Journal Mobile Options
Table of Contents
Vol. 81, No. 5-6, 2011
Issue release date: February 2012
Oncology 2011;81:372–380

Targeting Fibroblast Growth Factor Receptor Signaling in Hepatocellular Carcinoma

Cheng A.-L. · Shen Y.-C. · Zhu A.X.
Departments of aOncology and bInternal Medicine, National Taiwan University Hospital, cInstitute of Oncology, National Taiwan University, and dNational Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan; eMassachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Mass., USA

Individual Users: Register with Karger Login Information

Please create your User ID & Password

Contact Information

I have read the Karger Terms and Conditions and agree.

To view the fulltext, please log in

To view the pdf, please log in


Hepatocellular carcinoma (HCC) is the primary type of liver cancer, and both the age-adjusted incidence and mortality of HCC have steadily increased in recent years. Advanced HCC is associated with a very poor survival rate. Despite accumulating data regarding the risk factors for HCC, the mechanisms that contribute to HCC tumorigenesis remain poorly understood. Signaling through the fibroblast growth factor (FGF) family is involved in fibrosis and its progression to cirrhosis of the liver, which is a risk factor for the development of HCC. Furthermore, several alterations in FGF/FGF receptor (FGFR) signaling correlate with the outcomes of HCC patients, suggesting that signaling through this family of proteins contributes to the development or progression of HCC tumors. Currently, there are no established systemic treatments for patients with advanced HCC in whom sorafenib treatment has failed or who were unable to tolerate it. Recently, several multikinase inhibitors that target FGFRs have demonstrated some early evidence of antitumor activity in phase I/II trials. Therefore, this review discusses the molecular implications of FGFR-mediated signaling in HCC and summarizes the clinical evidence for novel FGFR-targeted therapies for HCC currently being studied in clinical trials.

Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.


  1. Altekruse SF, McGlynn KA, Reichman ME: Hepatocellular carcinoma incidence, mortality, and survival trends in the United States from 1975 to 2005. J Clin Oncol 2009;27:1485–1491.
  2. National Comprehensive Cancer Network: NCCN Clinical practice guidelines in oncology. Hepatobiliary Cancers, version 1. 2011.
  3. Bruix J, Sherman M: Management of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–1022.
  4. Motoo Y, Sawabu N, Yamaguchi Y, Terada T, Nakanuma Y: Sinusoidal capillarization of human hepatocellular carcinoma: possible promotion by fibroblast growth factor. Oncology 1993;50:270–274.
  5. Poon RT, Ng IO, Lau C, Yu WC, Fan ST, Wong J: Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinoma. Am J Surg 2001;182:298–304.
  6. Shackel NA, McGuinness PH, Abbott CA, Gorrell MD, McCaughan GW: Insights into the pathobiology of hepatitis C virus-associated cirrhosis: analysis of intrahepatic differential gene expression. Am J Pathol 2002;160:641–654.
  7. Turner N, Grose R: Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 2010;10:116–129.
  8. Hughes SE: Differential expression of the fibroblast growth factor receptor (FGFR) multigene family in normal human adult tissues. J Histochem Cytochem 1997;45:1005–1019.
  9. Presta M, Maier JAM, Rusnati M, Ragnotti G: Basic fibroblast growth factor is released from endothelial extracellular matrix in a biologically active form. J Cell Physiol 1989;140:68–74.
  10. Serls AE, Doherty S, Parvatiyar P, Wells JM, Deutsch GH: Different thresholds of fibroblast growth factors pattern the ventral foregut into liver and lung. Development 2005;132:35–47.
  11. Werner S, Peters KG, Longaker MT, Fuller-Pace F, Banda MJ, Williams LT: Large induction of keratinocyte growth factor expression in the dermis during wound healing. Proc Natl Acad Sci USA 1992;89:6896–6900.
  12. Desnoyers LR, Pai R, Ferrando RE, Hotzel K, Le T, Ross J, Carano R, D’Souza A, Qing J, Mohtashemi I, Ashkenazi A, French DM: Targeting FGF19 inhibits tumor growth in colon cancer xenograft and FGF19 transgenic hepatocellular carcinoma models. Oncogene 2008;27:85–97.
  13. Nicholes K, Guillet S, Tomlinson E, Hillan K, Wright B, Frantz GD, Pham TA, Dillard-Telm L, Tsai SP, Stephan JP, Stinson J, Stewart T, French DM: A mouse model of hepatocellular carcinoma: ectopic expression of fibroblast growth factor 19 in skeletal muscle of transgenic mice. Am J Pathol 2002;160:2295–2307.
  14. Wu X, Ge H, Lemon B, Vonderfecht S, Weiszmann J, Hecht R, Gupte J, Hager T, Wang Z, Lindberg R, Li Y: FGF19-induced hepatocyte proliferation is mediated through FGFR4 activation. J Biol Chem 2010;285:5165–5170.
  15. Sawey ET, Chanrion M, Cai C, Wu G, Zhang J, Zender L, Zhao A, Busuttil RW, Yee H, Stein L, French DM, Finn RS, Lowe SW, Powers S: Identification of a therapeutic strategy targeting amplified FGF19 in liver cancer by oncogenomic screening. Cancer Cell 2011;19:347–358.
  16. Mas VR, Maluf DG, Archer KJ, Yanek KC, Fisher RA: Angiogenesis soluble factors as hepatocellular carcinoma noninvasive markers for monitoring hepatitis C virus cirrhotic patients awaiting liver transplantation. Transplantation 2007;84:1262–1271.
  17. Harimoto N, Taguchi K, Shirabe K, Adachi E, Sakaguchi Y, Toh Y, Okamura T, Kayashima H, Taketomi A, Maehara Y: The significance of fibroblast growth factor receptor 2 expression in differentiation of hepatocellular carcinoma. Oncology 2010;78:361–368.
  18. Qiu WH, Zhou BS, Chu PG, Chen WG, Chung C, Shih J, Hwu P, Yeh C, Lopez R, Yen Y: Over-expression of fibroblast growth factor receptor 3 in human hepatocellular carcinoma. World J Gastroenterol 2005;11:5266–5272.
  19. Ho HK, Pok S, Streit S, Ruhe JE, Hart S, Lim KS, Loo HL, Aung MO, Lim SG, Ullrich A: 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. J Hepatol 2009;50:118–127.
  20. Gauglhofer C, Sagmeister S, Schrottmaier W, Fischer C, Rodgarkia-Dara C, Mohr T, Stattner S, Bichler C, Kandioler D, Wrba F, Schulte-Hermann R, Holzmann K, Grusch M, Marian B, Berger W, Grasl-Kraupp B: Up-regulation of the fibroblast growth factor 8 subfamily in human hepatocellular carcinoma for cell survival and neoangiogenesis. Hepatology 2011;53:854–864.
  21. Jin-no K, Tanimizu M, Hyodo I, Kurimoto F, Yamashita T: Plasma level of basic fibroblast growth factor increases with progression of chronic liver disease. J Gastroenterol 1997;32:119–121.
  22. Kanda S, Tomasini-Johansson B, Klint P, Dixelius J, Rubin K, Claesson-Welsh L: Signaling via fibroblast growth factor receptor-1 is dependent on extracellular matrix in capillary endothelial cell differentiation. Exp Cell Res 1999;248:203–213.
  23. Uematsu S, Higashi T, Nouso K, Kariyama K, Nakamura S, Suzuki M, Nakatsukasa H, Kobayashi Y, Hanafusa T, Tsuji T, Shiratori Y: Altered expression of vascular endothelial growth factor, fibroblast growth factor-2 and endostatin in patients with hepatocellular carcinoma. J Gastroenterol Hepatol 2005;20:583–588.
  24. Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG, Cohen KS, Kozak KR, Cahill DP, Chen PJ: AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. 2007;11:83–95.
  25. Casanovas O, Hicklin DJ, Bergers G, Hanahan D: Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 2005;8:299–309.
  26. Bataller R, Brenner DA: Liver fibrosis. J Clin Invest 2005;115:209–218.
  27. Gressner AM, Weiskirchen R: Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-β as major players and therapeutic targets. J Cell Mol Med 2006;10:76–99.
  28. Yu C, Wang F, Jin C, Huang X, Miller DL, Basilico C, McKeehan WL: Role of fibroblast growth factor type 1 and 2 in carbon tetrachloride-induced hepatic injury and fibrogenesis. Am J Pathol 2003;163:1653–1662.
  29. Antoine M, Wirz W, Tag CG, Gressner AM, Marvituna M, Wycislo M, Hellerbrand C, Kiefer P: Expression and function of fibroblast growth factor (FGF) 9 in hepatic stellate cells and its role in toxic liver injury. Biochem Biophys Res Commun 2007;361:335–341.
  30. Yu C, Wang F, Jin C, Wu X, Chan W, McKeehan WL: Increased carbon tetrachloride-induced liver injury and fibrosis in FGFR4-deficient mice. Am J Pathol 2002;161:2003–2010.
  31. Böhm F, Speicher T, Hellerbrand C, Dickson C, Partanen J, Ornitz D, Werner S: FGF receptors 1 and 2 control chemically-induced injury and compound detoxification in regenerating livers of mice. Gastroenterology 2010;139:1385–1396.
  32. Simonetti RG, Camma C, Fiorello F, Politi F, D’Amico G, Pagliaro L: Hepatocellular carcinoma. A worldwide problem and the major risk factors. Dig Dis Sci 1991;36:962–972.
  33. Bhide RS, Lombardo LJ, Hunt JT, Cai Z, Barrish JC, Galbraith S, Jeyaseelan R, Mortillo S, Wautlet BS, Krishnan B: The antiangiogenic activity in xenograft models of brivanib, a dual inhibitor of vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 kinases. Mol Cancer Ther 2010;9:369–378.
  34. Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, Thng CH, Ong HS, Chung A, Chow P, Pollock P, Byron S, Tran E: Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res 2008;14:6146–6153.
  35. Jonker DJ, Rosen LS, Sawyer MB, de Braud F, Wilding G, Sweeney CJ, Jayson GC, McArthur GA, Rustin G, Goss G, Kantor J, Velasquez L, Syed S, Mokliatchouk O, Feltquate DM, Kollia G, Nuyten DS, Galbraith S: A phase I study to determine the safety, pharmacokinetics and pharmacodynamics of a dual VEGFR and FGFR inhibitor, brivanib, in patients with advanced or metastatic solid tumors. Ann Oncol 2011;22:1413–1419.
  36. Park JW, Finn RS, Kim JS, Karwal M, Li RK, Ismail F, Thomas MB, Harris R, Baudelet C, Walters I, Raoul J: Phase II, open-label study of brivanib as first-line therapy in patients with advanced hepatocellular carcinoma. Clin Cancer Res 2011;17:1973–1983.
  37. Raoul JL, Finn RS, Kang YK, Park JW, Harris R, Coric V, Donica M, Walters I: An open-label phase II study of first- and second-line treatment with brivanib in patients with hepatocellular carcinoma (HCC) (abstract 4577). J Clin Oncol 2009;27:15s.

    External Resources

  38. Sarker D, Molife R, Evans TR, Hardie M, Marriott C, Butzberger-Zimmerli P, Morrison R, Fox JA, Heise C, Louie S, Aziz N, Garzon F, Michelson G, Judson IR, Jadayel D, Braendle E, de Bono JS: A phase I pharmacokinetic and pharmacodynamic study of TKI258, an oral, multitargeted receptor tyrosine kinase inhibitor in patients with advanced solid tumors. Clin Cancer Res 2008;14:2075–2081.
  39. Kanai F, Yoshida H, Tateishi R, Sato S, Kawabe T, Obi S, Kondo Y, Taniguchi M, Tagawa K, Ikeda M, Morizane C, Okusaka T, Arioka H, Shiina S, Omata M: A phase I/II trial of the oral antiangiogenic agent TSU-68 in patients with advanced hepatocellular carcinoma. Cancer Chemother Pharmacol 2011;67:315–324.
  40. Mross K, Stefanic M, Gmehling D, Frost A, Baas F, Unger C, Strecker R, Henning J, Gaschler-Markefski B, Stopfer P, de Rossi L, Kaiser R: Phase I study of the angiogenesis inhibitor BIBF 1120 in patients with advanced solid tumors. Clin Cancer Res 2010;16:311–319.
  41. Kudo K, Arao T, Tanaka K, Nagai T, Furuta K, Sakai K, Kaneda H, Matsumoto K, Tamura D, Aomatsu K, De Velasco MA, Fujita Y, Saijo N, Kudo M, Nishio K: Antitumor activity of BIBF 1120, a triple angiokinase inhibitor, and use of VEGFR2+pTyr+ peripheral blood leukocytes as a pharmacodynamic biomarker in vivo. Clin Cancer Res 2011;17:1373–1381.
  42. Chaudhary NI, Roth GJ, Hilberg F, Müller-Quernheim J, Prasse A, Zissel G, Schnapp A, Park JE: Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis. Eur Respir J 2007;29:976–985.
  43. Richeldi L, Costabel U, Selman M, Kim DS, Hansell DM, Nicholson AG, Brown KK, Flaherty KR, Noble PW, Raghu G, Brun M, Gupta A, Juhel N, Kluglich M, du Bois RM: Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011;365:1079–1087.
  44. Bello E, Colella G, Scarlato V, Oliva P, Berndt A, Valbusa G, Serra SC, D’Incalci M, Cavalletti E, Giavazzi R: E-3810 is a potent dual inhibitor of VEGFR and FGFR that exerts antitumor activity in multiple preclinical models. Cancer Res 2011;71:1396–1405.
  45. Soria J, De Braud FG, Cereda R, Bahleda R, Delmonte A, Angevin E, Varga A, Noberasco C, Dall’O’ E, Lassau N, Dromain C, Bellomi M, Farace F, Bertolini F, Zucchetti M, Marsoni S, Camboni MG: First-in-man study of E-3810, a novel VEGFR and FGFR inhibitor, in patients with advanced solid tumors. J Clin Oncol 2011;29(suppl):abstract TPS149.
  46. Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM: Receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 2006;281:15694–15700.
  47. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JÖ, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM: In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res 2003;9:327–337.
  48. Paz K, Zhu Z: Development of angiogenesis inhibitors to vascular endothelial growth factor receptor 2 for cancer therapy; in Bradbury RH (ed): Cancer. Top Med Chem. Berlin, Springer, 2007, vol 1, pp 333–382.

Pay-per-View Options
Direct payment This item at the regular price: USD 38.00
Payment from account With a Karger Pay-per-View account (down payment USD 150) you profit from a special rate for this and other single items.
This item at the discounted price: USD 26.50