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Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo | Anticancer Research
<!DOCTYPE html> <html lang="en" dir="ltr" xmlns="http://www.w3.org/1999/xhtml" xmlns:mml="http://www.w3.org/1998/Math/MathML"> <head prefix="og: http://ogp.me/ns# article: http://ogp.me/ns/article# book: http://ogp.me/ns/book#" > <!--[if IE]><![endif]--> <link rel="dns-prefetch" href="//cdn.jsdelivr.net" /> <link rel="dns-prefetch" href="//cdn.foxycart.com" /> <link rel="dns-prefetch" href="//scholar.google.com" /> <meta http-equiv="Content-Type" content="text/html; charset=utf-8" /> <meta name="Generator" content="Drupal 7 (http://drupal.org)" /> <link rel="canonical" href="https://ar.iiarjournals.org/content/39/11/5973" /> <link rel="alternate" type="application/pdf" title="Full Text (PDF)" href="/content/39/11/5973.full.pdf" /> <link rel="alternate" type="text/plain" title="Full Text (Plain)" href="/content/39/11/5973.full.txt" /> <link rel="alternate" type="application/vnd.ms-powerpoint" title="Powerpoint" href="/content/39/11/5973.ppt" /> <meta name="issue_cover_image" content="https://ar.iiarjournals.org/sites/default/files/highwire/default/covers/acr_default_cover_0.gif" /> <meta name="type" content="article" /> <meta name="category" content="research-article" /> <meta name="HW.identifier" content="/anticanres/39/11/5973.atom" /> <meta name="HW.pisa" content="anticanres;39/11/5973" /> <meta name="DC.Format" content="text/html" /> <meta name="DC.Language" content="en" /> <meta name="DC.Title" content="Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo" /> <meta name="DC.Identifier" content="10.21873/anticanres.13802" /> <meta name="DC.Date" content="2019-11-01" /> <meta name="DC.Publisher" content="International Institute of Anticancer Research" /> <meta name="DC.Rights" content="Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved" /> <meta name="DC.AccessRights" content="restricted" /> <meta name="DC.Description" content="Background/Aim: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. Materials and Methods: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. Results: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. Conclusion: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells." /> <meta name="DC.Contributor" content="SACHIKO OGASAWARA" /> <meta name="DC.Contributor" content="YUTARO MIHARA" /> <meta name="DC.Contributor" content="REIICHIRO KONDO" /> <meta name="DC.Contributor" content="HIRONORI KUSANO" /> <meta name="DC.Contributor" content="JUN AKIBA" /> <meta name="DC.Contributor" content="HIROHISA YANO" /> <meta name="article:published_time" content="2019-11-01" /> <meta name="article:section" content="Experimental Studies" /> <meta name="citation_title" content="Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo" /> <meta name="citation_abstract" lang="en" content="<p>Background/Aim: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. Materials and Methods: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. Results: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. Conclusion: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells.</p>" /> <meta name="citation_journal_title" content="Anticancer Research" /> <meta name="citation_publisher" content="International Institute of Anticancer Research" /> <meta name="citation_publication_date" content="2019/11/01" /> <meta name="citation_mjid" content="anticanres;39/11/5973" /> <meta name="citation_id" content="39/11/5973" /> <meta name="citation_public_url" content="https://ar.iiarjournals.org/content/39/11/5973" /> <meta name="citation_abstract_html_url" content="https://ar.iiarjournals.org/content/39/11/5973.abstract" /> <meta name="citation_full_html_url" content="https://ar.iiarjournals.org/content/39/11/5973.full" /> <meta name="citation_pdf_url" content="https://ar.iiarjournals.org/content/anticanres/39/11/5973.full.pdf" /> <meta name="citation_issn" content="0250-7005" /> <meta name="citation_issn" content="1791-7530" /> <meta name="citation_doi" content="10.21873/anticanres.13802" /> <meta name="citation_pmid" content="31704822" /> <meta name="citation_volume" content="39" /> <meta name="citation_issue" content="11" /> <meta name="citation_article_type" content="Research Article" /> <meta name="citation_section" content="Experimental Studies" /> <meta name="citation_firstpage" content="5973" /> <meta name="citation_lastpage" content="5982" /> <meta name="citation_author" content="SACHIKO OGASAWARA" /> <meta name="citation_author_institution" content="Department of Pathology, Kurume University School of Medicine, Kurume, Japan" /> <meta name="citation_author_email" content="sachiko@med.kurume-u.ac.jp" /> <meta name="citation_author" content="YUTARO MIHARA" /> <meta name="citation_author_institution" content="Department of Pathology, Kurume University School of Medicine, Kurume, Japan" /> <meta name="citation_author" content="REIICHIRO KONDO" /> <meta name="citation_author_institution" content="Department of Pathology, Kurume University School of Medicine, Kurume, Japan" /> <meta name="citation_author" content="HIRONORI KUSANO" /> <meta name="citation_author_institution" content="Department of Pathology, Kurume University School of Medicine, Kurume, Japan" /> <meta name="citation_author" content="JUN AKIBA" /> <meta name="citation_author_institution" content="Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan" /> <meta name="citation_author" content="HIROHISA YANO" /> <meta name="citation_author_institution" content="Department of Pathology, Kurume University School of Medicine, Kurume, Japan" /> <meta name="citation_reference" content="citation_journal_title=Int J Cancer;citation_author=J. Ferlay;citation_author=I. Soerjomataram;citation_author=R. Dikshit;citation_author=S. Eser;citation_author=C. Mathers;citation_author=M. Rebelo;citation_author=DM. Parkin;citation_author=D. Forman;citation_author=F. Bray;citation_title=Cancer incidence and mortality worldwide: Sources, methods and major patterns in globocan 2012;citation_pages=E359-386;citation_volume=136;citation_year=2015;citation_issue=5;citation_pmid=25220842;citation_doi=10.1002/ijc.29210" /> <meta name="citation_reference" content="citation_journal_title=CA Cancer J Clin;citation_author=LA. Torre;citation_author=F. Bray;citation_author=RL. Siegel;citation_author=J. Ferlay;citation_author=J. Lortet-Tieulent;citation_author=A. Jemal;citation_title=Global cancer statistics, 2012;citation_pages=87-108;citation_volume=65;citation_year=2015;citation_issue=2;citation_pmid=25651787;citation_doi=10.3322/caac.21262" /> <meta name="citation_reference" content="citation_journal_title=Journal of hepatology;citation_journal_abbrev=J Hepatol;citation_author=D. Semela;citation_author=JF. Dufour;citation_title=Angiogenesis and hepatocellular carcinoma.;citation_pages=864-880;citation_volume=41;citation_year=2004;citation_issue=5;citation_pmid=15519663;citation_doi=10.1016/j.jhep.2004.09.006" /> <meta name="citation_reference" content="citation_journal_title=Cancer Research;citation_journal_abbrev=Cancer Res.;citation_author=SM. Wilhelm;citation_author=C. Carter;citation_author=L. Tang;citation_author=D. Wilkie;citation_author=A. McNabola;citation_author=H. Rong;citation_author=C. Chen;citation_author=X. Zhang;citation_author=P. Vincent;citation_author=M. McHugh;citation_author=Y. Cao;citation_author=J. Shujath;citation_author=S. Gawlak;citation_author=D. Eveleigh;citation_author=B. Rowley;citation_author=L. Liu;citation_author=L. Adnane;citation_author=M. Lynch;citation_author=D. Auclair;citation_author=I. Taylor;citation_author=R. Gedrich;citation_author=A. Voznesensky;citation_author=B. Riedl;citation_author=LE. Post;citation_author=G. Bollag;citation_author=PA. Trail;citation_title=BAY 43-9006 Exhibits Broad Spectrum Oral Antitumor Activity and Targets the RAF/MEK/ERK Pathway and Receptor Tyrosine Kinases Involved in Tumor Progression and Angiogenesis;citation_pages=7099-7109;citation_volume=64;citation_year=2004;citation_issue=19;citation_pmid=15466206;citation_doi=10.1158/0008-5472.CAN-04-1443" /> <meta name="citation_reference" content="citation_journal_title=J Thyroid Res;citation_author=O. Tohyama;citation_author=J. Matsui;citation_author=K. Kodama;citation_author=N. Hata-Sugi;citation_author=T. Kimura;citation_author=K. Okamoto;citation_author=Y. Minoshima;citation_author=M. Iwata;citation_author=Y. Funahashi;citation_title=Antitumor activity of lenvatinib (e7080): An angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models;citation_pages=638747;citation_volume=2014;citation_year=2014;citation_pmid=25295214;citation_doi=10.1155/2014/638747" /> <meta name="citation_reference" content="citation_journal_title=New England Journal of Medicine;citation_journal_abbrev=NEJM;citation_author=JM. Llovet;citation_author=S. Ricci;citation_author=V. Mazzaferro;citation_author=P. Hilgard;citation_author=E. Gane;citation_author=JF. Blanc;citation_author=AC. de Oliveira;citation_author=A. Santoro;citation_author=JL. Raoul;citation_author=A. Forner;citation_author=M. Schwartz;citation_author=C. Porta;citation_author=S. Zeuzem;citation_author=L. Bolondi;citation_author=TF. Greten;citation_author=PR. Galle;citation_author=JF. Seitz;citation_author=I. Borbath;citation_author=D. Haussinger;citation_author=T. Giannaris;citation_author=M. Shan;citation_author=M. Moscovici;citation_author=D. Voliotis;citation_author=J. Bruix;citation_title=Sorafenib in Advanced Hepatocellular Carcinoma;citation_pages=378-390;citation_volume=359;citation_year=2008;citation_issue=4;citation_pmid=18650514;citation_doi=10.1056/NEJMoa0708857" /> <meta name="citation_reference" content="citation_journal_title=The lancet oncology;citation_journal_abbrev=Lancet Oncol;citation_author=A-L. Cheng;citation_author=Y-K. Kang;citation_author=Z. Chen;citation_author=C-J. Tsao;citation_author=S. Qin;citation_author=JS. Kim;citation_author=R. Luo;citation_author=J. Feng;citation_author=S. Ye;citation_author=T-S. Yang;citation_author=J. Xu;citation_author=Y. Sun;citation_author=H. Liang;citation_author=J. Liu;citation_author=J. Wang;citation_author=WY. Tak;citation_author=H. Pan;citation_author=K. Burock;citation_author=J. Zou;citation_author=D. Voliotis;citation_author=Z. Guan;citation_title=Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial.;citation_pages=25-34;citation_volume=10;citation_year=2009;citation_issue=1;citation_pmid=19095497;citation_doi=10.1016/S1470-2045(08)70285-7" /> <meta name="citation_reference" content="citation_journal_title=J Clin Oncol;citation_author=AL. Cheng;citation_author=YK. Kang;citation_author=DY. Lin;citation_author=JW. Park;citation_author=M. Kudo;citation_author=S. Qin;citation_author=HC. Chung;citation_author=X. Song;citation_author=J. Xu;citation_author=G. Poggi;citation_author=M. Omata;citation_author=S. Pitman Lowenthal;citation_author=S. Lanzalone;citation_author=L. Yang;citation_author=MJ. Lechuga;citation_author=E. Raymond;citation_title=Sunitinib versus sorafenib in advanced hepatocellular cancer: Results of a randomized phase III trial;citation_volume=31;citation_year=2013;citation_issue=32;citation_pmid=24081937;citation_doi=10.1200/JCO.2012.45.8372" /> <meta name="citation_reference" content="citation_journal_title=J Clin Oncol;citation_author=PJ. Johnson;citation_author=S. Qin;citation_author=JW. Park;citation_author=RT. Poon;citation_author=JL. Raoul;citation_author=PA. Philip;citation_author=CH. Hsu;citation_author=TH. Hu;citation_author=J. Heo;citation_author=J. Xu;citation_author=L. Lu;citation_author=Y. Chao;citation_author=E. Boucher;citation_author=KH. Han;citation_author=SW. Paik;citation_author=J. Robles-Avina;citation_author=M. Kudo;citation_author=L. Yan;citation_author=A. Sobhonslidsuk;citation_author=D. Komov;citation_author=T. Decaens;citation_author=WY. Tak;citation_author=LB. Jeng;citation_author=D. Liu;citation_author=R. Ezzeddine;citation_author=I. Walters;citation_author=AL. Cheng;citation_title=Brivanib versus sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: Results from the randomized phase III BRISK-FL study;citation_volume=31;citation_year=2013;citation_issue=28;citation_pmid=23980084;citation_doi=10.1200/JCO.2012.48.4410" /> <meta name="citation_reference" content="citation_journal_title=J Clin Oncol;citation_author=C. Cainap;citation_author=S. Qin;citation_author=WT. Huang;citation_author=IJ. Chung;citation_author=H. Pan;citation_author=Y. Cheng;citation_author=M. Kudo;citation_author=YK. Kang;citation_author=PJ. Chen;citation_author=HC. Toh;citation_author=V. Gorbunova;citation_author=FA. Eskens;citation_author=J. Qian;citation_author=MD. McKee;citation_author=JL. Ricker;citation_author=DM. Carlson;citation_author=S. El-Nowiem;citation_title=Linifanib versus sorafenib in patients with advanced hepatocellular carcinoma: Results of a randomized phase III trial;citation_volume=33;citation_year=2015;citation_issue=2;citation_pmid=25488963;citation_doi=10.1200/JCO.2013.54.3298" /> <meta name="citation_reference" content="citation_journal_title=J Clin Oncol;citation_author=AX. Zhu;citation_author=O. Rosmorduc;citation_author=TR. Evans;citation_author=PJ. Ross;citation_author=A. Santoro;citation_author=FJ. Carrilho;citation_author=J. Bruix;citation_author=S. Qin;citation_author=PJ. Thuluvath;citation_author=JM. Llovet;citation_author=MA. Leberre;citation_author=M. Jensen;citation_author=G. Meinhardt;citation_author=YK. Kang;citation_title=Search: A phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma;citation_volume=33;citation_year=2015;citation_issue=6;citation_pmid=25547503;citation_doi=10.1200/JCO.2013.53.7746" /> <meta name="citation_reference" content="citation_journal_title=Clinical Cancer Research;citation_journal_abbrev=Clin. Cancer Res.;citation_author=J. Matsui;citation_author=Y. Funahashi;citation_author=T. Uenaka;citation_author=T. Watanabe;citation_author=A. Tsuruoka;citation_author=M. Asada;citation_title=Multi-Kinase Inhibitor E7080 Suppresses Lymph Node and Lung Metastases of Human Mammary Breast Tumor MDA-MB-231 via Inhibition of Vascular Endothelial Growth Factor-Receptor (VEGF-R) 2 and VEGF-R3 Kinase;citation_pages=5459-5465;citation_volume=14;citation_year=2008;citation_issue=17;citation_pmid=18765537;citation_doi=10.1158/1078-0432.CCR-07-5270" /> <meta name="citation_reference" content="citation_journal_title=Vasc Cell;citation_author=Y. Yamamoto;citation_author=J. Matsui;citation_author=T. Matsushima;citation_author=H. Obaishi;citation_author=K. Miyazaki;citation_author=K. Nakamura;citation_author=O. Tohyama;citation_author=T. Semba;citation_author=A. Yamaguchi;citation_author=SS. Hoshi;citation_author=F. Mimura;citation_author=T. Haneda;citation_author=Y. Fukuda;citation_author=JI. Kamata;citation_author=K. Takahashi;citation_author=M. Matsukura;citation_author=T. Wakabayashi;citation_author=M. Asada;citation_author=KI. Nomoto;citation_author=T. Watanabe;citation_author=Z. Dezso;citation_author=K. Yoshimatsu;citation_author=Y. Funahashi;citation_author=A. Tsuruoka;citation_title=Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage;citation_pages=18;citation_volume=6;citation_year=2014;citation_pmid=25197551;citation_doi=10.1186/2045-824X-6-18" /> <meta name="citation_reference" content="citation_journal_title=Lancet;citation_author=M. Kudo;citation_author=RS. Finn;citation_author=S. Qin;citation_author=KH. Han;citation_author=K. Ikeda;citation_author=F. Piscaglia;citation_author=A. Baron;citation_author=JW. Park;citation_author=G. Han;citation_author=J. Jassem;citation_author=JF. Blanc;citation_author=A. Vogel;citation_author=D. Komov;citation_author=TRJ. Evans;citation_author=C. Lopez;citation_author=C. Dutcus;citation_author=M. Guo;citation_author=K. Saito;citation_author=S. Kraljevic;citation_author=T. Tamai;citation_author=M. Ren;citation_author=AL. Cheng;citation_title=Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial;citation_pages=1163-1173;citation_volume=391;citation_year=2018;citation_issue=10126;citation_pmid=29433850;citation_doi=10.1016/S0140-6736(18)30207-1" /> <meta name="citation_reference" content="citation_journal_title=Act Hepatol Jpn;citation_author=T. Murakami;citation_title=Establishment and characterization of human hepatoma cell line (KIM-1);citation_pages=532-539;citation_volume=25;citation_year=1984" /> <meta name="citation_reference" content="citation_journal_title=Acta pathologica japonica;citation_journal_abbrev=Acta Pathol Jpn;citation_author=H. Yano;citation_author=M. Maruiwa;citation_author=T. Murakami;citation_author=K. Fukuda;citation_author=Y. Ito;citation_author=S. Sugihara;citation_author=M. Kojiro;citation_title=A new human pleomorphic hepatocellular carcinoma cell line, KYN-2.;citation_pages=953-966;citation_volume=38;citation_year=1988;citation_issue=8;citation_pmid=2847482;citation_doi=10.1111/j.1440-1827.1988.tb02368.x" /> <meta name="citation_reference" content="citation_journal_title=Jpn J Cancer Res Proc Jpn Cancer Assoc;citation_title=Establishment and characterization of a new human hepatoma cell line (KYN-3) derived from the ascites of the hepatoma patient (Abstract);citation_author=T. Murakami;citation_author=M. Maruiwa;citation_author=K. Fukuda;citation_author=M. Kojiro;citation_author=M. Tanaka;citation_author=K. Tanikawa;citation_pages=292;citation_year=1988" /> <meta name="citation_reference" content="citation_journal_title=Hepatology (Baltimore, Md.);citation_journal_abbrev=Hepatology;citation_author=H. Yano;citation_author=A. Iemura;citation_author=K. Fukuda;citation_author=A. Mizoguchi;citation_author=M. Haramaki;citation_author=M. Kojiro;citation_title=Establishment of two distinct human hepatocellular carcinoma cell lines from a single nodule showing clonal dedifferentiation of cancer cells;citation_pages=320-327;citation_volume=18;citation_year=1993;citation_issue=2;citation_pmid=8393423;citation_doi=10.1016/0270-9139(93)90015-F" /> <meta name="citation_reference" content="citation_journal_title=Human cell : official journal of Human Cell Research Society;citation_journal_abbrev=Hum Cell;citation_author=M. Haramaki;citation_author=H. Yano;citation_author=A. Iemura;citation_author=S. Momosaki;citation_author=S. Ogasawara;citation_author=M. Inoue;citation_author=R. Yamaguchi;citation_author=A. Kusaba;citation_author=I. Utsunomiya;citation_author=M. Kojiro;citation_title=A new human hepatocellular carcinoma cell line (HAK-2) forms various structures in collagen gel matrices.;citation_pages=183-192;citation_volume=10;citation_year=1997;citation_issue=3;citation_pmid=9436038" /> <meta name="citation_reference" content="citation_journal_title=International journal of oncology;citation_journal_abbrev=Int J Oncol;citation_author=I. Utsunomiya;citation_author=A. Iemura;citation_author=H. Yano;citation_author=J. Akiba;citation_author=M. Kojiro;citation_title=Establishment and characterization of a new human hepatocellular carcinoma cell line, HAK-3, and its response to growth factors.;citation_pages=669-675;citation_volume=15;citation_year=1999;citation_issue=4;citation_pmid=10493947;citation_doi=10.3892/ijo.15.4.669" /> <meta name="citation_reference" content="citation_journal_title=Hepatology (Baltimore, Md.);citation_journal_abbrev=Hepatology;citation_author=T. Murakami;citation_author=H. Yano;citation_author=M. Maruiwa;citation_author=S. Sugihara;citation_author=M. Kojiro;citation_title=Establishment and characterization of a human combined hepatocholangiocarcinoma cell line and its heterologous transplantation in nude mice;citation_pages=551-556;citation_volume=7;citation_year=1987;citation_issue=3;citation_pmid=3032760;citation_doi=10.1002/hep.1840070322" /> <meta name="citation_reference" content="citation_journal_title=Journal of hepatology;citation_journal_abbrev=J Hepatol;citation_author=H. Yano;citation_author=A. Iemura;citation_author=M. Haramaki;citation_author=S. Momosaki;citation_author=S. Ogasawara;citation_author=K. Higaki;citation_author=M. Kojiro;citation_title=A human combined hepatocellular and cholangiocarcinoma cell line (KMCH-2) that shows the features of hepatocellular carcinoma or cholangiocarcinoma under different growth conditions.;citation_pages=413-422;citation_volume=24;citation_year=1996;citation_issue=4;citation_pmid=8738727;citation_doi=10.1016/s0168-8278(96)80161-9" /> <meta name="citation_reference" content="citation_journal_title=Hepatology (Baltimore, Md.);citation_journal_abbrev=Hepatology;citation_author=S. Ogasawara;citation_author=H. Yano;citation_author=A. Iemura;citation_author=T. Hisaka;citation_author=M. 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Patel;citation_author=CJ. Ren;citation_author=A. Gualandris;citation_author=G. Pintucci;citation_author=ES. Robbins;citation_author=RL. Shapiro;citation_author=AC. Galloway;citation_author=DB. Rifkin;citation_author=P. Mignatti;citation_title=Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: An autocrine mechanism contributing to angiogenesis;citation_volume=141;citation_year=1998;citation_issue=7;citation_pmid=9647657;citation_doi=10.1083/jcb.141.7.1659" /> <meta name="twitter:title" content="Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo" /> <meta name="twitter:card" content="summary_large_image" /> <meta name="twitter:image" content="https://ar.iiarjournals.org/sites/default/files/highwire/default/covers/acr_default_cover_0.gif" /> <meta name="twitter:description" content="Background/Aim: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. Materials and Methods: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. Results: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. Conclusion: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells." /> <meta name="og-title" property="og:title" content="Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo" /> <meta name="og-url" property="og:url" content="https://ar.iiarjournals.org/content/39/11/5973" /> <meta name="og-site-name" property="og:site_name" content="Anticancer Research" /> <meta name="og-description" property="og:description" content="Background/Aim: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. Materials and Methods: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. Results: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. Conclusion: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells." /> <meta name="og-type" property="og:type" content="article" /> <meta name="og-image" property="og:image" content="https://ar.iiarjournals.org/sites/default/files/highwire/default/covers/acr_default_cover_0.gif" /> <link rel="shortlink" href="/node/56184" /> <link rel="shortcut icon" href="https://ar.iiarjournals.org/sites/default/files/images/favicon.ico" type="image/vnd.microsoft.icon" /> <meta name="viewport" content="width=device-width, initial-scale=1" /> <title>Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines In Vitro and In Vivo | Anticancer Research</title> <link type="text/css" rel="stylesheet" href="/sites/default/files/advagg_css/css__jWTA71lTJRw6O5vEuUSZ5ccEo0TzdWEFys_86eA5m-A__f_2-SlzGRsBm-tAYSTbBtIHjguGEAgw8dk4inZhqqLo__M8F9fri-b1QX8RwJbNRiWvN_bqCXCQEG9-9ZZDMJpyg.css" media="all" /> <link 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highwire-citation-highwire-article-top-a"> <div class="highwire-cite-overline"><span class="highwire-cite-metadata-article-type highwire-cite-metadata">Research Article</span><span class="separator-pipe"></span><span class="highwire-cite-metadata-art-cat highwire-cite-metadata"><span class="wrapper">Experimental Studies</span></span></div> <div class="highwire-cite-access"><span class="highwire-citation-access highwire-citation-access-check" data-pisa-id="anticanres;39/11/5973" data-atom-uri="/anticanres/39/11/5973.atom" data-request-view="full"></span></div> <h1 class="highwire-cite-title" id="page-title">Antiproliferative Effect of Lenvatinib on Human Liver Cancer Cell Lines <em>In Vitro</em> and <em>In Vivo</em></h1> <div class="highwire-cite-authors"><span class="highwire-citation-authors"><span class="highwire-citation-author first" data-delta="0">SACHIKO OGASAWARA</span>, <span class="highwire-citation-author" data-delta="1">YUTARO MIHARA</span>, <span class="highwire-citation-author" data-delta="2">REIICHIRO KONDO</span>, <span class="highwire-citation-author" data-delta="3">HIRONORI KUSANO</span>, <span class="highwire-citation-author" data-delta="4">JUN AKIBA</span> and <span class="highwire-citation-author" data-delta="5">HIROHISA YANO</span></span></div> <div class="highwire-cite-metadata"><span class="highwire-cite-metadata-journal highwire-cite-metadata">Anticancer Research </span><span class="highwire-cite-metadata-date highwire-cite-metadata">November 2019, </span><span class="highwire-cite-metadata-volume highwire-cite-metadata">39 </span><span class="highwire-cite-metadata-issue highwire-cite-metadata">(11) </span><span class="highwire-cite-metadata-pages highwire-cite-metadata">5973-5982; </span><span class="highwire-cite-metadata-doi highwire-cite-metadata">DOI: https://doi.org/10.21873/anticanres.13802 </span></div> <div class="highwire-cite-extras"><span class="highwire-foxycart-add-to-cart-ahah highwire-foxycart-add-to-cart-ahah" data-text="Add to Cart (%short-price)" data-apath="/anticanres/39/11/5973.atom" data-type="link" data-font-icon="" data-parent-id="56005"></span></div> </div> <div id="hw-article-author-popups-top-node-56184--61546303309" style="display: none;"><div class="author-tooltip-0"><div class="author-tooltip-name">SACHIKO OGASAWARA </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Department of Pathology, Kurume University School of Medicine, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=SACHIKO%2BOGASAWARA%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=OGASAWARA%20S&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link"><a href="/search/author1%3ASACHIKO%2BOGASAWARA%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li><li class="author-corresp-email-link last"><span>For correspondence: <a href="mailto:sachiko@med.kurume-u.ac.jp" class="" data-icon-position="" data-hide-link-title="0">sachiko@med.kurume-u.ac.jp</a></span></li></ul></div><div class="author-tooltip-1"><div class="author-tooltip-name">YUTARO MIHARA </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Department of Pathology, Kurume University School of Medicine, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=YUTARO%2BMIHARA%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=MIHARA%20Y&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AYUTARO%2BMIHARA%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-2"><div class="author-tooltip-name">REIICHIRO KONDO </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Department of Pathology, Kurume University School of Medicine, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=REIICHIRO%2BKONDO%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=KONDO%20R&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AREIICHIRO%2BKONDO%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-3"><div class="author-tooltip-name">HIRONORI KUSANO </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Department of Pathology, Kurume University School of Medicine, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=HIRONORI%2BKUSANO%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=KUSANO%20H&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AHIRONORI%2BKUSANO%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-4"><div class="author-tooltip-name">JUN AKIBA </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>2</span>Department of Diagnostic Pathology, Kurume University Hospital, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=JUN%2BAKIBA%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=AKIBA%20J&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AJUN%2BAKIBA%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div><div class="author-tooltip-5"><div class="author-tooltip-name">HIROHISA YANO </div><div class="author-tooltip-affiliation"><span class="author-tooltip-text"><div class='author-affiliation'><span class='nlm-sup'>1</span>Department of Pathology, Kurume University School of Medicine, Kurume, Japan</div></span></div><ul class="author-tooltip-find-more"><li class="author-tooltip-gs-link first"><a href="/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=HIROHISA%2BYANO%2B" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on Google Scholar</a></li><li class="author-tooltip-pubmed-link"><a href="/lookup/external-ref?access_num=YANO%20H&link_type=AUTHORSEARCH" target="_blank" class="" data-icon-position="" data-hide-link-title="0">Find this author on PubMed</a></li><li class="author-site-search-link last"><a href="/search/author1%3AHIROHISA%2BYANO%2B" rel="nofollow" class="" data-icon-position="" data-hide-link-title="0">Search for this author on this site</a></li></ul></div></div></div> </div> </div> </div> </div> </div> </div> <!-- /.panel-row-wrapper --> <div class="panel-row-wrapper clearfix"> <div class="main-content-wrapper grid-17 suffix-1 alpha"> <div class="panel-panel panel-region-content"> <div class="inside"><div class="panel-pane pane-highwire-panel-tabs pane-panels-ajax-tab-tabs" > <div class="pane-content"> <div class="item-list"><ul class="tabs inline panels-ajax-tab"><li class="first"><a href="/content/39/11/5973" class="panels-ajax-tab-tab" data-panel-name="jnl_iiar_tab_art" data-target-id="highwire_article_tabs" data-entity-context="node:56184" data-trigger="" data-url-enabled="1">Article</a><a href="/panels_ajax_tab/jnl_iiar_tab_art/node:56184/1" rel="nofollow" style="display:none" class="js-crawler-link"></a></li><li><a href="/content/39/11/5973/tab-figures-data" class="panels-ajax-tab-tab" data-panel-name="jnl_iiar_tab_data" data-target-id="highwire_article_tabs" data-entity-context="node:56184" data-trigger="tab-figures-data" data-url-enabled="1">Figures & Data</a><a 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class="panel-pane pane-highwire-panel-tabs-container" > <div class="pane-content"> <div data-panels-ajax-tab-preloaded="jnl_iiar_tab_art" id="panels-ajax-tab-container-highwire_article_tabs" class="panels-ajax-tab-container"><div class="panels-ajax-tab-loading" style ="display:none"><img class="loading" src="https://ar.iiarjournals.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif" alt="Loading" title="Loading" /></div><div class="panels-ajax-tab-wrap-jnl_iiar_tab_art"><div class="panel-display panel-1col clearfix" > <div class="panel-panel panel-col"> <div><div class="panel-pane pane-highwire-markup" > <div class="pane-content"> <div class="highwire-markup"><div xmlns="http://www.w3.org/1999/xhtml" data-highwire-cite-ref-tooltip-instance="highwire_reflinks_tooltip" class="content-block-markup" xmlns:xhtml="http://www.w3.org/1999/xhtml"><div class="article fulltext-view "><span class="highwire-journal-article-marker-start"></span><div class="section abstract" id="abstract-1"><h2>Abstract</h2><p id="p-3">Background/Aim: Lenvatinib is a potent inhibitor of receptor tyrosine kinases, targeting vascular endothelial growth factor receptors (VEGFR1-3), fibroblast growth factor receptors (FGFR1-4), KIT, and RET. Here, we investigated the antiproliferative effects of lenvatinib in liver cancer cells in vitro and in vivo. Materials and Methods: Eleven hepatocellular carcinoma cell lines and two combined hepatocellular/cholangiocarcinoma cell lines were treated with 0-30 μM lenvatinib. Cell growth, apoptosis and the expression of FGFR1-4, FGF19, fibroblast growth factor receptor substrate (FRS)2α and RET were examined. Two HCC cell lines were subcutaneously implanted on nude mice and mice were treated with 3, 10, 30 mg/kg/day of lenvatinib or vehicle for 14 consecutive days. Tumor volume was measured every 3 days. Mice were sacrificed on day 15 and tumors were processed for histological examination. Blood vessels, microvessel density, necrosis, and apoptosis were also examined. Results: Lenvatinib dose- and time-dependently inhibited growth of all cell lines; however, sensitivity to lenvatinib varied. Apoptosis was not observed in any cell line, and expression of FGFR1, -2, -3 and -4, FGF19, FRS2α, and RET were observed in these cell lines. Cell lines with high expression of these factors showed higher response to lenvatinib. In mice, lenvatinib dose-dependently suppressed tumor growth. Blood vessels and microvessel density were significantly reduced and the rate of necrosis was significantly increased by lenvatinib; apoptosis was not observed. Conclusion: Antiproliferative effects of lenvatinib on liver cancer cells were observed in vitro and in vivo. Lenvatinib may suppress tumor formation by inhibiting angiogenesis, and via an additional direct antiproliferative effect in some liver cancer cells.</p></div><ul class="kwd-group"><li class="kwd"><a href="/keyword/liver-cancer" class="hw-term hw-article-keyword hw-article-keyword-liver-cancer" rel="nofollow">Liver cancer</a></li><li class="kwd"><a href="/keyword/tyrosine-kinase-inhibitor" class="hw-term hw-article-keyword hw-article-keyword-tyrosine-kinase-inhibitor" rel="nofollow">tyrosine kinase inhibitor</a></li><li class="kwd"><a href="/keyword/lenvatinib" class="hw-term hw-article-keyword hw-article-keyword-lenvatinib" rel="nofollow">lenvatinib</a></li><li class="kwd"><a href="/keyword/angiogenesis" class="hw-term hw-article-keyword hw-article-keyword-angiogenesis" rel="nofollow">angiogenesis</a></li><li class="kwd"><a href="/keyword/fibroblast-growth-factor" class="hw-term hw-article-keyword hw-article-keyword-fibroblast-growth-factor" rel="nofollow">fibroblast growth factor</a></li></ul><p id="p-4">Liver cancer is one of the most prevalent and leading causes of cancer-related mortality worldwide, and has a high incidence in Asia (<a id="xref-ref-1-1" class="xref-bibr" href="#ref-1">1</a>). Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer (<a id="xref-ref-2-1" class="xref-bibr" href="#ref-2">2</a>). The major risk factors for HCC are chronic viral hepatitis (type B and C), excessive alcohol consumption, and exposure to aflatoxin and the contributions of these factors may vary depending upon geographical location.</p><p id="p-5">The progression of HCC is associated with growth factors such as vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), and fibroblast growth factor (FGF) (<a id="xref-ref-3-1" class="xref-bibr" href="#ref-3">3</a>). Sorafenib, an oral multi-kinase inhibitor targeting RAF kinase, VEGF receptors (VEGFR1-3), PDGF receptor (PDGFR), fms-like tyrosine kinase 3, RET, and KIT (<a id="xref-ref-4-1" class="xref-bibr" href="#ref-4">4</a>, <a id="xref-ref-5-1" class="xref-bibr" href="#ref-5">5</a>), was approved for first-line treatment of advanced HCC in 2007. However, the objective response rate (ORR) is low, and several studies have reported substantial toxicities associated with sorafenib (<a id="xref-ref-6-1" class="xref-bibr" href="#ref-6">6</a>, <a id="xref-ref-7-1" class="xref-bibr" href="#ref-7">7</a>). Therefore, alternative therapies that are less toxic and more efficacious are necessary. Although several tyrosine kinase inhibitors (TKIs) have been compared to sorafenib in clinical studies of patients with advanced HCC, the clinical trials did not show non-inferiority (<a id="xref-ref-8-1" class="xref-bibr" href="#ref-8">8</a>-<a id="xref-ref-10-1" class="xref-bibr" href="#ref-10">10</a>) or superiority (<a id="xref-ref-11-1" class="xref-bibr" href="#ref-11">11</a>) in prolonging survival when used as first-line treatment of HCC.</p><p id="p-6">Lenvatinib is an oral multi-kinase inhibitor that targets VEGFR1-3, FGFR1-4, PDGFR, RET, and KIT and has shown antitumor activity against advanced solid tumors (<a id="xref-ref-5-2" class="xref-bibr" href="#ref-5">5</a>, <a id="xref-ref-12-1" class="xref-bibr" href="#ref-12">12</a>, <a id="xref-ref-13-1" class="xref-bibr" href="#ref-13">13</a>). Lenvatinib has shown promising antitumor effect for the treatment of radioiodine-refractory differentiated thyroid cancer and is approved in more than 50 countries including the United States, Japan, and Europe.</p><p id="p-7">The phase III trial of lenvatinib demonstrated an effect on the overall survival (OS) of 954 patients with previously untreated unresectable HCC tumors by statistical confirmation of non-inferiority when compared to sorafenib (<a id="xref-ref-14-1" class="xref-bibr" href="#ref-14">14</a>). In this study, lenvatinib demonstrated statistically significant superiority in progression-free survival, time to progression, and ORR and was approved for the treatment of HCC in Japan, the United States, Europe, South Korea and China in 2018.</p><p id="p-8">In this study, we examined: i) The antiproliferative effects of lenvatinib on liver cancer cell lines <em>in vitro</em> and <em>in vivo</em>; ii) the protein expression of growth-related factors in liver cancer cells; and iii) the mechanism of action of lenvatinib in liver cancer cells.</p><div class="section materials-methods" id="sec-1"><h2 class="">Materials and Methods</h2><p id="p-9"><em>Cell lines and reagents.</em> This study utilized 11 HCC cell lines (KIM-1, KYN-1, KYN-2, KYN-3, HAK-1A, HAK-1B, HAK-2, HAK-3, HAK-4, HAK-5 and HAK-6) and two combined hepatocellular-cholangiocarcinoma cell lines (KMCH-1 and KMCH-2). These cell lines were originally established in our laboratory, and each cell line retains the morphological and functional features of the original tumor as described elsewhere (<a id="xref-ref-15-1" class="xref-bibr" href="#ref-15">15</a>-<a id="xref-ref-22-1" class="xref-bibr" href="#ref-22">22</a>). The cells were grown in Dulbecco's modified Eagle's medium (Nissui Pharmaceutical, Co., Tokyo, Japan) supplemented with 2.5% heat-inactivated (56°C, 30 min) fetal bovine serum (Bioserum, Victoria, NSW, Australia), 100 u/ml penicillin, 100 μg/ml streptomycin (GIBCO BRL/Life Technologies, Inc., Gaithersburg, MD, USA) and 12 mmol/l sodium bicarbonate, in an incubator with humidified atmosphere containing 5% CO<sub>2</sub> at 37°C. Lenvatinib was supplied from Eisai, Tokyo Japan.</p><p id="p-10"><em>Effects of lenvatinib on the proliferation of liver cell lines in vitro</em>. The cells (2-10×10<sup>3</sup> cells per well) were seeded in 96-well plates (Thermo Fisher Science, Roskilde, Denmark), cultured for 24 h, and the culture medium was changed to a new medium with or without lenvatinib at 1.875, 3.75, 7.5, 15 and 30 μM. After culturing for 24, 48, or 72 h, the number of viable cells was examined using the MTT cell growth assay kit (International Inc., Temecula, CA, USA). The 50% inhibitory concentration (IC<sub>50</sub>) for each cell line was estimated after 72 h of culture with lenvatinib.</p><p id="p-11"><em>Quantitative analysis of lenvatinib-induced apoptosis in vitro.</em> Cells cultured with or without lenvatinib (7.5 and 30 μM) for 48 h were stained using the Annexin V-EGFP Apoptosis Detection Kit (Medical & Biological Laboratories, Co., Ltd, Nagoya, Japan), according to the manufacturer's protocol. After staining, cells were analyzed using the FACS Aria II flow cytometer (Becton Dickinson Immunocytometry Systems, San Jose, CA, USA), and the annexin V-EGFP-positive apoptotic cells were quantified.</p><p id="p-12"><em>Expression of growth-related factors in liver cancer cell lines.</em> Western blot analysis was performed according to previously described methods (<a id="xref-ref-23-1" class="xref-bibr" href="#ref-23">23</a>). To examine the expression of growth-related factors, a sample (20 μg total protein per lane) was resolved by Any kD™ Mini-PROTEAN TGX Precast acrylamide gels (Bio-Rad, Hercules, CA, USA). The proteins were transferred to PVDF membranes (Merck, Darmstadt, Germany), which were incubated with primary antibodies against the following: FGFR1 (D8E4, 1:1000; Cell Signaling, Beverly, MA, USA), FGFR2 (D4L2V, 1:1000; Cell Signaling), FGFR3 [EPR2305(3), 1:10000; Abcam, Cambridge, MA, USA], FGFR4 (D3B12, 1:1000; Cell Signaling), FRS2 (462910, 1:500; R&D Systems, Minneapolis, MN, USA), FGF19 (D1N3R, 1:1000; Cell Signaling), RET (E1N8X, 1:1000; Cell Signaling) and β-actin (AC-15, 1:2000; Sigma-Aldrich, St. Louis, MO, USA). Blots were detected with ImmunoStar LD (Wako Pure Chemical Ind., Tokyo, Japan). Immunoreactive bands were visualized by using FluorChem™ FC3 (ProteinSimple, San Jose, CA, USA).</p><p id="p-13">Effects of lenvatinib on tumor formation of HCC cell lines in nude mice. KYN-2 cells (8×10<sup>6</sup> cells/100 μl) or HAK-1B cells (8×10<sup>6</sup> cells/100 μl) were transplanted subcutaneously into the backs of 4-week-old female BALB/c nude mice. After tumor formation was confirmed, the mice were divided into four groups (n=6 per group) and treated with 3, 10, or 30 mg/kg/day of lenvatinib or vehicle (control) administered orally for 14 consecutive days. The tumor size was measured in two directions using calipers (until day 15), and tumor volume (mm<sup>3</sup>) was estimated using the equation [length×(width)<sup>2</sup>×0.5] on every 3 days. On day 15, the mice were sacrificed and the resected tumors were weighed before formalin fixation. Paraffin sections were prepared for histological analysis.</p><p id="p-14"><em>Histological analysis.</em> Paraffin sections were stained with hematoxylin-eosin. The terminal deoxynucleotidyl transferase (Tdt)-mediated nick end labeling (TUNEL) technique (Apoptag Peroxidase In Situ Apoptosis Detection kit; Chemicon International Inc., Temecula, CA, USA) was used to detect apoptotic cells. Immunohistochemical staining with anti-mouse CD34 (Rat monoclonal, MEC14.7, 1:50 dilution; Abcam) was performed by standard avidin-biotin-peroxidase complex method and 3,3’-diaminobenzidine solution was used for color development. To quantify the number of blood vessels and microvessel density (MVD), the slides were stained with antibody to CD34. Under microscopy, five areas were selected at a high power (×200), and the number of blood vessels and the MVD in each specimen were measured using the WinROOF software package (version 6.1; Mitani Corporation, Fukui, Japan). The slides stained with hematoxylin-eosin were photographed using a loupe in the image and necrosis in the entire tumor was analyzed using the WinROOF software package.</p><p id="p-15"><em>Statistical analysis</em>. Data are expressed as the mean±standard deviation (SD). Comparisons between groups were performed using Student's <em>t</em>-test and two-way factorial analysis of variance (ANOVA); <em>p</em><0.05 was considered significant.</p><p id="p-16"><em>Ethics statement.</em> This study was approved by the Ethics Committee of Kurume University (approval 2017#319). Animal experiments for this study were approved by the Ethics Review Committee for Animal Experimentation of Kurume University School of Medicine (approval 2017#217), according to guidelines created on the basis of the ‘Guide for the Care and Use of Laboratory Animals’ prepared by the National Academy of Sciences and published by the National Institutes of Health (NIH publication 86-23 revised 1985).</p></div><div class="section results" id="sec-2"><h2 class="">Results</h2><p id="p-17"><em>Effects of lenvatinib on the proliferation of liver cell lines in vitro.</em> In all cell lines, a time-dependent antiproliferative effect was observed to various degrees upon treatment with lenvatinib for 24, 48 and 72 h in comparison to the control (<a id="xref-fig-1-1" class="xref-fig" href="#F1">Figure 1A</a>). A decrease in cell viability of at least 20% was observed in all 13 cell lines after 72 h of 30 μmol/l lenvatinib treatment. After 72 h, the relative number of viable cells decreased in every cell line in a dose-dependent manner (<a id="xref-fig-1-2" class="xref-fig" href="#F1">Figure 1B</a>). The number of viable cells at 72 h decreased to <50% of the control in eight cell lines and the IC<sub>50</sub> of lenvatinib was 5.8 μM for HAK-5, 10.4 μM for KYN-2, 12.5 μM for HAK-1A, 15.4 μM for KMCH-2, 18.2 μM for KMCH-1, 20.3 μM for KYN-1, 20.4 μM for HAK-1B, and 28.5 μM for HAK-6.</p><div id="F1" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F1.large.jpg?width=800&height=600&carousel=1" title="Antiproliferative effect of lenvatinib. A: Chronological changes in relative viable cell number (% of the control) after adding 30 μM of lenvatinib. B: Relative viable cell number 72 h after adding 1.875, 3.75, 7.5, 15, or 30 μM of lenvatinib. Figures represent the average±SD." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-671488890" data-figure-caption="<div class="highwire-markup">Antiproliferative effect of lenvatinib. A: Chronological changes in relative viable cell number (% of the control) after adding 30 μM of lenvatinib. B: Relative viable cell number 72 h after adding 1.875, 3.75, 7.5, 15, or 30 μM of lenvatinib. Figures represent the average±SD.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 1." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F1.medium.gif" width="440" height="245"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 1." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F1.medium.gif" width="440" height="245"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F1.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 1." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F1.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/58094" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption" xmlns:xhtml="http://www.w3.org/1999/xhtml"><span class="fig-label">Figure 1.</span> <p id="p-18" class="first-child">Antiproliferative effect of lenvatinib. A: Chronological changes in relative viable cell number (% of the control) after adding 30 μM of lenvatinib. B: Relative viable cell number 72 h after adding 1.875, 3.75, 7.5, 15, or 30 μM of lenvatinib. Figures represent the average±SD.</p><div class="sb-div caption-clear"></div></div></div><p id="p-19"><em>Quantitative analysis of lenvatinib-induced apoptosis in vitro</em>. In all cell lines, quantitative analysis of apoptosis revealed that lenvatinib did not induce an increase in the amount of apoptosis <em>in vitro</em> (<a id="xref-fig-2-1" class="xref-fig" href="#F2">Figure 2</a>).</p><p id="p-20"><em>Expression of growth-related factors in liver cancer cell lines.</em> The protein expression of FGFR1-4 and FRS2α varied among cell lines (<a id="xref-fig-3-1" class="xref-fig" href="#F3">Figure 3</a>). The expression of FGF19 was observed only in KYN-2 and HAK-6, and the expression of RET was observed in HAK-5.</p><p id="p-21">The protein expression of FGFR1, FGFR2, FGFR3, FGFR4, FGF19, FRS2α, and RET was clearly observed in 11 cell lines (all except KYN-1 and HAK-1A), five (KIM-1, KYN-2, HAK-1A, HAK-1B, and KMCH-2), nine (all except KIM-1, KYN-1, HAK-2, and HAK-6), 10 (except HAK-1A, HAK-3, and HAK-4), two (KYN-2 and HAK-6), 13, and 1 (HAK-5), respectively, of the 13 cell lines analyzed.</p><p id="p-22"><em>Effects of lenvatinib on tumor formation of HCC cell line in nude mice.</em> Lenvatinib dose-dependently suppressed tumor growth in nude mice subcutaneously implanted with KYN-2 and HAK-1B HCC cell lines. The average volume of each KYN-2 tumor in mice receiving 3, 10, and 30 mg/kg of lenvatinib decreased to 37% (<em>p</em><0.05), 29% (<em>p</em><0.01), and 20% (<em>p</em><0.01), respectively, compared to the control (<a id="xref-fig-4-1" class="xref-fig" href="#F4">Figure 4A</a>). Tumor weights after 3, 10, and 30 mg/kg of lenvatinib also decreased by 50%, 27% (<em>p</em><0.05), and 22% (<em>p</em><0.05), respectively (<a id="xref-fig-4-2" class="xref-fig" href="#F4">Figure 4B</a>). In addition, the average volume of each HAK-1B tumor in mice receiving 3, 10, and 30 mg/kg of lenvatinib decreased to 61%, 32% (<em>p</em><0.01), and 17% (<em>p</em><0.01), respectively (<a id="xref-fig-4-3" class="xref-fig" href="#F4">Figure 4A</a>) with tumor weights also decreasing by 74%, 42% (<em>p</em><0.01), and 40% (<em>p</em><0.01), respectively (<a id="xref-fig-4-4" class="xref-fig" href="#F4">Figure 4B</a>). Lenvatinib administration did not affect the body weights of mice (data not shown).</p><p id="p-23"><em>Histological analysis.</em> Lenvatinib did not induce apoptosis of KYN-2 and HAK-1B HCC cells <em>in vivo</em> (<a id="xref-fig-5-1" class="xref-fig" href="#F5">Figure 5</a>). The number of blood vessels and the MVD per unit area decreased as the concentration of lenvatinib increased (<a id="xref-fig-6-1" class="xref-fig" href="#F6">Figure 6</a>). In the KYN-2 cell transplant model, the number of blood vessels in mice receiving 3, 10, and 30 mg/kg of lenvatinib decreased to 72% (<em>p</em><0.01), 39% (<em>p</em><0.001), and 21% (<em>p</em><0.001), respectively (<a id="xref-fig-7-1" class="xref-fig" href="#F7">Figure 7A</a>) compared to the control and the MVD under the same treatment condition decreased to 90%, 14% (<em>p</em><0.01), and 6% (<em>p</em><0.01), respectively (<a id="xref-fig-7-2" class="xref-fig" href="#F7">Figure 7B</a>). The rate of necrosis was significantly increased by lenvatinib in a dose-dependent manner in mice implanted with KYN-2 cells and treated with lenvatinib (control <em>vs.</em> 10 mg/kg or 30 mg/kg, <em>p</em><0.05) (<a id="xref-fig-7-3" class="xref-fig" href="#F7">Figure 7C</a>). In HAK-1B-transplanted mice, the number of blood vessels in mice receiving 3, 10, and 30 mg/kg of lenvatinib decreased to 59% (<em>p</em><0.01), 29% (<em>p</em><0.001), and 27% (<em>p</em><0.001), respectively (<a id="xref-fig-7-4" class="xref-fig" href="#F7">Figure 7A</a>), and the MVD under the same treatment decreased to 48% (<em>p</em><0.05), 19% (<em>p</em><0.01), and 1% (<em>p</em><0.01), respectively (<a id="xref-fig-7-5" class="xref-fig" href="#F7">Figure 7B</a>). The rate of necrosis of transplanted HAK-1B cells increased by more than two-fold with 3, 10, and 30 mg/kg lenvatinib treatment (<em>p</em><0.05) compared with the control (<a id="xref-fig-7-6" class="xref-fig" href="#F7">Figure 7C</a>).</p><div id="F2" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F2.large.jpg?width=800&height=600&carousel=1" title="Quantitative analysis of lenvatinib-induced apoptosis cells in vitro. Representative data of three cell line experiments are shown." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-671488890" data-figure-caption="<div class="highwire-markup">Quantitative analysis of lenvatinib-induced apoptosis cells in vitro. Representative data of three cell line experiments are shown.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 2." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F2.medium.gif" width="440" height="385"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 2." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F2.medium.gif" width="440" height="385"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F2.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 2." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F2.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/57930" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">Figure 2.</span> <p id="p-24" class="first-child">Quantitative analysis of lenvatinib-induced apoptosis cells in vitro. Representative data of three cell line experiments are shown.</p><div class="sb-div caption-clear"></div></div></div></div><div class="section discussion" id="sec-3"><h2 class="">Discussion</h2><p id="p-25">In this study, we examined the effect of lenvatinib on cell proliferation <em>in vitro</em> using 13 different cell lines of liver cancer. There was a suppression of cell proliferation in response to lenvatinib in all the cell lines tested. However, the sensitivity varied among the cell lines. The IC<sub>50</sub> values ranged between 5.8 and 28.5 μM in 8/13 cell lines, however IC<sub>50</sub> values could not be determined in the remaining five cell lines. We previously examined the effect of sorafenib in the same liver cancer cell lines and observed IC<sub>50</sub> values ranging from 2.1 to 4.3 μM [(<a id="xref-ref-24-1" class="xref-bibr" href="#ref-24">24</a>) for KIM-1 and HAK-1B, data not shown for others]. Yamamoto <em>et al.</em> also examined the suppressive effect of lenvatinib on cell proliferation <em>in vitro</em> using lung cancer and colon cancer cell lines, in which the IC<sub>50</sub> values ranged from approximately 20 to 30 μM (<a id="xref-ref-13-2" class="xref-bibr" href="#ref-13">13</a>); in addition, the IC<sub>50</sub> values for lenvatinib were relatively higher than those for sorafenib.</p><div id="F3" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F3.large.jpg?width=800&height=600&carousel=1" title="Western blot analysis of fibroblast growth factor receptor 1-4, FGF19, fibroblast growth factor receptor substrate 2α, and RET in different liver cancer cell lines. Lane 1: KIM-1, 2: KYN-1, 3: KYN-2, 4: KYN-3, 5: HAK-1A, 6: HAK-1B, 7: HAK-2, 8: HAK-3, 9: HAK-4, 10: HAK-5, 11: HAK-6, 12: KMCH-1, 13: KMCH-2." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-671488890" data-figure-caption="<div class="highwire-markup">Western blot analysis of fibroblast growth factor receptor 1-4, FGF19, fibroblast growth factor receptor substrate 2α, and RET in different liver cancer cell lines. Lane 1: KIM-1, 2: KYN-1, 3: KYN-2, 4: KYN-3, 5: HAK-1A, 6: HAK-1B, 7: HAK-2, 8: HAK-3, 9: HAK-4, 10: HAK-5, 11: HAK-6, 12: KMCH-1, 13: KMCH-2.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 3." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F3.medium.gif" width="440" height="430"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 3." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F3.medium.gif" width="440" height="430"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F3.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 3." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F3.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/58100" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">Figure 3.</span> <p id="p-26" class="first-child">Western blot analysis of fibroblast growth factor receptor 1-4, FGF19, fibroblast growth factor receptor substrate 2α, and RET in different liver cancer cell lines. Lane 1: KIM-1, 2: KYN-1, 3: KYN-2, 4: KYN-3, 5: HAK-1A, 6: HAK-1B, 7: HAK-2, 8: HAK-3, 9: HAK-4, 10: HAK-5, 11: HAK-6, 12: KMCH-1, 13: KMCH-2.</p><div class="sb-div caption-clear"></div></div></div><div id="F4" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F4.large.jpg?width=800&height=600&carousel=1" title="Antitumor effect of lenvatinib on tumors developed after subcutaneous transplantation of KYN-2 and HAK-1B cells in nude mice. A: Estimated volume of tumors generated by subcutaneously implanted HCC cells over a time course. The mice received 3 (●), 10 (▴), or 30 mg/kg/mouse/day (▪), lenvatinib or vehicle (control) (□). B: All mice were sacrificed on day 15, and tumor weight was measured. Figures represent the average±SD. Significantly different at *p" class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-671488890" data-figure-caption="<div class="highwire-markup">Antitumor effect of lenvatinib on tumors developed after subcutaneous transplantation of KYN-2 and HAK-1B cells in nude mice. A: Estimated volume of tumors generated by subcutaneously implanted HCC cells over a time course. The mice received 3 (●), 10 (▴), or 30 mg/kg/mouse/day (▪), lenvatinib or vehicle (control) (□). B: All mice were sacrificed on day 15, and tumor weight was measured. Figures represent the average±SD. Significantly different at *p<0.05 or **p<0.01 vs. control.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 4." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F4.medium.gif" width="440" height="332"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 4." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F4.medium.gif" width="440" height="332"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F4.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 4." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F4.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/58126" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">Figure 4.</span> <p id="p-27" class="first-child">Antitumor effect of lenvatinib on tumors developed after subcutaneous transplantation of KYN-2 and HAK-1B cells in nude mice. A: Estimated volume of tumors generated by subcutaneously implanted HCC cells over a time course. The mice received 3 (●), 10 (▴), or 30 mg/kg/mouse/day (▪), lenvatinib or vehicle (control) (□). B: All mice were sacrificed on day 15, and tumor weight was measured. Figures represent the average±SD. Significantly different at *p<0.05 or **p<0.01 vs. control.</p><div class="sb-div caption-clear"></div></div></div><p id="p-28">Our analysis on the expression of growth-related factors indicated that cell lines showing high response to lenvatinib expressed growth-related factors in abundance including RET, FGFRs and FGF19. Because lenvatinib is a potent inihibitor of tyrosine receptor kinases including RET and FGFRs, the inhibitory action of lenvatinib may depend upon the expression of growth-related factors. RET was most highly expressed in HAK-5 cells among the cell lines studied, whose IC<sub>50</sub> value was the lowest in response to treatment of lenvatinib. Lenvatinib was shown to be effective in thyroid cancer (<a id="xref-ref-25-1" class="xref-bibr" href="#ref-25">25</a>), where RET is highly expressed and is known to be highly mutated (<a id="xref-ref-26-1" class="xref-bibr" href="#ref-26">26</a>, <a id="xref-ref-27-1" class="xref-bibr" href="#ref-27">27</a>). However, in contrast to some studies reporting that RET is highly mutated in thyroid cancer, Kato <em>et al.</em> reported that in the analysis of aberrations including <em>RET</em> mutations and amplifications, aberrations were only observed in 88 (1.8%) of 4,871 cases of other cancer types and of them, aberrations were observed only in one of 44 types of HCC (<a id="xref-ref-28-1" class="xref-bibr" href="#ref-28">28</a>). The frequency of <em>RET</em> aberrations is low in other types of cancer and the effect of lenvatinib <em>via</em> RET inhibition may be limited to some cases. The expression of RET protein was observed in response to lenvatinib; therefore, analyses of both mutations and protein levels of RET need to be performed.</p><p id="p-29">In our previous study using six out of these 13 cell lines, FGF2 and FGFRs expression was detected and cell proliferation was suppressed by an FGF2-neutralizing antibody (<a id="xref-ref-23-2" class="xref-bibr" href="#ref-23">23</a>); therefore, FGF2 and FGFRs have been shown to be involved in the proliferation of HCC cells. The proliferation of liver cancer cells may have been suppressed by the direct interaction of lenvatinib with cancer cells <em>via</em> FGFR <em>in vitro</em>. The growth of some HCC is considered to be related to the signal transduction system of FGFs and FGFRs (<a id="xref-ref-29-1" class="xref-bibr" href="#ref-29">29</a>, <a id="xref-ref-30-1" class="xref-bibr" href="#ref-30">30</a>). It has been reported that the expression of FGFR4, which is involved in angiogenesis, is found in one-third of HCC cases (<a id="xref-ref-31-1" class="xref-bibr" href="#ref-31">31</a>-<a id="xref-ref-33-1" class="xref-bibr" href="#ref-33">33</a>). Since there are few inhibitors of FGFR4 (<a id="xref-ref-34-1" class="xref-bibr" href="#ref-34">34</a>), drugs such as lenvatinib that reliably inhibit FGFR are useful for the treatment of HCC.</p><div id="F5" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F5.large.jpg?width=800&height=600&carousel=1" title="Analysis of lenvatinib-induced apoptosis in human hepatocellular carcinoma tumor HAK-1B subcutaneously transplanted in a nude mouse that received vehicle (A) and in a mouse that received 30 mg/kg of lenvatinib (B). Left panel: Hematoxylin and eosin staining. Right panel: Staining by the TUNEL technique. Scale bar=50 μm." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-671488890" data-figure-caption="<div class="highwire-markup">Analysis of lenvatinib-induced apoptosis in human hepatocellular carcinoma tumor HAK-1B subcutaneously transplanted in a nude mouse that received vehicle (A) and in a mouse that received 30 mg/kg of lenvatinib (B). Left panel: Hematoxylin and eosin staining. Right panel: Staining by the TUNEL technique. Scale bar=50 μm.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 5." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F5.medium.gif" width="440" height="320"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 5." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F5.medium.gif" width="440" height="320"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F5.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 5." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F5.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/58162" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">Figure 5.</span> <p id="p-30" class="first-child">Analysis of lenvatinib-induced apoptosis in human hepatocellular carcinoma tumor HAK-1B subcutaneously transplanted in a nude mouse that received vehicle (A) and in a mouse that received 30 mg/kg of lenvatinib (B). Left panel: Hematoxylin and eosin staining. Right panel: Staining by the TUNEL technique. Scale bar=50 μm.</p><div class="sb-div caption-clear"></div></div></div><p id="p-31">Although lenvatinib did not induce apoptosis of liver cancer cells <em>in vitro</em> or <em>in vivo</em> in this study, it has been reported to do so in thyroid cancer (<a id="xref-ref-35-1" class="xref-bibr" href="#ref-35">35</a>) and nasopharyngeal carcinoma (<a id="xref-ref-36-1" class="xref-bibr" href="#ref-36">36</a>). Lenvatinib-induced apoptosis appears to be cancer type specific.</p><p id="p-32">We observed suppression of tumor growth and angiogenesis with lenvatinib treatment and an increase in the rate of necrosis of KYN-2 and HAK-1B HCC cells implanted in mice <em>in vivo</em>. In our previous study on sorafenib in the same liver cancer cell lines, IC<sub>50</sub> values were obtained for all 13 cell lines and apoptosis was induced in 8/13 cell lines <em>in vitro</em> [(<a id="xref-ref-24-2" class="xref-bibr" href="#ref-24">24</a>) for KIM-1and HAK-1B, data not shown for others]. Both tumor volume and tumor weight only decreased to 50% with sorafenib administration in mice transplanted with KYN-2 cells (<a id="xref-ref-37-1" class="xref-bibr" href="#ref-37">37</a>); whereas, a decrease to below 30% was observed with lenvatinib administration. The vascular density did not decrease to below 50% with sorafenib administration, but decreased to 14% with lenvatinib administration. We found the effect of lenvatinib to be inferior to that of sorafenib in the suppression of cell growth <em>in vitro</em>, but superior in tumor-growth suppression <em>in vivo</em>. Type I to V kinase inhibitors binding to VEGFR2 have been reported, of which sorafenib is a type II (<a id="xref-ref-38-1" class="xref-bibr" href="#ref-38">38</a>) and lenvatinib a type V inhibitor (<a id="xref-ref-39-1" class="xref-bibr" href="#ref-39">39</a>). Type V inhibitors are reported to possess faster binding and higher affinity for VEGFR2, making their kinase-inhibitory activities stronger compared to type II inhibitors. FGFR signaling increases VEGF as well as VEGFR, and when VEGF and VEGFR are suppressed, FGF production is activated to enhance FGFR signaling, which causes VEGFR and FGFR to cooperatively promote tumor angiogenesis (<a id="xref-ref-40-1" class="xref-bibr" href="#ref-40">40</a>). Therefore, we presume that the suppressive effect of lenvatinib on angiogenesis was exerted by quickly binding to factors (such as VEGFR and FGFR) involved in tumor angiogenesis with increased affinity, which led to the highly suppressive effect on tumor growth <em>in vivo</em>, likely by the indirect activity of lenvatinib rather than its direct activity.</p><p id="p-33">In conclusion, our study suggests that lenvatinib exhibits an antitumor effect mainly by suppressing angiogenesis, but it may directly suppress cell proliferation in cells with high FGFR expression.</p><div id="F6" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F6.large.jpg?width=800&height=600&carousel=1" title="Effect of lenvatinib on suppression of angiogenesis in tumors developed after subcutaneous transplantation of hepatocellular carcinoma cells. Immunohistochemical staining of CD34 in KYN-2 cell tumors (A-D) and HAK-1B cell tumors (E-H). Scale bar=50 μm. Mice received vehicle (control) (A, E), or lenvatinib of at 3 (B, F), 10 (C, G), or (D, H) 30 mg/kg/mouse/day." class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-671488890" data-figure-caption="<div class="highwire-markup">Effect of lenvatinib on suppression of angiogenesis in tumors developed after subcutaneous transplantation of hepatocellular carcinoma cells. Immunohistochemical staining of CD34 in KYN-2 cell tumors (A-D) and HAK-1B cell tumors (E-H). Scale bar=50 μm. Mice received vehicle (control) (A, E), or lenvatinib of at 3 (B, F), 10 (C, G), or (D, H) 30 mg/kg/mouse/day.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 6." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F6.medium.gif" width="292" height="440"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 6." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F6.medium.gif" width="292" height="440"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F6.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 6." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F6.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/57989" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">Figure 6.</span> <p id="p-34" class="first-child">Effect of lenvatinib on suppression of angiogenesis in tumors developed after subcutaneous transplantation of hepatocellular carcinoma cells. Immunohistochemical staining of CD34 in KYN-2 cell tumors (A-D) and HAK-1B cell tumors (E-H). Scale bar=50 μm. Mice received vehicle (control) (A, E), or lenvatinib of at 3 (B, F), 10 (C, G), or (D, H) 30 mg/kg/mouse/day.</p><div class="sb-div caption-clear"></div></div></div><div id="F7" class="fig pos-float odd"><div class="highwire-figure"><div class="fig-inline-img-wrapper"><div class="fig-inline-img"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F7.large.jpg?width=800&height=600&carousel=1" title="Effect of lenvatinib on blood vessel frequency (A), microvessel density (B), and necrosis rate of tumors (C) in nude mice. Figures represent the average±SD. Significantly different at *p" class="highwire-fragment fragment-images colorbox-load" rel="gallery-fragment-images-671488890" data-figure-caption="<div class="highwire-markup">Effect of lenvatinib on blood vessel frequency (A), microvessel density (B), and necrosis rate of tumors (C) in nude mice. Figures represent the average±SD. Significantly different at *p<0.05, **p<0.01, or ***p<0.001 vs. control.</div>" data-icon-position="" data-hide-link-title="0"><span class="hw-responsive-img"><img class="highwire-fragment fragment-image lazyload" alt="Figure 7." src="data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7" data-src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F7.medium.gif" width="440" height="260"/><noscript><img class="highwire-fragment fragment-image" alt="Figure 7." src="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F7.medium.gif" width="440" height="260"/></noscript></span></a></div></div><ul class="highwire-figure-links inline"><li class="download-fig first"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F7.large.jpg?download=true" class="highwire-figure-link highwire-figure-link-download" title="Download Figure 7." data-icon-position="" data-hide-link-title="0">Download figure</a></li><li class="new-tab"><a href="https://ar.iiarjournals.org/content/anticanres/39/11/5973/F7.large.jpg" class="highwire-figure-link highwire-figure-link-newtab" target="_blank" data-icon-position="" data-hide-link-title="0">Open in new tab</a></li><li class="download-ppt last"><a href="/highwire/powerpoint/58028" class="highwire-figure-link highwire-figure-link-ppt" data-icon-position="" data-hide-link-title="0">Download powerpoint</a></li></ul></div><div class="fig-caption"><span class="fig-label">Figure 7.</span> <p id="p-35" class="first-child">Effect of lenvatinib on blood vessel frequency (A), microvessel density (B), and necrosis rate of tumors (C) in nude mice. Figures represent the average±SD. Significantly different at *p<0.05, **p<0.01, or ***p<0.001 vs. control.</p><div class="sb-div caption-clear"></div></div></div></div><div class="section ack" id="ack-1"><h2 class="">Acknowledgements</h2><p id="p-36">The Authors gratefully acknowledge Ms. Akemi Fujiyoshi, Ms. Sachiyo Maeda and Ms. Akiko Tanaka for their assistance in our experiment.</p></div><div class="section fn-group" id="fn-group-1"><h2>Footnotes</h2><ul><li class="fn" id="fn-1"><p id="p-1"><strong>Authors' Contributions</strong></p><p id="p-2">Sachiko Ogasawara: Performed the entire experiment. Article preparation and submission. Yutaro Mihara: Cooperation in animal experiments. Reiichiro Kondo: Cooperation in examination of tissue specimens. Hironori Kusano: Cooperation in examination of tissue specimens. Jun Akiba: Input in evaluating results. Hirohisa Yano: Input in evaluating results.</p></li><li class="fn" id="fn-2"><p id="p-37"><strong>Conflicts of Interest</strong></p><p id="p-38">The Authors have no conflicts of interest to disclose.</p></li></ul></div><ul class="history-list"><li xmlns:hwp="http://schema.highwire.org/Journal" class="received" hwp:start="2019-10-01"><span class="received-label">Received </span>October 1, 2019.</li><li xmlns:hwp="http://schema.highwire.org/Journal" class="rev-recd" hwp:start="2019-10-17"><span class="rev-recd-label">Revision received </span>October 17, 2019.</li><li xmlns:hwp="http://schema.highwire.org/Journal" class="accepted" hwp:start="2019-10-21"><span class="accepted-label">Accepted </span>October 21, 2019.</li></ul><ul class="copyright-statement"><li class="fn" id="copyright-statement-1">Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved</li></ul><div class="section ref-list" id="ref-list-1"><h2 class="">References</h2><ol class="cit-list"><li><a class="rev-xref-ref" href="#xref-ref-1-1" title="View reference 1 in text" id="ref-1">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.1" data-doi="10.1002/ijc.29210"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Ferlay</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Soerjomataram</span> <span class="cit-name-given-names">I</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Dikshit</span> <span class="cit-name-given-names">R</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Eser</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Mathers</span> <span class="cit-name-given-names">C</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Rebelo</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Parkin</span> <span class="cit-name-given-names">DM</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Forman</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Bray</span> <span class="cit-name-given-names">F</span></span></li></ol><cite>: <span class="cit-article-title">Cancer incidence and mortality worldwide: Sources, methods and major patterns in globocan 2012</span>. <abbr class="cit-jnl-abbrev">Int J Cancer</abbr> <span class="cit-vol">136</span>(<span class="cit-issue">5</span>): <span class="cit-fpage">E359</span>-<span class="cit-lpage">386</span>, <span class="cit-pub-date">2015</span>. <span class="cit-comment">PMID: 25220842. DOI: 10.1002/ijc.29210</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DInt%2BJ%2BCancer%26rft.volume%253D136%26rft.spage%253DE359%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fijc.29210%26rft_id%253Dinfo%253Apmid%252F25220842%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1002/ijc.29210&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=25220842&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-2-1" title="View reference 2 in text" id="ref-2">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.2" data-doi="10.3322/caac.21262"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Torre</span> <span class="cit-name-given-names">LA</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Bray</span> <span class="cit-name-given-names">F</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Siegel</span> <span class="cit-name-given-names">RL</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ferlay</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Lortet-Tieulent</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Jemal</span> <span class="cit-name-given-names">A</span></span></li></ol><cite>: <span class="cit-article-title">Global cancer statistics, 2012</span>. <abbr class="cit-jnl-abbrev">CA Cancer J Clin</abbr> <span class="cit-vol">65</span>(<span class="cit-issue">2</span>): <span class="cit-fpage">87</span>-<span class="cit-lpage">108</span>, <span class="cit-pub-date">2015</span>. <span class="cit-comment">PMID: 25651787. DOI: 10.3322/caac.21262</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DCA%2BCancer%2BJ%2BClin%26rft.volume%253D65%26rft.spage%253D87%26rft_id%253Dinfo%253Adoi%252F10.3322%252Fcaac.21262%26rft_id%253Dinfo%253Apmid%252F25651787%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.3322/caac.21262&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=25651787&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-3-1" title="View reference 3 in text" id="ref-3">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.3" data-doi="10.1016/j.jhep.2004.09.006"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Semela</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Dufour</span> <span class="cit-name-given-names">JF</span></span></li></ol><cite>: <span class="cit-article-title">Angiogenesis and hepatocellular carcinoma</span>. <abbr class="cit-jnl-abbrev">J Hepatol</abbr> <span class="cit-vol">41</span>(<span class="cit-issue">5</span>): <span class="cit-fpage">864</span>-<span class="cit-lpage">880</span>, <span class="cit-pub-date">2004</span>. <span class="cit-comment">PMID: 15519663. DOI: 10.1016/j.jhep.2004.09.006</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DJournal%2Bof%2Bhepatology%26rft.stitle%253DJ%2BHepatol%26rft.aulast%253DSemela%26rft.auinit1%253DD.%26rft.volume%253D41%26rft.issue%253D5%26rft.spage%253D864%26rft.epage%253D880%26rft.atitle%253DAngiogenesis%2Band%2Bhepatocellular%2Bcarcinoma.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.jhep.2004.09.006%26rft_id%253Dinfo%253Apmid%252F15519663%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1016/j.jhep.2004.09.006&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=15519663&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-4-1" title="View reference 4 in text" id="ref-4">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.4" data-doi="10.1158/0008-5472.CAN-04-1443"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Wilhelm</span> <span class="cit-name-given-names">SM</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Carter</span> <span class="cit-name-given-names">C</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tang</span> <span class="cit-name-given-names">L</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Wilkie</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">McNabola</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Rong</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Chen</span> <span class="cit-name-given-names">C</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Zhang</span> <span class="cit-name-given-names">X</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Vincent</span> <span class="cit-name-given-names">P</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">McHugh</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Cao</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Shujath</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Gawlak</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Eveleigh</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Rowley</span> <span class="cit-name-given-names">B</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Liu</span> <span class="cit-name-given-names">L</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Adnane</span> <span class="cit-name-given-names">L</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Lynch</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Auclair</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Taylor</span> <span class="cit-name-given-names">I</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Gedrich</span> <span class="cit-name-given-names">R</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Voznesensky</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Riedl</span> <span class="cit-name-given-names">B</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Post</span> <span class="cit-name-given-names">LE</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Bollag</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Trail</span> <span class="cit-name-given-names">PA</span></span></li></ol><cite>: <span class="cit-article-title">Bay 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis</span>. <abbr class="cit-jnl-abbrev">Cancer Res</abbr> <span class="cit-vol">64</span>: <span class="cit-fpage">7099</span>-<span class="cit-lpage">7109</span>, <span class="cit-pub-date">2004</span>. <span class="cit-comment">PMID: 15466206. DOI: 10.1158/0008-5472.CAN-04-1443</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DCancer%2BResearch%26rft.stitle%253DCancer%2BRes.%26rft.aulast%253DWilhelm%26rft.auinit1%253DS.%2BM.%26rft.volume%253D64%26rft.issue%253D19%26rft.spage%253D7099%26rft.epage%253D7109%26rft.atitle%253DBAY%2B43-9006%2BExhibits%2BBroad%2BSpectrum%2BOral%2BAntitumor%2BActivity%2Band%2BTargets%2Bthe%2BRAF%252FMEK%252FERK%2BPathway%2Band%2BReceptor%2BTyrosine%2BKinases%2BInvolved%2Bin%2BTumor%2BProgression%2Band%2BAngiogenesis%26rft_id%253Dinfo%253Adoi%252F10.1158%252F0008-5472.CAN-04-1443%26rft_id%253Dinfo%253Apmid%252F15466206%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="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" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">Abstract</span><span class="cit-sep cit-reflinks-variant-name-sep">/</span><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-5-1" title="View reference 5 in text" id="ref-5">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.5" data-doi="10.1155/2014/638747"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Tohyama</span> <span class="cit-name-given-names">O</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Matsui</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kodama</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Hata-Sugi</span> <span class="cit-name-given-names">N</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kimura</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Okamoto</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Minoshima</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Iwata</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Funahashi</span> <span class="cit-name-given-names">Y</span></span></li></ol><cite>: <span class="cit-article-title">Antitumor activity of lenvatinib (e7080): An angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models</span>. <abbr class="cit-jnl-abbrev">J Thyroid Res</abbr> <span class="cit-vol">2014</span>: <span class="cit-fpage">638747</span>, <span class="cit-pub-date">2014</span>. <span class="cit-comment">PMID: 25295214. DOI: 10.1155/2014/638747</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DJ%2BThyroid%2BRes%26rft.volume%253D2014%26rft.spage%253D638747%26rft_id%253Dinfo%253Adoi%252F10.1155%252F2014%252F638747%26rft_id%253Dinfo%253Apmid%252F25295214%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1155/2014/638747&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=25295214&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-6-1" title="View reference 6 in text" id="ref-6">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.6" data-doi="10.1056/NEJMoa0708857"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Llovet</span> <span class="cit-name-given-names">JM</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ricci</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Mazzaferro</span> <span class="cit-name-given-names">V</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Hilgard</span> <span class="cit-name-given-names">P</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Gane</span> <span class="cit-name-given-names">E</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Blanc</span> <span class="cit-name-given-names">JF</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">de Oliveira</span> <span class="cit-name-given-names">AC</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Santoro</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Raoul</span> <span class="cit-name-given-names">JL</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Forner</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Schwartz</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Porta</span> <span class="cit-name-given-names">C</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Zeuzem</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Bolondi</span> <span class="cit-name-given-names">L</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Greten</span> <span class="cit-name-given-names">TF</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Galle</span> <span class="cit-name-given-names">PR</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Seitz</span> <span class="cit-name-given-names">JF</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Borbath</span> <span class="cit-name-given-names">I</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Haussinger</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Giannaris</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Shan</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Moscovici</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Voliotis</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Bruix</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth cit-collab">Group SIS</span></li></ol><cite>: <span class="cit-article-title">Sorafenib in advanced hepatocellular carcinoma</span>. <abbr class="cit-jnl-abbrev">N Engl J Med</abbr> <span class="cit-vol">359</span>(<span class="cit-issue">4</span>): <span class="cit-fpage">378</span>-<span class="cit-lpage">390</span>, <span class="cit-pub-date">2008</span>. <span class="cit-comment">PMID: 18650514. DOI: 10.1056/NEJMoa0708857</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DNew%2BEngland%2BJournal%2Bof%2BMedicine%26rft.stitle%253DNEJM%26rft.aulast%253DLlovet%26rft.auinit1%253DJ.%2BM.%26rft.volume%253D359%26rft.issue%253D4%26rft.spage%253D378%26rft.epage%253D390%26rft.atitle%253DSorafenib%2Bin%2BAdvanced%2BHepatocellular%2BCarcinoma%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa0708857%26rft_id%253Dinfo%253Apmid%252F18650514%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1056/NEJMoa0708857&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=18650514&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-7-1" title="View reference 7 in text" id="ref-7">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.7" data-doi="10.1016/S1470-2045(08)70285-7"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Cheng</span> <span class="cit-name-given-names">A-L</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kang</span> <span class="cit-name-given-names">Y-K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Chen</span> <span class="cit-name-given-names">Z</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tsao</span> <span class="cit-name-given-names">C-J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Qin</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kim</span> <span class="cit-name-given-names">JS</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Luo</span> <span class="cit-name-given-names">R</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Feng</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ye</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yang</span> <span class="cit-name-given-names">T-S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Xu</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Sun</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Liang</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Liu</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Wang</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tak</span> <span class="cit-name-given-names">WY</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Pan</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Burock</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Zou</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Voliotis</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Guan</span> <span class="cit-name-given-names">Z</span></span></li></ol><cite>: <span class="cit-article-title">Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: A phase III randomised, double-blind, placebo-controlled trial</span>. <abbr class="cit-jnl-abbrev">Lancet Oncol</abbr> <span class="cit-vol">10</span>(<span class="cit-issue">1</span>): <span class="cit-fpage">25</span>-<span class="cit-lpage">34</span>, <span class="cit-pub-date">2009</span>. <span class="cit-comment">PMID: 19095497. DOI: 10.1016/s1470-2045 (08)70285-7</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DThe%2Blancet%2Boncology%26rft.stitle%253DLancet%2BOncol%26rft.aulast%253DCheng%26rft.auinit1%253DA.%2BL.%26rft.volume%253D10%26rft.issue%253D1%26rft.spage%253D25%26rft.epage%253D34%26rft.atitle%253DEfficacy%2Band%2Bsafety%2Bof%2Bsorafenib%2Bin%2Bpatients%2Bin%2Bthe%2BAsia-Pacific%2Bregion%2Bwith%2Badvanced%2Bhepatocellular%2Bcarcinoma%253A%2Ba%2Bphase%2BIII%2Brandomised%252C%2Bdouble-blind%252C%2Bplacebo-controlled%2Btrial.%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS1470-2045%252808%252970285-7%26rft_id%253Dinfo%253Apmid%252F19095497%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1016/S1470-2045(08)70285-7&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=19095497&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-8-1" title="View reference 8 in text" id="ref-8">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.8" data-doi="10.1200/JCO.2012.45.8372"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Cheng</span> <span class="cit-name-given-names">AL</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kang</span> <span class="cit-name-given-names">YK</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Lin</span> <span class="cit-name-given-names">DY</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Park</span> <span class="cit-name-given-names">JW</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kudo</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Qin</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Chung</span> <span class="cit-name-given-names">HC</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Song</span> <span class="cit-name-given-names">X</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Xu</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Poggi</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Omata</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Pitman Lowenthal</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Lanzalone</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yang</span> <span class="cit-name-given-names">L</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Lechuga</span> <span class="cit-name-given-names">MJ</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Raymond</span> <span class="cit-name-given-names">E</span></span></li></ol><cite>: <span class="cit-article-title">Sunitinib <em>versus</em> sorafenib in advanced hepatocellular cancer: Results of a randomized phase III trial</span>. <abbr class="cit-jnl-abbrev">J Clin Oncol</abbr> <span class="cit-vol">31</span>(<span class="cit-issue">32</span>): <span class="cit-fpage">4067</span>-<span class="cit-lpage">4075</span>, <span class="cit-pub-date">2013</span>. <span class="cit-comment">PMID: 24081937. DOI: 10.1200/JCO.2012.45.8372</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DJ%2BClin%2BOncol%26rft_id%253Dinfo%253Adoi%252F10.1200%252FJCO.2012.45.8372%26rft_id%253Dinfo%253Apmid%252F24081937%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="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" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">Abstract</span><span class="cit-sep cit-reflinks-variant-name-sep">/</span><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></span></a></div></div></li><li><div class="cit ref-cit ref-journal no-rev-xref" id="cit-39.11.5973.9" data-doi="10.1200/JCO.2012.48.4410"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Johnson</span> <span class="cit-name-given-names">PJ</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Qin</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Park</span> <span class="cit-name-given-names">JW</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Poon</span> <span class="cit-name-given-names">RT</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Raoul</span> <span class="cit-name-given-names">JL</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Philip</span> <span class="cit-name-given-names">PA</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Hsu</span> <span class="cit-name-given-names">CH</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Hu</span> <span class="cit-name-given-names">TH</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Heo</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Xu</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Lu</span> <span class="cit-name-given-names">L</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Chao</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Boucher</span> <span class="cit-name-given-names">E</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Han</span> <span class="cit-name-given-names">KH</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Paik</span> <span class="cit-name-given-names">SW</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Robles-Avina</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kudo</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yan</span> <span class="cit-name-given-names">L</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Sobhonslidsuk</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Komov</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Decaens</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tak</span> <span class="cit-name-given-names">WY</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Jeng</span> <span class="cit-name-given-names">LB</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Liu</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ezzeddine</span> <span class="cit-name-given-names">R</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Walters</span> <span class="cit-name-given-names">I</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Cheng</span> <span class="cit-name-given-names">AL</span></span></li></ol><cite>: <span class="cit-article-title">Brivanib <em>versus</em> sorafenib as first-line therapy in patients with unresectable, advanced hepatocellular carcinoma: Results from the randomized phase III BRISK-FL study</span>. <abbr class="cit-jnl-abbrev">J Clin Oncol</abbr> <span class="cit-vol">31</span>(<span class="cit-issue">28</span>): <span class="cit-fpage">3517</span>-<span class="cit-lpage">3524</span>, <span class="cit-pub-date">2013</span>. <span class="cit-comment">PMID: 23980084. DOI: 10.1200/JCO.2012.48.4410</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DJ%2BClin%2BOncol%26rft_id%253Dinfo%253Adoi%252F10.1200%252FJCO.2012.48.4410%26rft_id%253Dinfo%253Apmid%252F23980084%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="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" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">Abstract</span><span class="cit-sep cit-reflinks-variant-name-sep">/</span><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-10-1" title="View reference 10 in text" id="ref-10">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.10" data-doi="10.1200/JCO.2013.54.3298"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Cainap</span> <span class="cit-name-given-names">C</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Qin</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Huang</span> <span class="cit-name-given-names">WT</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Chung</span> <span class="cit-name-given-names">IJ</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Pan</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Cheng</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kudo</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kang</span> <span class="cit-name-given-names">YK</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Chen</span> <span class="cit-name-given-names">PJ</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Toh</span> <span class="cit-name-given-names">HC</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Gorbunova</span> <span class="cit-name-given-names">V</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Eskens</span> <span class="cit-name-given-names">FA</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Qian</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">McKee</span> <span class="cit-name-given-names">MD</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ricker</span> <span class="cit-name-given-names">JL</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Carlson</span> <span class="cit-name-given-names">DM</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">El-Nowiem</span> <span class="cit-name-given-names">S</span></span></li></ol><cite>: <span class="cit-article-title">Linifanib <em>versus</em> sorafenib in patients with advanced hepatocellular carcinoma: Results of a randomized phase III trial</span>. <abbr class="cit-jnl-abbrev">J Clin Oncol</abbr> <span class="cit-vol">33</span>(<span class="cit-issue">2</span>): <span class="cit-fpage">172</span>-<span class="cit-lpage">179</span>, <span class="cit-pub-date">2015</span>. <span class="cit-comment">PMID: 25488963. DOI: 10.1200/JCO.2013.54.3298</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DJ%2BClin%2BOncol%26rft_id%253Dinfo%253Adoi%252F10.1200%252FJCO.2013.54.3298%26rft_id%253Dinfo%253Apmid%252F25488963%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiamNvIjtzOjU6InJlc2lkIjtzOjg6IjMzLzIvMTcyIjtzOjQ6ImF0b20iO3M6Mjc6Ii9hbnRpY2FucmVzLzM5LzExLzU5NzMuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9/YTozOntzOjQ6InBhdGgiO3M6MjkxOiIvbG9va3VwL2lqbGluay9ZVG96T250ek9qUTZJbkJoZEdnaU8zTTZNVFE2SWk5c2IyOXJkWEF2YVdwc2FXNXJJanR6T2pVNkluRjFaWEo1SWp0aE9qUTZlM002T0RvaWJHbHVhMVI1Y0dVaU8zTTZORG9pUVVKVFZDSTdjem94TVRvaWFtOTFjbTVoYkVOdlpHVWlPM002TXpvaWFtTnZJanR6T2pVNkluSmxjMmxrSWp0ek9qZzZJak16THpJdk1UY3lJanR6T2pRNkltRjBiMjBpTzNNNk1qYzZJaTloYm5ScFkyRnVjbVZ6THpNNUx6RXhMelU1TnpNdVlYUnZiU0k3ZlhNNk9Eb2labkpoWjIxbGJuUWlPM002TURvaUlqdDkiO3M6NToicXVlcnkiO2E6MDp7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">Abstract</span><span class="cit-sep cit-reflinks-variant-name-sep">/</span><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-11-1" title="View reference 11 in text" id="ref-11">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.11" data-doi="10.1200/JCO.2013.53.7746"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Zhu</span> <span class="cit-name-given-names">AX</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Rosmorduc</span> <span class="cit-name-given-names">O</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Evans</span> <span class="cit-name-given-names">TR</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ross</span> <span class="cit-name-given-names">PJ</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Santoro</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Carrilho</span> <span class="cit-name-given-names">FJ</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Bruix</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Qin</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Thuluvath</span> <span class="cit-name-given-names">PJ</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Llovet</span> <span class="cit-name-given-names">JM</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Leberre</span> <span class="cit-name-given-names">MA</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Jensen</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Meinhardt</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kang</span> <span class="cit-name-given-names">YK</span></span></li></ol><cite>: <span class="cit-article-title">Search: A phase III, randomized, double-blind, placebo-controlled trial of sorafenib plus erlotinib in patients with advanced hepatocellular carcinoma</span>. <abbr class="cit-jnl-abbrev">J Clin Oncol</abbr> <span class="cit-vol">33</span>(<span class="cit-issue">6</span>): <span class="cit-fpage">559</span>-<span class="cit-lpage">566</span>, <span class="cit-pub-date">2015</span>. <span class="cit-comment">PMID: 25547503. DOI: 10.1200/JCO.2013.53.7746</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DJ%2BClin%2BOncol%26rft_id%253Dinfo%253Adoi%252F10.1200%252FJCO.2013.53.7746%26rft_id%253Dinfo%253Apmid%252F25547503%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="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" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">Abstract</span><span class="cit-sep cit-reflinks-variant-name-sep">/</span><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-12-1" title="View reference 12 in text" id="ref-12">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.12" data-doi="10.1158/1078-0432.CCR-07-5270"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Matsui</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Funahashi</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Uenaka</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Watanabe</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tsuruoka</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Asada</span> <span class="cit-name-given-names">M</span></span></li></ol><cite>: <span class="cit-article-title">Multi-kinase inhibitor e7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 <em>via</em> inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase</span>. <abbr class="cit-jnl-abbrev">Clin Cancer Res</abbr> <span class="cit-vol">14</span>(<span class="cit-issue">17</span>): <span class="cit-fpage">5459</span>-<span class="cit-lpage">5465</span>, <span class="cit-pub-date">2008</span>. <span class="cit-comment">PMID: 18765537. DOI: 10.1158/1078-0432.CCR-07-5270</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DClinical%2BCancer%2BResearch%26rft.stitle%253DClin.%2BCancer%2BRes.%26rft.aulast%253DMatsui%26rft.auinit1%253DJ.%26rft.volume%253D14%26rft.issue%253D17%26rft.spage%253D5459%26rft.epage%253D5465%26rft.atitle%253DMulti-Kinase%2BInhibitor%2BE7080%2BSuppresses%2BLymph%2BNode%2Band%2BLung%2BMetastases%2Bof%2BHuman%2BMammary%2BBreast%2BTumor%2BMDA-MB-231%2Bvia%2BInhibition%2Bof%2BVascular%2BEndothelial%2BGrowth%2BFactor-Receptor%2B%2528VEGF-R%2529%2B2%2Band%2BVEGF-R3%2BKinase%26rft_id%253Dinfo%253Adoi%252F10.1158%252F1078-0432.CCR-07-5270%26rft_id%253Dinfo%253Apmid%252F18765537%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MTA6ImNsaW5jYW5yZXMiO3M6NToicmVzaWQiO3M6MTA6IjE0LzE3LzU0NTkiO3M6NDoiYXRvbSI7czoyNzoiL2FudGljYW5yZXMvMzkvMTEvNTk3My5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=/YTozOntzOjQ6InBhdGgiO3M6MzA3OiIvbG9va3VwL2lqbGluay9ZVG96T250ek9qUTZJbkJoZEdnaU8zTTZNVFE2SWk5c2IyOXJkWEF2YVdwc2FXNXJJanR6T2pVNkluRjFaWEo1SWp0aE9qUTZlM002T0RvaWJHbHVhMVI1Y0dVaU8zTTZORG9pUVVKVFZDSTdjem94TVRvaWFtOTFjbTVoYkVOdlpHVWlPM002TVRBNkltTnNhVzVqWVc1eVpYTWlPM002TlRvaWNtVnphV1FpTzNNNk1UQTZJakUwTHpFM0x6VTBOVGtpTzNNNk5Eb2lZWFJ2YlNJN2N6b3lOem9pTDJGdWRHbGpZVzV5WlhNdk16a3ZNVEV2TlRrM015NWhkRzl0SWp0OWN6bzRPaUptY21GbmJXVnVkQ0k3Y3pvd09pSWlPMzA9IjtzOjU6InF1ZXJ5IjthOjA6e31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">Abstract</span><span class="cit-sep cit-reflinks-variant-name-sep">/</span><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-13-1" title="View reference 13 in text" id="ref-13">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.13" data-doi="10.1186/2045-824X-6-18"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Yamamoto</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Matsui</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Matsushima</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Obaishi</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Miyazaki</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Nakamura</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tohyama</span> <span class="cit-name-given-names">O</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Semba</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yamaguchi</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Hoshi</span> <span class="cit-name-given-names">SS</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Mimura</span> <span class="cit-name-given-names">F</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Haneda</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Fukuda</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kamata</span> <span class="cit-name-given-names">JI</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Takahashi</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Matsukura</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Wakabayashi</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Asada</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Nomoto</span> <span class="cit-name-given-names">KI</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Watanabe</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Dezso</span> <span class="cit-name-given-names">Z</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yoshimatsu</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Funahashi</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tsuruoka</span> <span class="cit-name-given-names">A</span></span></li></ol><cite>: <span class="cit-article-title">Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage</span>. <abbr class="cit-jnl-abbrev">Vasc Cell</abbr> <span class="cit-vol">6</span>: <span class="cit-fpage">18</span>, <span class="cit-pub-date">2014</span>. <span class="cit-comment">PMID: 25197551. DOI: 10.1186/2045-824X-6-18</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DVasc%2BCell%26rft.volume%253D6%26rft.spage%253D18%26rft_id%253Dinfo%253Adoi%252F10.1186%252F2045-824X-6-18%26rft_id%253Dinfo%253Apmid%252F25197551%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1186/2045-824X-6-18&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=25197551&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-14-1" title="View reference 14 in text" id="ref-14">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.14" data-doi="10.1016/S0140-6736(18)30207-1"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Kudo</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Finn</span> <span class="cit-name-given-names">RS</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Qin</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Han</span> <span class="cit-name-given-names">KH</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ikeda</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Piscaglia</span> <span class="cit-name-given-names">F</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Baron</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Park</span> <span class="cit-name-given-names">JW</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Han</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Jassem</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Blanc</span> <span class="cit-name-given-names">JF</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Vogel</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Komov</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Evans</span> <span class="cit-name-given-names">TRJ</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Lopez</span> <span class="cit-name-given-names">C</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Dutcus</span> <span class="cit-name-given-names">C</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Guo</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Saito</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kraljevic</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tamai</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ren</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Cheng</span> <span class="cit-name-given-names">AL</span></span></li></ol><cite>: <span class="cit-article-title">Lenvatinib <em>versus</em> sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial</span>. <abbr class="cit-jnl-abbrev">Lancet</abbr> <span class="cit-vol">391</span>(<span class="cit-issue">10126</span>): <span class="cit-fpage">1163</span>-<span class="cit-lpage">1173</span>, <span class="cit-pub-date">2018</span>. <span class="cit-comment">PMID: 29433850. DOI: 10.1016/s0140-6736(18)30207-1</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DLancet%26rft.volume%253D391%26rft.spage%253D1163%26rft_id%253Dinfo%253Adoi%252F10.1016%252FS0140-6736%252818%252930207-1%26rft_id%253Dinfo%253Apmid%252F29433850%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1016/S0140-6736(18)30207-1&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=29433850&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-15-1" title="View reference 15 in text" id="ref-15">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.15"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Murakami</span> <span class="cit-name-given-names">T</span></span></li></ol><cite>: <span class="cit-article-title">Establishment and characterization of human hepatoma cell line (KIM-1)</span>. <abbr class="cit-jnl-abbrev">Act Hepatol Jpn</abbr> <span class="cit-vol">25</span>: <span class="cit-fpage">532</span>-<span class="cit-lpage">539</span>, <span class="cit-pub-date">1984</span>. </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DAct%2BHepatol%2BJpn%26rft.volume%253D25%26rft.spage%253D532%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a></div></div></li><li><div class="cit ref-cit ref-journal no-rev-xref" id="cit-39.11.5973.16" data-doi="10.1111/j.1440-1827.1988.tb02368.x"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Yano</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Maruiwa</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Murakami</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Fukuda</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ito</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Sugihara</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kojiro</span> <span class="cit-name-given-names">M</span></span></li></ol><cite>: <span class="cit-article-title">A new human pleomorphic hepatocellular carcinoma cell line, KYN-2</span>. <abbr class="cit-jnl-abbrev">Acta Pathol Jpn</abbr> <span class="cit-vol">38</span>(<span class="cit-issue">8</span>): <span class="cit-fpage">953</span>-<span class="cit-lpage">966</span>, <span class="cit-pub-date">1988</span>. <span class="cit-comment">PMID: 2847482. DOI: 10.1111/j.1440-1827.1988.tb02368.x</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DActa%2Bpathologica%2Bjaponica%26rft.stitle%253DActa%2BPathol%2BJpn%26rft.aulast%253DYano%26rft.auinit1%253DH.%26rft.volume%253D38%26rft.issue%253D8%26rft.spage%253D953%26rft.epage%253D966%26rft.atitle%253DA%2Bnew%2Bhuman%2Bpleomorphic%2Bhepatocellular%2Bcarcinoma%2Bcell%2Bline%252C%2BKYN-2.%26rft_id%253Dinfo%253Adoi%252F10.1111%252Fj.1440-1827.1988.tb02368.x%26rft_id%253Dinfo%253Apmid%252F2847482%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1111/j.1440-1827.1988.tb02368.x&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=2847482&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><div class="cit ref-cit ref-journal no-rev-xref" id="cit-39.11.5973.17"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Murakami</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Maruiwa</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Fukuda</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kojiro</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tanaka</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tanikawa</span> <span class="cit-name-given-names">K</span></span></li></ol><cite>: <span class="cit-article-title">Establishment and characterization of a new human hepatoma cell line (KYN-3) derived from the ascites of the hepatoma patient (Abstract)</span>. <abbr class="cit-jnl-abbrev">Jpn J Cancer Res Proc Jpn Cancer Assoc</abbr> <span class="cit-fpage">292</span>, <span class="cit-pub-date">1988</span>. </cite></div><div class="cit-extra"></div></div></li><li><div class="cit ref-cit ref-journal no-rev-xref" id="cit-39.11.5973.18" data-doi="10.1016/0270-9139(93)90015-F"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Yano</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Iemura</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Fukuda</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Mizoguchi</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Haramaki</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kojiro</span> <span class="cit-name-given-names">M</span></span></li></ol><cite>: <span class="cit-article-title">Establishment of two distinct human hepatocellular carcinoma cell lines from a single nodule showing clonal dedifferentiation of cancer cells</span>. <abbr class="cit-jnl-abbrev">Hepatology</abbr> <span class="cit-vol">18</span>(<span class="cit-issue">2</span>): <span class="cit-fpage">320</span>-<span class="cit-lpage">327</span>, <span class="cit-pub-date">1993</span>. <span class="cit-comment">PMID: 8393423.</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DHepatology%2B%2528Baltimore%252C%2BMd.%2529%26rft.stitle%253DHepatology%26rft.aulast%253DYano%26rft.auinit1%253DH%26rft.volume%253D18%26rft.issue%253D2%26rft.spage%253D320%26rft.epage%253D327%26rft.atitle%253DEstablishment%2Bof%2Btwo%2Bdistinct%2Bhuman%2Bhepatocellular%2Bcarcinoma%2Bcell%2Blines%2Bfrom%2Ba%2Bsingle%2Bnodule%2Bshowing%2Bclonal%2Bdedifferentiation%2Bof%2Bcancer%2Bcells%26rft_id%253Dinfo%253Adoi%252F10.1016%252F0270-9139%252893%252990015-F%26rft_id%253Dinfo%253Apmid%252F8393423%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1016/0270-9139(93)90015-F&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=8393423&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><div class="cit ref-cit ref-journal no-rev-xref" id="cit-39.11.5973.19"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Haramaki</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yano</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Iemura</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Momosaki</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ogasawara</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Inoue</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yamaguchi</span> <span class="cit-name-given-names">R</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kusaba</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Utsunomiya</span> <span class="cit-name-given-names">I</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kojiro</span> <span class="cit-name-given-names">M</span></span></li></ol><cite>: <span class="cit-article-title">A new human hepatocellular carcinoma cell line (HAK-2) forms various structures in collagen gel matrices</span>. <abbr class="cit-jnl-abbrev">Hum Cell</abbr> <span class="cit-vol">10</span>(<span class="cit-issue">3</span>): <span class="cit-fpage">183</span>-<span class="cit-lpage">192</span>, <span class="cit-pub-date">1997</span>. <span class="cit-comment">PMID: 9436038.</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DHuman%2Bcell%2B%253A%2B%2Bofficial%2Bjournal%2Bof%2BHuman%2BCell%2BResearch%2BSociety%26rft.stitle%253DHum%2BCell%26rft.aulast%253DHaramaki%26rft.auinit1%253DM.%26rft.volume%253D10%26rft.issue%253D3%26rft.spage%253D183%26rft.epage%253D192%26rft.atitle%253DA%2Bnew%2Bhuman%2Bhepatocellular%2Bcarcinoma%2Bcell%2Bline%2B%2528HAK-2%2529%2Bforms%2Bvarious%2Bstructures%2Bin%2Bcollagen%2Bgel%2Bmatrices.%26rft_id%253Dinfo%253Apmid%252F9436038%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=9436038&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><div class="cit ref-cit ref-journal no-rev-xref" id="cit-39.11.5973.20" data-doi="10.3892/ijo.15.4.669"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Utsunomiya</span> <span class="cit-name-given-names">I</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Iemura</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yano</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Akiba</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kojiro</span> <span class="cit-name-given-names">M</span></span></li></ol><cite>: <span class="cit-article-title">Establishment and characterization of a new human hepatocellular carcinoma cell line, HAK-3, and its response to growth factors</span>. <abbr class="cit-jnl-abbrev">Int J Oncol</abbr> <span class="cit-vol">15</span>(<span class="cit-issue">4</span>): <span class="cit-fpage">669</span>-<span class="cit-lpage">675</span>, <span class="cit-pub-date">1999</span>. <span class="cit-comment">PMID: 10493947. DOI: 10.3892/ijo.15.4.669</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DInternational%2Bjournal%2Bof%2Boncology%26rft.stitle%253DInt%2BJ%2BOncol%26rft.aulast%253DUtsunomiya%26rft.auinit1%253DI.%26rft.volume%253D15%26rft.issue%253D4%26rft.spage%253D669%26rft.epage%253D675%26rft.atitle%253DEstablishment%2Band%2Bcharacterization%2Bof%2Ba%2Bnew%2Bhuman%2Bhepatocellular%2Bcarcinoma%2Bcell%2Bline%252C%2BHAK-3%252C%2Band%2Bits%2Bresponse%2Bto%2Bgrowth%2Bfactors.%26rft_id%253Dinfo%253Adoi%252F10.3892%252Fijo.15.4.669%26rft_id%253Dinfo%253Apmid%252F10493947%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.3892/ijo.15.4.669&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=10493947&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><div class="cit ref-cit ref-journal no-rev-xref" id="cit-39.11.5973.21" data-doi="10.1002/hep.1840070322"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Murakami</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yano</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Maruiwa</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Sugihara</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kojiro</span> <span class="cit-name-given-names">M</span></span></li></ol><cite>: <span class="cit-article-title">Establishment and characterization of a human combined hepatocholangiocarcinoma cell line and its heterologous transplantation in nude mice</span>. <abbr class="cit-jnl-abbrev">Hepatology</abbr> <span class="cit-vol">7</span>(<span class="cit-issue">3</span>): <span class="cit-fpage">551</span>-<span class="cit-lpage">556</span>, <span class="cit-pub-date">1987</span>. <span class="cit-comment">PMID: 3032760. DOI: 10.1002/hep.1840070322</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DHepatology%2B%2528Baltimore%252C%2BMd.%2529%26rft.stitle%253DHepatology%26rft.aulast%253DMurakami%26rft.auinit1%253DT%26rft.volume%253D7%26rft.issue%253D3%26rft.spage%253D551%26rft.epage%253D556%26rft.atitle%253DEstablishment%2Band%2Bcharacterization%2Bof%2Ba%2Bhuman%2Bcombined%2Bhepatocholangiocarcinoma%2Bcell%2Bline%2Band%2Bits%2Bheterologous%2Btransplantation%2Bin%2Bnude%2Bmice%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fhep.1840070322%26rft_id%253Dinfo%253Apmid%252F3032760%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1002/hep.1840070322&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=3032760&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-22-1" title="View reference 22 in text" id="ref-22">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.22" data-doi="10.1016/s0168-8278(96)80161-9"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Yano</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Iemura</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Haramaki</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Momosaki</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ogasawara</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Higaki</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kojiro</span> <span class="cit-name-given-names">M</span></span></li></ol><cite>: <span class="cit-article-title">A human combined hepatocellular and cholangiocarcinoma cell line (KMCH-2) that shows the features of hepatocellular carcinoma or cholangiocarcinoma under different growth conditions</span>. <abbr class="cit-jnl-abbrev">J Hepatol</abbr> <span class="cit-vol">24</span>(<span class="cit-issue">4</span>): <span class="cit-fpage">413</span>-<span class="cit-lpage">422</span>, <span class="cit-pub-date">1996</span>. <span class="cit-comment">PMID: 8738727. DOI: 10.1016/s0168-8272(96)80161-9</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DJournal%2Bof%2Bhepatology%26rft.stitle%253DJ%2BHepatol%26rft.aulast%253DYano%26rft.auinit1%253DH.%26rft.volume%253D24%26rft.issue%253D4%26rft.spage%253D413%26rft.epage%253D422%26rft.atitle%253DA%2Bhuman%2Bcombined%2Bhepatocellular%2Band%2Bcholangiocarcinoma%2Bcell%2Bline%2B%2528KMCH-2%2529%2Bthat%2Bshows%2Bthe%2Bfeatures%2Bof%2Bhepatocellular%2Bcarcinoma%2Bor%2Bcholangiocarcinoma%2Bunder%2Bdifferent%2Bgrowth%2Bconditions.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fs0168-8278%252896%252980161-9%26rft_id%253Dinfo%253Apmid%252F8738727%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1016/s0168-8278(96)80161-9&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=8738727&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-23-1" title="View reference 23 in text" id="ref-23">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.23" data-doi="10.1002/hep.510240132"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Ogasawara</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yano</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Iemura</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Hisaka</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kojiro</span> <span class="cit-name-given-names">M</span></span></li></ol><cite>: <span class="cit-article-title">Expressions of basic fibroblast growth factor and its receptors and their relationship to proliferation of human hepatocellular carcinoma cell lines</span>. <abbr class="cit-jnl-abbrev">Hepatology</abbr> <span class="cit-vol">24</span>(<span class="cit-issue">1</span>): <span class="cit-fpage">198</span>-<span class="cit-lpage">205</span>, <span class="cit-pub-date">1996</span>. <span class="cit-comment">PMID: 8707262. DOI: 10.1053/jhep.1996.v24.pm0008707262</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DHepatology%2B%2528Baltimore%252C%2BMd.%2529%26rft.stitle%253DHepatology%26rft.aulast%253DOgasawara%26rft.auinit1%253DS%26rft.volume%253D24%26rft.issue%253D1%26rft.spage%253D198%26rft.epage%253D205%26rft.atitle%253DExpressions%2Bof%2Bbasic%2Bfibroblast%2Bgrowth%2Bfactor%2Band%2Bits%2Breceptors%2Band%2Btheir%2Brelationship%2Bto%2Bproliferation%2Bof%2Bhuman%2Bhepatocellular%2Bcarcinoma%2Bcell%2Blines.%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fhep.510240132%26rft_id%253Dinfo%253Apmid%252F8707262%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1002/hep.510240132&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=8707262&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-24-1" title="View reference 24 in text" id="ref-24">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.24"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Kusano</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ogasawara</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Akiba</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Nakayama</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ueda</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yano</span> <span class="cit-name-given-names">H</span></span></li></ol><cite>: <span class="cit-article-title">Antiproliferative effects of sorafenib and pegylated IFNalpha2b on human liver cancer cells <em>in vitro</em> and <em>in vivo</em></span>. <abbr class="cit-jnl-abbrev">Int J Oncol</abbr> <span class="cit-vol">42</span>(<span class="cit-issue">6</span>): <span class="cit-fpage">1897</span>-<span class="cit-lpage">1903</span>, <span class="cit-pub-date">2013</span>. <span class="cit-comment">PMID: 23588838. DOI: 10.3892/ijo.2013.1904</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DInt%2BJ%2BOncol%26rft.volume%253D42%26rft.spage%253D1897%26rft_id%253Dinfo%253Apmid%252F23588838%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=23588838&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-25-1" title="View reference 25 in text" id="ref-25">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.25" data-doi="10.1056/NEJMoa1406470"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Schlumberger</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tahara</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Wirth</span> <span class="cit-name-given-names">LJ</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Robinson</span> <span class="cit-name-given-names">B</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Brose</span> <span class="cit-name-given-names">MS</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Elisei</span> <span class="cit-name-given-names">R</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Habra</span> <span class="cit-name-given-names">MA</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Newbold</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Shah</span> <span class="cit-name-given-names">MH</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Hoff</span> <span class="cit-name-given-names">AO</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Gianoukakis</span> <span class="cit-name-given-names">AG</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kiyota</span> <span class="cit-name-given-names">N</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Taylor</span> <span class="cit-name-given-names">MH</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kim</span> <span class="cit-name-given-names">SB</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Krzyzanowska</span> <span class="cit-name-given-names">MK</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Dutcus</span> <span class="cit-name-given-names">CE</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">de las Heras</span> <span class="cit-name-given-names">B</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Zhu</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Sherman</span> <span class="cit-name-given-names">SI</span></span></li></ol><cite>: <span class="cit-article-title">Lenvatinib <em>versus</em> placebo in radioiodine-refractory thyroid cancer</span>. <abbr class="cit-jnl-abbrev">N Engl J Med</abbr> <span class="cit-vol">372</span>(<span class="cit-issue">7</span>): <span class="cit-fpage">621</span>-<span class="cit-lpage">630</span>, <span class="cit-pub-date">2015</span>. <span class="cit-comment">PMID: 25671254. DOI: 10.1056/NEJMoa1406470</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DN%2BEngl%2BJ%2BMed%26rft.volume%253D372%26rft.spage%253D621%26rft_id%253Dinfo%253Adoi%252F10.1056%252FNEJMoa1406470%26rft_id%253Dinfo%253Apmid%252F25671254%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1056/NEJMoa1406470&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=25671254&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-26-1" title="View reference 26 in text" id="ref-26">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.26" data-doi="10.1210/jc.2007-1714"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Elisei</span> <span class="cit-name-given-names">R</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Cosci</span> <span class="cit-name-given-names">B</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Romei</span> <span class="cit-name-given-names">C</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Bottici</span> <span class="cit-name-given-names">V</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Renzini</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Molinaro</span> <span class="cit-name-given-names">E</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Agate</span> <span class="cit-name-given-names">L</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Vivaldi</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Faviana</span> <span class="cit-name-given-names">P</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Basolo</span> <span class="cit-name-given-names">F</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Miccoli</span> <span class="cit-name-given-names">P</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Berti</span> <span class="cit-name-given-names">P</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Pacini</span> <span class="cit-name-given-names">F</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Pinchera</span> <span class="cit-name-given-names">A</span></span></li></ol><cite>: <span class="cit-article-title">Prognostic significance of somatic ret oncogene mutations in sporadic medullary thyroid cancer: A 10-year follow-up study</span>. <abbr class="cit-jnl-abbrev">J Clin Endocrinol Metab</abbr> <span class="cit-vol">93</span>(<span class="cit-issue">3</span>): <span class="cit-fpage">682</span>-<span class="cit-lpage">687</span>, <span class="cit-pub-date">2008</span>. <span class="cit-comment">PMID: 18073307. DOI: 10.1210/jc.2007-1714</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DJ%2BClin%2BEndocrinol%2BMetab%26rft_id%253Dinfo%253Adoi%252F10.1210%252Fjc.2007-1714%26rft_id%253Dinfo%253Apmid%252F18073307%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1210/jc.2007-1714&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=18073307&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-27-1" title="View reference 27 in text" id="ref-27">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.27" data-doi="10.1038/sj.bjc.6605056"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Moura</span> <span class="cit-name-given-names">MM</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Cavaco</span> <span class="cit-name-given-names">BM</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Pinto</span> <span class="cit-name-given-names">AE</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Domingues</span> <span class="cit-name-given-names">R</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Santos</span> <span class="cit-name-given-names">JR</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Cid</span> <span class="cit-name-given-names">MO</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Bugalho</span> <span class="cit-name-given-names">MJ</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Leite</span> <span class="cit-name-given-names">V</span></span></li></ol><cite>: <span class="cit-article-title">Correlation of <em>RET</em> somatic mutations with clinicopathological features in sporadic medullary thyroid carcinomas</span>. <abbr class="cit-jnl-abbrev">Br J Cancer</abbr> <span class="cit-vol">100</span>(<span class="cit-issue">11</span>): <span class="cit-fpage">1777</span>-<span class="cit-lpage">1783</span>, <span class="cit-pub-date">2009</span>. <span class="cit-comment">PMID: 19401695. DOI: 10.1038/sj.bjc.6605056</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DBritish%2BJournal%2Bof%2BCancer%26rft.stitle%253DBritish%2BJournal%2Bof%2BCancer%26rft.aulast%253DMoura%26rft.auinit1%253DM.%2BM.%26rft.volume%253D100%26rft.issue%253D11%26rft.spage%253D1777%26rft.epage%253D1783%26rft.atitle%253DCorrelation%2Bof%2BRET%2Bsomatic%2Bmutations%2Bwith%2Bclinicopathological%2Bfeatures%2Bin%2Bsporadic%2Bmedullary%2Bthyroid%2Bcarcinomas.%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fsj.bjc.6605056%26rft_id%253Dinfo%253Apmid%252F19401695%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1038/sj.bjc.6605056&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=19401695&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-28-1" title="View reference 28 in text" id="ref-28">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.28" data-doi="10.1158/1078-0432.CCR-16-1679"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Kato</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Subbiah</span> <span class="cit-name-given-names">V</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Marchlik</span> <span class="cit-name-given-names">E</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Elkin</span> <span class="cit-name-given-names">SK</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Carter</span> <span class="cit-name-given-names">JL</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kurzrock</span> <span class="cit-name-given-names">R</span></span></li></ol><cite>: <span class="cit-article-title"><em>RET</em> aberrations in diverse cancers: Next-generation sequencing of 4,871 patients</span>. <abbr class="cit-jnl-abbrev">Clin Cancer Res</abbr> <span class="cit-vol">23</span>(<span class="cit-issue">8</span>): <span class="cit-fpage">1988</span>-<span class="cit-lpage">1997</span>, <span class="cit-pub-date">2017</span>. <span class="cit-comment">PMID: 27683183. DOI: 10.1158/1078-0432.CCR-16-1679</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DClin%2BCancer%2BRes%26rft_id%253Dinfo%253Adoi%252F10.1158%252F1078-0432.CCR-16-1679%26rft_id%253Dinfo%253Apmid%252F27683183%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="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" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">Abstract</span><span class="cit-sep cit-reflinks-variant-name-sep">/</span><span class="cit-reflinks-full-text"><span class="free-full-text">FREE </span>Full Text</span></span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-29-1" title="View reference 29 in text" id="ref-29">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.29" data-doi="10.1002/hep.26679"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Sandhu</span> <span class="cit-name-given-names">DS</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Baichoo</span> <span class="cit-name-given-names">E</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Roberts</span> <span class="cit-name-given-names">LR</span></span></li></ol><cite>: <span class="cit-article-title">Fibroblast growth factor signaling in liver carcinogenesis</span>. <abbr class="cit-jnl-abbrev">Hepatology</abbr> <span class="cit-vol">59</span>(<span class="cit-issue">3</span>): <span class="cit-fpage">1166</span>-<span class="cit-lpage">1173</span>, <span class="cit-pub-date">2014</span>. <span class="cit-comment">PMID: 24716202. DOI: 10.1002/hep.26679</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DHepatology%26rft.volume%253D59%26rft.spage%253D1166%26rft_id%253Dinfo%253Adoi%252F10.1002%252Fhep.26679%26rft_id%253Dinfo%253Apmid%252F24716202%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1002/hep.26679&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=24716202&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-30-1" title="View reference 30 in text" id="ref-30">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.30"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Matsuki</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Hoshi</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yamamoto</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ikemori-Kawada</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Minoshima</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Funahashi</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Matsui</span> <span class="cit-name-given-names">J</span></span></li></ol><cite>: <span class="cit-article-title">Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models</span>. <abbr class="cit-jnl-abbrev">Cancer Med</abbr> <span class="cit-vol">7</span>(<span class="cit-issue">6</span>): <span class="cit-fpage">2641</span>-<span class="cit-lpage">2653</span>, <span class="cit-pub-date">2018</span>. <span class="cit-comment">PMID: 29733511. DOI: 10.1002/cam4.1517</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DCancer%2BMed%26rft.volume%253D7%26rft.spage%253D2641%26rft_id%253Dinfo%253Apmid%252F29733511%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=29733511&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-31-1" title="View reference 31 in text" id="ref-31">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.31"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Repana</span> <span class="cit-name-given-names">D</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ross</span> <span class="cit-name-given-names">P</span></span></li></ol><cite>: <span class="cit-article-title">Targeting FGF19/FGFR4 pathway: A novel therapeutic strategy for hepatocellular carcinoma</span>. <abbr class="cit-jnl-abbrev">Diseases</abbr> <span class="cit-vol">3</span>(<span class="cit-issue">4</span>): <span class="cit-fpage">294</span>-<span class="cit-lpage">305</span>, <span class="cit-pub-date">2015</span>. <span class="cit-comment">PMID: 28943626. DOI: 10.3390/diseases3040294</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DDiseases%26rft.volume%253D3%26rft.spage%253D294%26rft_id%253Dinfo%253Apmid%252F28943626%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=28943626&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><div class="cit ref-cit ref-journal no-rev-xref" id="cit-39.11.5973.32" data-doi="10.1371/journal.pone.0036713"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">French</span> <span class="cit-name-given-names">DM</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Lin</span> <span class="cit-name-given-names">BC</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Wang</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Adams</span> <span class="cit-name-given-names">C</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Shek</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Hotzel</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Bolon</span> <span class="cit-name-given-names">B</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ferrando</span> <span class="cit-name-given-names">R</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Blackmore</span> <span class="cit-name-given-names">C</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Schroeder</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Rodriguez</span> <span class="cit-name-given-names">LA</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Hristopoulos</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Venook</span> <span class="cit-name-given-names">R</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ashkenazi</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Desnoyers</span> <span class="cit-name-given-names">LR</span></span></li></ol><cite>: <span class="cit-article-title">Targeting FGFR4 inhibits hepatocellular carcinoma in preclinical mouse models</span>. <abbr class="cit-jnl-abbrev">PLoS One</abbr> <span class="cit-vol">7</span>(<span class="cit-issue">5</span>): <span class="cit-fpage">e36713</span>, <span class="cit-pub-date">2012</span>. <span class="cit-comment">PMID: 22615798. DOI: 10.1371/journal.pone.0036713</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.stitle%253DPLoS%2BONE%26rft.aulast%253DFrench%26rft.auinit1%253DD.%2BM.%26rft.volume%253D7%26rft.issue%253D5%26rft.spage%253De36713%26rft.epage%253De36713%26rft.atitle%253DTargeting%2BFGFR4%2Binhibits%2Bhepatocellular%2Bcarcinoma%2Bin%2Bpreclinical%2Bmouse%2Bmodels.%26rft_id%253Dinfo%253Adoi%252F10.1371%252Fjournal.pone.0036713%26rft_id%253Dinfo%253Apmid%252F22615798%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1371/journal.pone.0036713&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=22615798&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-33-1" title="View reference 33 in text" id="ref-33">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.33" data-doi="10.1016/j.jhep.2008.08.015"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Ho</span> <span class="cit-name-given-names">HK</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Pok</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Streit</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ruhe</span> <span class="cit-name-given-names">JE</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Hart</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Lim</span> <span class="cit-name-given-names">KS</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Loo</span> <span class="cit-name-given-names">HL</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Aung</span> <span class="cit-name-given-names">MO</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Lim</span> <span class="cit-name-given-names">SG</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ullrich</span> <span class="cit-name-given-names">A</span></span></li></ol><cite>: <span class="cit-article-title">Fibroblast growth factor receptor 4 regulates proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma progression and represents a potential target for therapeutic intervention</span>. <abbr class="cit-jnl-abbrev">J Hepatol</abbr> <span class="cit-vol">50</span>(<span class="cit-issue">1</span>): <span class="cit-fpage">118</span>-<span class="cit-lpage">127</span>, <span class="cit-pub-date">2009</span>. <span class="cit-comment">PMID: 19008009. DOI: 10.1016/j.jhep.2008.08.015</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DJournal%2Bof%2Bhepatology%26rft.stitle%253DJ%2BHepatol%26rft.aulast%253DHo%26rft.auinit1%253DH.%2BK.%26rft.volume%253D50%26rft.issue%253D1%26rft.spage%253D118%26rft.epage%253D127%26rft.atitle%253DFibroblast%2Bgrowth%2Bfactor%2Breceptor%2B4%2Bregulates%2Bproliferation%252C%2Banti-apoptosis%2Band%2Balpha-fetoprotein%2Bsecretion%2Bduring%2Bhepatocellular%2Bcarcinoma%2Bprogression%2Band%2Brepresents%2Ba%2Bpotential%2Btarget%2Bfor%2Btherapeutic%2Bintervention.%26rft_id%253Dinfo%253Adoi%252F10.1016%252Fj.jhep.2008.08.015%26rft_id%253Dinfo%253Apmid%252F19008009%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1016/j.jhep.2008.08.015&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=19008009&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-34-1" title="View reference 34 in text" id="ref-34">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.34" data-doi="10.1038/nrc.2017.8"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Babina</span> <span class="cit-name-given-names">IS</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Turner</span> <span class="cit-name-given-names">NC</span></span></li></ol><cite>: <span class="cit-article-title">Advances and challenges in targeting FGFR signalling in cancer</span>. <abbr class="cit-jnl-abbrev">Nat Rev Cancer</abbr> <span class="cit-vol">17</span>(<span class="cit-issue">5</span>): <span class="cit-fpage">318</span>-<span class="cit-lpage">332</span>, <span class="cit-pub-date">2017</span>. <span class="cit-comment">PMID: 28303906. DOI: 10.1038/nrc.2017.8</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DNat%2BRev%2BCancer%26rft.volume%253D17%26rft.spage%253D318%26rft_id%253Dinfo%253Adoi%252F10.1038%252Fnrc.2017.8%26rft_id%253Dinfo%253Apmid%252F28303906%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1038/nrc.2017.8&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=28303906&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-35-1" title="View reference 35 in text" id="ref-35">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.35"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Ferrari</span> <span class="cit-name-given-names">SM</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Bocci</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Di Desidero</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Elia</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ruffilli</span> <span class="cit-name-given-names">I</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ragusa</span> <span class="cit-name-given-names">F</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Orlandi</span> <span class="cit-name-given-names">P</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Paparo</span> <span class="cit-name-given-names">SR</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Patrizio</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Piaggi</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">La Motta</span> <span class="cit-name-given-names">C</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ulisse</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Baldini</span> <span class="cit-name-given-names">E</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Materazzi</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Miccoli</span> <span class="cit-name-given-names">P</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Antonelli</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Fallahi</span> <span class="cit-name-given-names">P</span></span></li></ol><cite>: <span class="cit-article-title">Lenvatinib exhibits antineoplastic activity in anaplastic thyroid cancer <em>in vitro</em> and <em>in vivo</em></span>. <abbr class="cit-jnl-abbrev">Oncol Rep</abbr> <span class="cit-vol">39</span>(<span class="cit-issue">5</span>): <span class="cit-fpage">2225</span>-<span class="cit-lpage">2234</span>, <span class="cit-pub-date">2018</span>. <span class="cit-comment">PMID: 29517103. DOI: 10.3892/or.2018.6306</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DOncol%2BRep%26rft.volume%253D39%26rft.spage%253D2225%26rft_id%253Dinfo%253Apmid%252F29517103%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=29517103&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-36-1" title="View reference 36 in text" id="ref-36">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.36"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Wang</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Zhuang</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ni</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ye</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">He</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Xia</span> <span class="cit-name-given-names">W</span></span></li></ol><cite>: <span class="cit-article-title">Combined effects of lenvatinib and iodine-131 on cell apoptosis in nasopharyngeal carcinoma through inducing endoplasmic reticulum stress</span>. <abbr class="cit-jnl-abbrev">Exp Ther Med</abbr> <span class="cit-vol">16</span>(<span class="cit-issue">4</span>): <span class="cit-fpage">3325</span>-<span class="cit-lpage">3332</span>, <span class="cit-pub-date">2018</span>. <span class="cit-comment">PMID: 30233679. DOI: 10.3892/etm.2018.6652</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DExp%2BTher%2BMed%26rft.volume%253D16%26rft.spage%253D3325%26rft_id%253Dinfo%253Apmid%252F30233679%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=30233679&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-37-1" title="View reference 37 in text" id="ref-37">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.37"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Ogasawara</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Nakayama</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Akiba</span> <span class="cit-name-given-names">J</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Kusano</span> <span class="cit-name-given-names">H</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Yano</span> <span class="cit-name-given-names">H</span></span></li></ol><cite>: <span class="cit-article-title">Effect of sorafenib on des-gamma-carboxyprothrombin secretion by a human hepatocellular carcinoma cell line</span>. <abbr class="cit-jnl-abbrev">Oncol Lett</abbr> <span class="cit-vol">14</span>(<span class="cit-issue">2</span>): <span class="cit-fpage">2170</span>-<span class="cit-lpage">2176</span>, <span class="cit-pub-date">2017</span>. <span class="cit-comment">PMID: 28781657. DOI: 10.3892/ol.2017.6451</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DOncol%2BLett%26rft.volume%253D14%26rft.spage%253D2170%26rft_id%253Dinfo%253Apmid%252F28781657%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=28781657&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-38-1" title="View reference 38 in text" id="ref-38">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.38" data-doi="10.1021/jm8010299"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Kufareva</span> <span class="cit-name-given-names">I</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Abagyan</span> <span class="cit-name-given-names">R</span></span></li></ol><cite>: <span class="cit-article-title">Type-II kinase inhibitor docking, screening, and profiling using modified structures of active kinase states</span>. <abbr class="cit-jnl-abbrev">J Med Chem</abbr> <span class="cit-vol">51</span>(<span class="cit-issue">24</span>): <span class="cit-fpage">7921</span>-<span class="cit-lpage">7932</span>, <span class="cit-pub-date">2008</span>. <span class="cit-comment">PMID: 19053777. DOI: 10.1021/jm8010299</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DJournal%2Bof%2Bmedicinal%2Bchemistry%26rft.stitle%253DJ%2BMed%2BChem%26rft.aulast%253DKufareva%26rft.auinit1%253DI.%26rft.volume%253D51%26rft.issue%253D24%26rft.spage%253D7921%26rft.epage%253D7932%26rft.atitle%253DType-II%2Bkinase%2Binhibitor%2Bdocking%252C%2Bscreening%252C%2Band%2Bprofiling%2Busing%2Bmodified%2Bstructures%2Bof%2Bactive%2Bkinase%2Bstates.%26rft_id%253Dinfo%253Adoi%252F10.1021%252Fjm8010299%26rft_id%253Dinfo%253Apmid%252F19053777%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1021/jm8010299&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=19053777&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-39-1" title="View reference 39 in text" id="ref-39">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.39" data-doi="10.1021/ml500394m"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Okamoto</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ikemori-Kawada</span> <span class="cit-name-given-names">M</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Jestel</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">von Konig</span> <span class="cit-name-given-names">K</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Funahashi</span> <span class="cit-name-given-names">Y</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Matsushima</span> <span class="cit-name-given-names">T</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Tsuruoka</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Inoue</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Matsui</span> <span class="cit-name-given-names">J</span></span></li></ol><cite>: <span class="cit-article-title">Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization</span>. <abbr class="cit-jnl-abbrev">ACS Med Chem Lett</abbr> <span class="cit-vol">6</span>(<span class="cit-issue">1</span>): <span class="cit-fpage">89</span>-<span class="cit-lpage">94</span>, <span class="cit-pub-date">2015</span>. <span class="cit-comment">PMID: 25589937. DOI: 10.1021/ml500394m</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DACS%2BMed%2BChem%2BLett%26rft.volume%253D6%26rft.spage%253D89%26rft_id%253Dinfo%253Adoi%252F10.1021%252Fml500394m%26rft_id%253Dinfo%253Apmid%252F25589937%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="/lookup/external-ref?access_num=10.1021/ml500394m&link_type=DOI" class="cit-ref-sprinkles cit-ref-sprinkles-doi cit-ref-sprinkles-crossref"><span>CrossRef</span></a><a href="/lookup/external-ref?access_num=25589937&link_type=MED&atom=%2Fanticanres%2F39%2F11%2F5973.atom" class="cit-ref-sprinkles cit-ref-sprinkles-medline"><span>PubMed</span></a></div></div></li><li><a class="rev-xref-ref" href="#xref-ref-40-1" title="View reference 40 in text" id="ref-40">↵</a><div class="cit ref-cit ref-journal" id="cit-39.11.5973.40" data-doi="10.1083/jcb.141.7.1659"><div class="cit-metadata"><ol class="cit-auth-list"><li><span class="cit-auth"><span class="cit-name-surname">Seghezzi</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Patel</span> <span class="cit-name-given-names">S</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Ren</span> <span class="cit-name-given-names">CJ</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Gualandris</span> <span class="cit-name-given-names">A</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Pintucci</span> <span class="cit-name-given-names">G</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Robbins</span> <span class="cit-name-given-names">ES</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Shapiro</span> <span class="cit-name-given-names">RL</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Galloway</span> <span class="cit-name-given-names">AC</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Rifkin</span> <span class="cit-name-given-names">DB</span></span>, </li><li><span class="cit-auth"><span class="cit-name-surname">Mignatti</span> <span class="cit-name-given-names">P</span></span></li></ol><cite>: <span class="cit-article-title">Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: An autocrine mechanism contributing to angiogenesis</span>. <abbr class="cit-jnl-abbrev">J Cell Biol</abbr> <span class="cit-vol">141</span>(<span class="cit-issue">7</span>): <span class="cit-fpage">1659</span>-<span class="cit-lpage">1673</span>, <span class="cit-pub-date">1998</span>. <span class="cit-comment">PMID: 9647657. DOI: 10.1083/jcb.141.7.1659</span> </cite></div><div class="cit-extra"><a href="{openurl}?query=rft.jtitle%253DJ%2BCell%2BBiol%26rft_id%253Dinfo%253Adoi%252F10.1083%252Fjcb.141.7.1659%26rft_id%253Dinfo%253Apmid%252F9647657%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx" class="cit-ref-sprinkles cit-ref-sprinkles-openurl cit-ref-sprinkles-open-url"><span>OpenUrl</span></a><a href="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" class="cit-ref-sprinkles cit-ref-sprinkles-ijlink"><span><span class="cit-reflinks-abstract">Abstract</span><span class="cit-sep cit-reflinks-variant-name-sep">/</span><span class="cit-reflinks-full-text"><span 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