">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:DyaK2sXpsFSktQ%3D%3D" aria-label="CAS reference 3">CAS</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=Endostatin%3A%20an%20endogenous%20inhibitor%20of%20angiogenesis%20and%20tumor%20growth&journal=Cell&doi=10.1016%2FS0092-8674%2800%2981848-6&volume=88&pages=277-285&publication_year=1997&author=O%27Reilly%2CMS"> 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">Millauer, B., Shawver, L.K., Plate, K.H., Risau, W. & Ullrich, A. Glioblastoma growth inhibited <i>in vivo</i> by a dominant negative Flk-1 mutant. <i>Nature</i> <b>367</b>, 576–579 (1994).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/367576a0" data-track-item_id="10.1038/367576a0" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2F367576a0" aria-label="Article reference 4" data-doi="10.1038/367576a0">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:DyaK2cXhs1Sgt7w%3D" aria-label="CAS reference 4">CAS</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=Glioblastoma%20growth%20inhibited%20in%20vivo%20by%20a%20dominant%20negative%20Flk-1%20mutant&journal=Nature&doi=10.1038%2F367576a0&volume=367&pages=576-579&publication_year=1994&author=Millauer%2CB&author=Shawver%2CLK&author=Plate%2CKH&author=Risau%2CW&author=Ullrich%2CA"> 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">Millauer, B. et al. Dominant-negative inhibition of Flk-1 suppresses the growth of many tumor types <i>in vivo</i>. <i>Cancer Res.</i> <b>56</b>, 1615–1620 (1996).</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:DyaK28XitVemtr4%3D" 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=8603410" 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=Dominant-negative%20inhibition%20of%20Flk-1%20suppresses%20the%20growth%20of%20many%20tumor%20types%20in%20vivo&journal=Cancer%20Res.&volume=56&pages=1615-1620&publication_year=1996&author=Millauer%2CB"> 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">Kim, K.J. et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth <i>in vivo</i>. <i>Nature</i> <b>362</b>, 841–844 (1993).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1038/362841a0" data-track-item_id="10.1038/362841a0" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1038%2F362841a0" aria-label="Article reference 6" data-doi="10.1038/362841a0">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:DyaK3sXktVKju7s%3D" aria-label="CAS reference 6">CAS</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=Inhibition%20of%20vascular%20endothelial%20growth%20factor-induced%20angiogenesis%20suppresses%20tumour%20growth%20in%20vivo&journal=Nature&doi=10.1038%2F362841a0&volume=362&pages=841-844&publication_year=1993&author=Kim%2CKJ"> 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">Saleh, M., Stacker, S.A. & Wilks, A.F. Inhibition of growth of C6 glioma cells <i>in vivo</i> by expression of antisense vascular endothelial growth factor sequence. <i>Cancer Res.</i> <b>56</b>, 393–401 (1996).</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:DyaK28XmtVGlsg%3D%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=8542597" 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=Inhibition%20of%20growth%20of%20C6%20glioma%20cells%20in%20vivo%20by%20expression%20of%20antisense%20vascular%20endothelial%20growth%20factor%20sequence&journal=Cancer%20Res.&volume=56&pages=393-401&publication_year=1996&author=Saleh%2CM&author=Stacker%2CSA&author=Wilks%2CAF"> 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">Achen, M.G. et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk-1) and VEGF receptor 3 (Flt-4). <i>Proc. Natl. Acad. Sci. USA</i> <b>95</b>, 548–553 (1998).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1073/pnas.95.2.548" data-track-item_id="10.1073/pnas.95.2.548" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1073%2Fpnas.95.2.548" aria-label="Article reference 8" data-doi="10.1073/pnas.95.2.548">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:DyaK1cXmtFWqsg%3D%3D" aria-label="CAS reference 8">CAS</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=Vascular%20endothelial%20growth%20factor%20D%20%28VEGF-D%29%20is%20a%20ligand%20for%20the%20tyrosine%20kinases%20VEGF%20receptor%202%20%28Flk-1%29%20and%20VEGF%20receptor%203%20%28Flt-4%29&journal=Proc.%20Natl.%20Acad.%20Sci.%20USA&doi=10.1073%2Fpnas.95.2.548&volume=95&pages=548-553&publication_year=1998&author=Achen%2CMG"> 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">Orlandini, M., Marconcini, L., Ferruzzi, R. & Oliviero, S. Identification of a C-<i>Fos</i>-induced gene that is related to the platelet-derived growth factor/vascular endothelial growth factor family. <i>Proc. Natl. Acad. Sci. USA</i> <b>93</b>, 11675–11680 (1996).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1073/pnas.93.21.11675" data-track-item_id="10.1073/pnas.93.21.11675" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1073%2Fpnas.93.21.11675" aria-label="Article reference 9" data-doi="10.1073/pnas.93.21.11675">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:DyaK28Xmtlansr8%3D" aria-label="CAS reference 9">CAS</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=Identification%20of%20a%20C-Fos-induced%20gene%20that%20is%20related%20to%20the%20platelet-derived%20growth%20factor%2Fvascular%20endothelial%20growth%20factor%20family&journal=Proc.%20Natl.%20Acad.%20Sci.%20USA&doi=10.1073%2Fpnas.93.21.11675&volume=93&pages=11675-11680&publication_year=1996&author=Orlandini%2CM&author=Marconcini%2CL&author=Ferruzzi%2CR&author=Oliviero%2CS"> 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">Kaipainen, A. et al. Expression of the Fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. <i>Proc. Natl. Acad. Sci. USA</i> <b>92</b>, 3566–3570 (1995).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1073/pnas.92.8.3566" data-track-item_id="10.1073/pnas.92.8.3566" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1073%2Fpnas.92.8.3566" aria-label="Article reference 10" data-doi="10.1073/pnas.92.8.3566">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:DyaK2MXltFSmsLg%3D" aria-label="CAS reference 10">CAS</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=Expression%20of%20the%20Fms-like%20tyrosine%20kinase%204%20gene%20becomes%20restricted%20to%20lymphatic%20endothelium%20during%20development&journal=Proc.%20Natl.%20Acad.%20Sci.%20USA&doi=10.1073%2Fpnas.92.8.3566&volume=92&pages=3566-3570&publication_year=1995&author=Kaipainen%2CA"> 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">Taipale, J. et al. Vascular endothelial growth factor receptor-3. <i>Curr. Top. Microbiol. Immunol.</i> <b>237</b>, 85–96 (1999).</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:DyaK1MXitVKgsA%3D%3D" aria-label="CAS reference 11">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=9893347" 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=Vascular%20endothelial%20growth%20factor%20receptor-3&journal=Curr.%20Top.%20Microbiol.%20Immunol.&volume=237&pages=85-96&publication_year=1999&author=Taipale%2CJ"> 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">Dukes, C.E. The classification of cancer of the rectum. <i>J. Pathol.</i> <b>35</b>, 323–332 (1932).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/path.1700350303" data-track-item_id="10.1002/path.1700350303" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fpath.1700350303" aria-label="Article reference 12" data-doi="10.1002/path.1700350303">Article</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=The%20classification%20of%20cancer%20of%20the%20rectum&journal=J.%20Pathol.&doi=10.1002%2Fpath.1700350303&volume=35&pages=323-332&publication_year=1932&author=Dukes%2CCE"> 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">Fisher, B. et al. Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update. <i>Cancer</i> <b>52</b>, 1551–1557 (1983).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/1097-0142(19831101)52:9<1551::AID-CNCR2820520902>3.0.CO;2-3" data-track-item_id="10.1002/1097-0142(19831101)52:9<1551::AID-CNCR2820520902>3.0.CO;2-3" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F1097-0142%2819831101%2952%3A9%3C1551%3A%3AAID-CNCR2820520902%3E3.0.CO%3B2-3" aria-label="Article reference 13" data-doi="10.1002/1097-0142(19831101)52:9<1551::AID-CNCR2820520902>3.0.CO;2-3">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:DyaL2c%2FgtFyhtQ%3D%3D" aria-label="CAS reference 13">CAS</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=Relation%20of%20number%20of%20positive%20axillary%20nodes%20to%20the%20prognosis%20of%20patients%20with%20primary%20breast%20cancer.%20An%20NSABP%20update&journal=Cancer&doi=10.1002%2F1097-0142%2819831101%2952%3A9%3C1551%3A%3AAID-CNCR2820520902%3E3.0.CO%3B2-3&volume=52&pages=1551-1557&publication_year=1983&author=Fisher%2CB"> 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">Stacker, S.A. & Achen, M.G. The vascular endothelial growth factor family: signaling for vascular development. <i>Growth Factors</i> <b>17</b>, 1–11 (1999).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3109/08977199909001058" data-track-item_id="10.3109/08977199909001058" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3109%2F08977199909001058" aria-label="Article reference 14" data-doi="10.3109/08977199909001058">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:DyaK1MvisF2ltw%3D%3D" aria-label="CAS reference 14">CAS</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=The%20vascular%20endothelial%20growth%20factor%20family%3A%20signaling%20for%20vascular%20development&journal=Growth%20Factors&doi=10.3109%2F08977199909001058&volume=17&pages=1-11&publication_year=1999&author=Stacker%2CSA&author=Achen%2CMG"> 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">Stacker, S.A. et al. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. <i>J. Biol. Chem.</i> <b>274</b>, 32127–32136 (1999).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1074/jbc.274.45.32127" data-track-item_id="10.1074/jbc.274.45.32127" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1074%2Fjbc.274.45.32127" aria-label="Article reference 15" data-doi="10.1074/jbc.274.45.32127">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:DyaK1MXnt12jtL8%3D" aria-label="CAS reference 15">CAS</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=Biosynthesis%20of%20vascular%20endothelial%20growth%20factor-D%20involves%20proteolytic%20processing%20which%20generates%20non-covalent%20homodimers&journal=J.%20Biol.%20Chem.&doi=10.1074%2Fjbc.274.45.32127&volume=274&pages=32127-32136&publication_year=1999&author=Stacker%2CSA"> 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">Achen, M.G. et al. Monoclonal antibodies to vascular endothelial growth factor-D block interactions with both VEGF receptor-2 and VEGF receptor-3. <i>Eur.J.Biochem.</i> <b>267</b>, 2505–2515 (2000).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1046/j.1432-1327.2000.01257.x" data-track-item_id="10.1046/j.1432-1327.2000.01257.x" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1046%2Fj.1432-1327.2000.01257.x" aria-label="Article reference 16" data-doi="10.1046/j.1432-1327.2000.01257.x">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%2BD3cXjtlKjurc%3D" aria-label="CAS reference 16">CAS</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=Monoclonal%20antibodies%20to%20vascular%20endothelial%20growth%20factor-D%20block%20interactions%20with%20both%20VEGF%20receptor-2%20and%20VEGF%20receptor-3&journal=Eur.J.Biochem.&doi=10.1046%2Fj.1432-1327.2000.01257.x&volume=267&pages=2505-2515&publication_year=2000&author=Achen%2CMG"> 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">Valtola, R. et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. <i>Am. J. Pathol.</i> <b>154</b>, 1381–1390 (1999).</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)65392-8" data-track-item_id="10.1016/S0002-9440(10)65392-8" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0002-9440%2810%2965392-8" aria-label="Article reference 17" data-doi="10.1016/S0002-9440(10)65392-8">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:DyaK1M3mtlektg%3D%3D" aria-label="CAS reference 17">CAS</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=VEGFR-3%20and%20its%20ligand%20VEGF-C%20are%20associated%20with%20angiogenesis%20in%20breast%20cancer&journal=Am.%20J.%20Pathol.&doi=10.1016%2FS0002-9440%2810%2965392-8&volume=154&pages=1381-1390&publication_year=1999&author=Valtola%2CR"> 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">Banerji, S. et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. <i>J. Cell Biol.</i> <b>144</b>, 789–801 (1999).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1083/jcb.144.4.789" data-track-item_id="10.1083/jcb.144.4.789" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1083%2Fjcb.144.4.789" aria-label="Article reference 18" data-doi="10.1083/jcb.144.4.789">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:DyaK1MXhvVWmsLc%3D" aria-label="CAS reference 18">CAS</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=LYVE-1%2C%20a%20new%20homologue%20of%20the%20CD44%20glycoprotein%2C%20is%20a%20lymph-specific%20receptor%20for%20hyaluronan&journal=J.%20Cell%20Biol.&doi=10.1083%2Fjcb.144.4.789&volume=144&pages=789-801&publication_year=1999&author=Banerji%2CS"> 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">de Waal, R.M.W. et al. Lack of lymphangiogenesis in human primary cutaneous melanoma. Consequences for the mechanism of lymphatic dissemination. <i>Am. J. Pathol.</i> <b>150</b>, 1951–1957 (1997).</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:DyaK2szhvFCrtA%3D%3D" 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=9176389" aria-label="PubMed reference 19">PubMed</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/PMC1858323" aria-label="PubMed Central reference 19">PubMed Central</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=Lack%20of%20lymphangiogenesis%20in%20human%20primary%20cutaneous%20melanoma.%20Consequences%20for%20the%20mechanism%20of%20lymphatic%20dissemination&journal=Am.%20J.%20Pathol.&volume=150&pages=1951-1957&publication_year=1997&author=de%20Waal%2CRMW"> 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">Prewett, M. et al. Antivascular endothelial growth factor receptor (fetal liver kinase 1) monoclonal antibody inhibits tumor angiogenesis and growth of several mouse and human tumors. <i>Cancer Res.</i> <b>59</b>, 5209–5218 (1999).</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:DyaK1MXmvFelsLo%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=10537299" 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=Antivascular%20endothelial%20growth%20factor%20receptor%20%28fetal%20liver%20kinase%201%29%20monoclonal%20antibody%20inhibits%20tumor%20angiogenesis%20and%20growth%20of%20several%20mouse%20and%20human%20tumors&journal=Cancer%20Res.&volume=59&pages=5209-5218&publication_year=1999&author=Prewett%2CM"> 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">Whiteside, T.L. & Herberman, R.B. The role of natural killer cells in immune surveillance of cancer. <i>Curr. Opin. Immunol.</i> <b>7</b>, 704–710 (1995).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/0952-7915(95)80080-8" data-track-item_id="10.1016/0952-7915(95)80080-8" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2F0952-7915%2895%2980080-8" aria-label="Article reference 21" data-doi="10.1016/0952-7915(95)80080-8">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:DyaK2MXpt1yju7o%3D" aria-label="CAS reference 21">CAS</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=The%20role%20of%20natural%20killer%20cells%20in%20immune%20surveillance%20of%20cancer&journal=Curr.%20Opin.%20Immunol.&doi=10.1016%2F0952-7915%2895%2980080-8&volume=7&pages=704-710&publication_year=1995&author=Whiteside%2CTL&author=Herberman%2CRB"> 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">Vujanovic, N.L., Basse, P., Herberman, R.B. & Whiteside, T.L. Antitumor functions of natural killer cells and control of metastases. <i>Methods</i> <b>9</b>, 394–408 (1996).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1006/meth.1996.0044" data-track-item_id="10.1006/meth.1996.0044" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1006%2Fmeth.1996.0044" aria-label="Article reference 22" data-doi="10.1006/meth.1996.0044">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:DyaK28Xjt1Wmsrk%3D" aria-label="CAS reference 22">CAS</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=Antitumor%20functions%20of%20natural%20killer%20cells%20and%20control%20of%20metastases&journal=Methods&doi=10.1006%2Fmeth.1996.0044&volume=9&pages=394-408&publication_year=1996&author=Vujanovic%2CNL&author=Basse%2CP&author=Herberman%2CRB&author=Whiteside%2CTL"> 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">Babu, S., Porte, P., Klei, T.R., Shultz, L.D. & Rajan, T.V. Host NK cells are required for the growth of the human filarial parasite <i>Brugia malayi</i> in mice. <i>J. Immunol.</i> <b>161</b>, 1428–1432 (1998).</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:DyaK1cXltVehtb0%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=9686607" 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=Host%20NK%20cells%20are%20required%20for%20the%20growth%20of%20the%20human%20filarial%20parasite%20Brugia%20malayi%20in%20mice&journal=J.%20Immunol.&volume=161&pages=1428-1432&publication_year=1998&author=Babu%2CS&author=Porte%2CP&author=Klei%2CTR&author=Shultz%2CLD&author=Rajan%2CTV"> 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">Ansink, A.C. et al. Identification of sentinel lymph nodes in vulvar carcinoma patients with the aid of a Patent Blue V injection: a multicenter study. <i>Cancer</i> <b>86</b>, 652–656 (1999).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/(SICI)1097-0142(19990815)86:4<652::AID-CNCR14>3.0.CO;2-R" data-track-item_id="10.1002/(SICI)1097-0142(19990815)86:4<652::AID-CNCR14>3.0.CO;2-R" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2F%28SICI%291097-0142%2819990815%2986%3A4%3C652%3A%3AAID-CNCR14%3E3.0.CO%3B2-R" aria-label="Article reference 24" data-doi="10.1002/(SICI)1097-0142(19990815)86:4<652::AID-CNCR14>3.0.CO;2-R">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:DyaK1MzmvFOmtA%3D%3D" aria-label="CAS reference 24">CAS</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=Identification%20of%20sentinel%20lymph%20nodes%20in%20vulvar%20carcinoma%20patients%20with%20the%20aid%20of%20a%20Patent%20Blue%20V%20injection%3A%20a%20multicenter%20study&journal=Cancer&doi=10.1002%2F%28SICI%291097-0142%2819990815%2986%3A4%3C652%3A%3AAID-CNCR14%3E3.0.CO%3B2-R&volume=86&pages=652-656&publication_year=1999&author=Ansink%2CAC"> 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">Folkman, J. Anti-angiogenesis: new concepts of therapy of solid tumors. <i>Ann. Surg.</i> <b>175</b>, 409–416 (1972).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1097/00000658-197203000-00014" data-track-item_id="10.1097/00000658-197203000-00014" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1097%2F00000658-197203000-00014" aria-label="Article reference 25" data-doi="10.1097/00000658-197203000-00014">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:DyaE3s%2FitV2gtA%3D%3D" aria-label="CAS reference 25">CAS</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=Anti-angiogenesis%3A%20new%20concepts%20of%20therapy%20of%20solid%20tumors&journal=Ann.%20Surg.&doi=10.1097%2F00000658-197203000-00014&volume=175&pages=409-416&publication_year=1972&author=Folkman%2CJ"> 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">Folkman, J. & Klagsburn, M. Angiogenic factors. <i>Science</i> <b>235</b>, 442–447 (1987).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1126/science.2432664" data-track-item_id="10.1126/science.2432664" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1126%2Fscience.2432664" aria-label="Article reference 26" data-doi="10.1126/science.2432664">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:DyaL2sXps1amsQ%3D%3D" aria-label="CAS reference 26">CAS</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=Angiogenic%20factors&journal=Science&doi=10.1126%2Fscience.2432664&volume=235&pages=442-447&publication_year=1987&author=Folkman%2CJ&author=Klagsburn%2CM"> 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">Folkman, J. What is the evidence that tumors are angiogenesis dependent? <i>J. Natl. Cancer Inst.</i> <b>82</b>, 4–6 (1990).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1093/jnci/82.1.4" data-track-item_id="10.1093/jnci/82.1.4" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1093%2Fjnci%2F82.1.4" aria-label="Article reference 27" data-doi="10.1093/jnci/82.1.4">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:DyaK3c%2FnvF2qug%3D%3D" aria-label="CAS reference 27">CAS</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=What%20is%20the%20evidence%20that%20tumors%20are%20angiogenesis%20dependent%3F&journal=J.%20Natl.%20Cancer%20Inst.&doi=10.1093%2Fjnci%2F82.1.4&volume=82&pages=4-6&publication_year=1990&author=Folkman%2CJ"> 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">Folkman, J. & D'Amore, P.A. Blood vessel formation:what is its molecular basis? <i>Cell</i> <b>87</b>, 1153–1155 (1996).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1016/S0092-8674(00)81810-3" data-track-item_id="10.1016/S0092-8674(00)81810-3" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0092-8674%2800%2981810-3" aria-label="Article reference 28" data-doi="10.1016/S0092-8674(00)81810-3">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:DyaK2sXit1ClsA%3D%3D" aria-label="CAS reference 28">CAS</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=Blood%20vessel%20formation%3Awhat%20is%20its%20molecular%20basis%3F&journal=Cell&doi=10.1016%2FS0092-8674%2800%2981810-3&volume=87&pages=1153-1155&publication_year=1996&author=Folkman%2CJ&author=D%27Amore%2CPA"> 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">Wood, J.M. et al. PTK787/ZK 222584, a novel and potent inhibitor of vascular endothelial growth factor receptor tyrosine kinases, impairs vascular endothelial growth factor-induced responses and tumor growth after oral administration. <i>Cancer Res.</i> <b>60</b>, 2178–2189 (2000).</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%2BD3cXivVaksb0%3D" aria-label="CAS reference 29">CAS</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=PTK787%2FZK%20222584%2C%20a%20novel%20and%20potent%20inhibitor%20of%20vascular%20endothelial%20growth%20factor%20receptor%20tyrosine%20kinases%2C%20impairs%20vascular%20endothelial%20growth%20factor-induced%20responses%20and%20tumor%20growth%20after%20oral%20administration&journal=Cancer%20Res.&volume=60&pages=2178-2189&publication_year=2000&author=Wood%2CJM"> 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">Drevs, J. et al. Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. <i>Cancer Res.</i> <b>60</b>, 4819–4824 (2000).</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%2BD3cXmsFWhs7g%3D" aria-label="CAS reference 30">CAS</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=Effects%20of%20PTK787%2FZK%20222584%2C%20a%20specific%20inhibitor%20of%20vascular%20endothelial%20growth%20factor%20receptor%20tyrosine%20kinases%2C%20on%20primary%20tumor%2C%20metastasis%2C%20vessel%20density%2C%20and%20blood%20flow%20in%20a%20murine%20renal%20cell%20carcinoma%20model&journal=Cancer%20Res.&volume=60&pages=4819-4824&publication_year=2000&author=Drevs%2CJ"> 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">Lymboussaki, A., Achen, M.G., Stacker, S.A. & Alitalo, K. Growth factors regulating lymphatic vessels. <i>Curr. Top. Microbiol. Immunol.</i> <b>251</b>, 75–82 (2000)</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%2BD3cXnslentbY%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=11036761" 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=Growth%20factors%20regulating%20lymphatic%20vessels&journal=Curr.%20Top.%20Microbiol.%20Immunol.&volume=251&pages=75-82&publication_year=2000&author=Lymboussaki%2CA&author=Achen%2CMG&author=Stacker%2CSA&author=Alitalo%2CK"> 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">Leu, A.J., Berk, D.A., Lymboussaki, A., Alitalo, K. & Jain, R.K. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. <i>Cancer Res.</i> <b>60</b>, 4324–4327 (2000).</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%2BD3cXmsVaitbk%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=10969769" 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=Absence%20of%20functional%20lymphatics%20within%20a%20murine%20sarcoma%3A%20a%20molecular%20and%20functional%20evaluation&journal=Cancer%20Res.&volume=60&pages=4324-4327&publication_year=2000&author=Leu%2CAJ&author=Berk%2CDA&author=Lymboussaki%2CA&author=Alitalo%2CK&author=Jain%2CRK"> 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">Lymboussaki, A. et al. Expression of the vascular endothelial growth factor C receptor VEGFR-3 in lymphatic endothelium of the skin and in vascular tumors. <i>Am. J. Pathol.</i> <b>153</b>, 395–403 (1998).</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)65583-6" data-track-item_id="10.1016/S0002-9440(10)65583-6" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0002-9440%2810%2965583-6" aria-label="Article reference 33" data-doi="10.1016/S0002-9440(10)65583-6">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:DyaK1cXls1ejtr8%3D" aria-label="CAS reference 33">CAS</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=Expression%20of%20the%20vascular%20endothelial%20growth%20factor%20C%20receptor%20VEGFR-3%20in%20lymphatic%20endothelium%20of%20the%20skin%20and%20in%20vascular%20tumors&journal=Am.%20J.%20Pathol.&doi=10.1016%2FS0002-9440%2810%2965583-6&volume=153&pages=395-403&publication_year=1998&author=Lymboussaki%2CA"> 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">Joukov, V. et al. A novel vascular endothelial growth factor, VEGF-C, Is a ligand for the Flt-4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. <i>EMBO J.</i> <b>15</b>, 290–298 (1996).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.1002/j.1460-2075.1996.tb00359.x" data-track-item_id="10.1002/j.1460-2075.1996.tb00359.x" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1002%2Fj.1460-2075.1996.tb00359.x" aria-label="Article reference 34" data-doi="10.1002/j.1460-2075.1996.tb00359.x">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:DyaK28XovFSktA%3D%3D" aria-label="CAS reference 34">CAS</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=A%20novel%20vascular%20endothelial%20growth%20factor%2C%20VEGF-C%2C%20Is%20a%20ligand%20for%20the%20Flt-4%20%28VEGFR-3%29%20and%20KDR%20%28VEGFR-2%29%20receptor%20tyrosine%20kinases&journal=EMBO%20J.&doi=10.1002%2Fj.1460-2075.1996.tb00359.x&volume=15&pages=290-298&publication_year=1996&author=Joukov%2CV"> 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">Kubo, H. et al. Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis. <i>Blood</i> <b>96</b>, 546–553 (2000).</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%2BD3cXltVGhur4%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=10887117" 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=Involvement%20of%20vascular%20endothelial%20growth%20factor%20receptor-3%20in%20maintenance%20of%20integrity%20of%20endothelial%20cell%20lining%20during%20tumor%20angiogenesis&journal=Blood&volume=96&pages=546-553&publication_year=2000&author=Kubo%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">Salven, P. et al. Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. <i>Am. J. Pathol.</i> <b>153</b>, 103–108 (1998).</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)65550-2" data-track-item_id="10.1016/S0002-9440(10)65550-2" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.1016%2FS0002-9440%2810%2965550-2" aria-label="Article reference 36" data-doi="10.1016/S0002-9440(10)65550-2">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:DyaK1cXks1GrsL8%3D" aria-label="CAS reference 36">CAS</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=Vascular%20endothelial%20growth%20factors%20VEGF-B%20and%20VEGF-C%20are%20expressed%20in%20human%20tumors&journal=Am.%20J.%20Pathol.&doi=10.1016%2FS0002-9440%2810%2965550-2&volume=153&pages=103-108&publication_year=1998&author=Salven%2CP"> 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">Achen, M.G. et al. Localisation of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumour angiogenesis <i>J. Pathol.</i> (in the press).</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">Plate, K.H., Breier, G., Millauer, B., Ullrich, A. & Risau, W. Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of tumor angiogenesis. <i>Cancer Res.</i> <b>53</b>, 5822–5827 (1993).</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:DyaK2cXltFCnsg%3D%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=7694795" 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=Up-regulation%20of%20vascular%20endothelial%20growth%20factor%20and%20its%20cognate%20receptors%20in%20a%20rat%20glioma%20model%20of%20tumor%20angiogenesis&journal=Cancer%20Res.&volume=53&pages=5822-5827&publication_year=1993&author=Plate%2CKH&author=Breier%2CG&author=Millauer%2CB&author=Ullrich%2CA&author=Risau%2CW"> 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">Niki, T. et al. Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma. <i>Clin. Cancer Res.</i> <b>6</b>, 2431–2439 (2000).</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%2BD3cXksVGhsb4%3D" aria-label="CAS reference 39">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=10873096" aria-label="PubMed reference 39">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 39" href="http://scholar.google.com/scholar_lookup?&title=Expression%20of%20vascular%20endothelial%20growth%20factors%20A%2C%20B%2C%20C%2C%20and%20D%20and%20their%20relationships%20to%20lymph%20node%20status%20in%20lung%20adenocarcinoma&journal=Clin.%20Cancer%20Res.&volume=6&pages=2431-2439&publication_year=2000&author=Niki%2CT"> 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">Mandriota, S.J. et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumor metastasis. <i>EMBOJ.</i> in press (2001).</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">Layton, J.E., Iaria, J. & Nicholson, S.E. Neutralising antibodies to the granulocyte colony-stimulating factor receptor recognise both the immunoglobulin-like domain and the cytokine receptor homologous domain. <i>Growth Factors.</i> <b>14</b>, 117–130 (1997).</p><p class="c-article-references__links u-hide-print"><a data-track="click_references" rel="nofollow noopener" data-track-label="10.3109/08977199709021515" data-track-item_id="10.3109/08977199709021515" data-track-value="article reference" data-track-action="article reference" href="https://doi.org/10.3109%2F08977199709021515" aria-label="Article reference 41" data-doi="10.3109/08977199709021515">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:DyaK2szpvFCktQ%3D%3D" aria-label="CAS reference 41">CAS</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=Neutralising%20antibodies%20to%20the%20granulocyte%20colony-stimulating%20factor%20receptor%20recognise%20both%20the%20immunoglobulin-like%20domain%20and%20the%20cytokine%20receptor%20homologous%20domain&journal=Growth%20Factors.&doi=10.3109%2F08977199709021515&volume=14&pages=117-130&publication_year=1997&author=Layton%2CJE&author=Iaria%2CJ&author=Nicholson%2CSE"> 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/10.1038/84635?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>We thank T. Helman and the staff of the animal house at the Ludwig Institute for Cancer Research for assistance with the SCID mice; A. Scott and C. Hall for advice on animal tumor models; B. Mann for discussions on dye injection; M. Smyth for discussions on mouse models; S. Squinto for supplying the pAPEX vector; and A. Burgess and M. Hibbs for critical reading of this manuscript. This work was funded in part by project grants from the National Health and Medical Research Council of Australia and the Anti-Cancer Council of Victoria. D. J. is supported by the UK Medical Research Council and by a project grant (00-311) from the Association for International Cancer Research.</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">Ludwig Institute for Cancer Research, Royal Melbourne Hospital, Victoria, Australia</p><p class="c-article-author-affiliation__authors-list">Steven A. Stacker, Carol Caesar, Megan E. Baldwin, Gillian E. Thornton & Marc G. Achen</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Department of Pathology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, Victoria, Australia</p><p class="c-article-author-affiliation__authors-list">Richard A. Williams</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Nuffield Department of Medicine/MRC Human Immunology Unit, University of Oxford, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, UK</p><p class="c-article-author-affiliation__authors-list">Remko Prevo & David G. Jackson</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Department of Molecular Genetics, Graduate School of Medicine, Kyoto University, Kyoto, Japan</p><p class="c-article-author-affiliation__authors-list">Shin-ichi Nishikawa & Hajime Kubo</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, Finland</p><p class="c-article-author-affiliation__authors-list">Hajime Kubo</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-Steven_A_-Stacker-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Steven A. 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