Top

Published in:

01-01-2014 | Review

The EGFR signalling system in the liver: from hepatoprotection to hepatocarcinogenesis

Authors: Carmen Berasain, Matías A. Avila

Published in: Journal of Gastroenterology | Issue 1/2014

Abstract

The liver displays an outstanding wound healing and regenerative capacity unmatched by any other organ. This reparative response is governed by a complex network of inflammatory mediators, growth factors and metabolites that are set in motion in response to hepatocellular injury. However, when liver injury is chronic, these regenerative mechanisms become dysregulated, facilitating the accumulation of genetic alterations leading to unrestrained cell proliferation and the development of hepatocellular carcinoma (HCC). The epidermal growth factor receptor (EGFR or ErbB1) signaling system has been identified as a key player in all stages of the liver response to injury, from early inflammation and hepatocellular proliferation to fibrogenesis and neoplastic transformation. The EGFR system engages in extensive crosstalk with other signaling pathways, acting as a true signaling hub for other growth factors, cytokines and inflammatory mediators. Here, we briefly review essential aspects of the biology of the EGFR, the other ErbB receptors, and their ligands in liver injury, regeneration and HCC development. Some aspects of the preclinical and clinical experience with EGFR therapeutic targeting in HCC are also discussed.

Schlessinger J. Ligand-induced, receptor-mediated dimerization and activation of EGF receptor. Cell. 2002;20(110):669–72.

Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7:505–16.PubMed

Schneider MR, Wolf E. The epidermal growth factor receptor ligands at a glance. J Cell Physiol. 2009;218:460–6.PubMed

Jorissen RN, Walker F, Pouliot N, Garrett TPJ, Ward CW, Burgess AW. Epidermal growth factor receptor: mechanisms of activation and signalling. Exp Cell Res. 2003;10(284):31–53.

Normanno N, De Luca A, Bianco C, Strizzi L, Mancino M, Maiello MR, et al. Epidermal growth factor receptor (EGFR) signaling in cancer. Gene. 2006;17(366):2–16.

Shi F, Telesco SE, Liu Y, Radhakrishnan R, Lemmon MA. ErbB3/HER3 intracellular domain is competent to bind ATP and catalyze autophosphorylation. Proc Natl Acad Sci USA. 2010;27(107):7692–7.

Soderquist AM, Todderud G, Carpenter G. The role of carbohydrate as a post-translational modification of the receptor for epidermal growth factor. Adv Exp Med Biol. 1988;231:569–82.PubMed

Bishayee S. Role of conformational alteration in the epidermal growth factor receptor (EGFR) function. Biochem Pharmacol. 2000;15(60):1217–23.

Holbro T, Hynes NE. ErbB receptors: directing key signaling networks throughout life. Annu Rev Pharmacol Toxicol. 2004;44:195–217.PubMed

10.

Prenzel N, Fischer OM, Streit S, Hart S, Ullrich A. The epidermal growth factor receptor family as a central element for cellular signal transduction and diversification. Endocr Relat Cancer. 2001;8:11–31.PubMed

11.

Cavin LG, Wang F, Factor VM, Kaur S, Venkatraman M, Thorgeirsson SS, et al. Transforming growth factor-alpha inhibits the intrinsic pathway of c-Myc-induced apoptosis through activation of nuclear factor-kappaB in murine hepatocellular carcinomas. Mol Cancer Res. 2005;3:403–12.PubMed

12.

Sibilia M, Kroismayr R, Lichtenberger BM, Natarajan A, Hecking M, Holcmann M. The epidermal growth factor receptor: from development to tumorigenesis. Differentiation. 2007;75:770–87.PubMed

13.

Andreu-Pérez P, Esteve-Puig R, de Torre-Minguela C, López-Fauqued M, Bech-Serra JJ, Tenbaum S, et al. Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF. Sci Signal. 2011;4:ra58.PubMed

14.

Segatto O, Anastasi S, Alemà S. Regulation of epidermal growth factor receptor signalling by inducible feedback inhibitors. J Cell Sci. 2011;1(124):1785–93.

15.

Zhang C, Li A, Zhang X, Xiao H. A novel TIP30 protein complex regulates EGF receptor signaling and endocytic degradation. J Biol Chem. 2011;18(286):9373–81.

16.

Avraham R, Yarden Y. Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat Rev Mol Cell Biol. 2011;12:104–17.PubMed

17.

Harris RC, Chung E, Coffey RJ. EGF receptor ligands. Exp Cell Res. 2003;10(284):2–13.

18.

Blobel CP. ADAMs: key components in EGFR signalling and development. Nat Rev Mol Cell Biol. 2005;6:32–43.PubMed

19.

Blobel CP, Carpenter G, Freeman M. The role of protease activity in ErbB biology. Exp Cell Res. 2009;315:671–82.PubMedCentralPubMed

20.

Adrain C, Strisovsky K, Zettl M, Hu L, Lemberg MK, Freeman M. Mammalian EGF receptor activation by the rhomboid protease RHBDL2. EMBO Rep. 2011;12:421–7.PubMedCentralPubMed

21.

Nishi E, Klagsbrun M. Heparin-binding epidermal growth factor-like growth factor (HB-EGF) is a mediator of multiple physiological and pathological pathways. Growth Factors. 2004;22:253–60.PubMed

22.

Stoll SW, Johnson JL, Li Y, Rittié L, Elder JT. Amphiregulin carboxy-terminal domain is required for autocrine keratinocyte growth. J Investig Dermatol. 2010;130:2031–40.PubMedCentralPubMed

23.

Ohtsu H, Dempsey PJ, Eguchi S. ADAMs as mediators of EGF receptor transactivation by G protein-coupled receptors. Am J Physiol Cell Physiol. 2006;291:C1–10.PubMed

24.

Almendro V, García-Recio S, Gascón P. Tyrosine kinase receptor transactivation associated to G protein-coupled receptors. Curr Drug Targets. 2010;11:1169–80.PubMed

25.

Liebmann C. EGF receptor activation by GPCRs: an universal pathway reveals different versions. Mol Cell Endocrinol. 2011;331:222–31.PubMed

26.

Berasain C, Perugorría MJ, Latasa MU, Castillo J, Goñi S, Santamaría M, et al. The epidermal growth factor receptor: a link between inflammation and liver cancer. Exp Biol Med (Maywood). 2009;234:713–25.

27.

Rodland KD, Bollinger N, Ippolito D, Opresko LK, Coffey RJ, Zangar R, et al. Multiple mechanisms are responsible for transactivation of the epidermal growth factor receptor in mammary epithelial cells. J Biol Chem. 2008;14(283):31477–87.

28.

Berasain C, Castillo J, Perugorría MJ, Latasa MU, Prieto J, Avila MA. Inflammation and liver cancer. Ann N Y Acad Sci. 2009;26(1155):206–21.

29.

Murphy G. Regulation of the proteolytic disintegrin metalloproteinases, the ‘Sheddases’. Semin Cell Dev Biol. 2009;20:138–45.PubMed

30.

Dang M, Armbruster N, Miller MA, Cermeno E, Hartmann M, Bell GW, et al. Regulated ADAM17-dependent EGF family ligand release by substrate-selecting signaling pathways. Proc Natl Acad Sci USA. 2013;11(110):9776–81.

31.

Berasain C, Ujue Latasa M, Urtasun R, Goñi S, Elizalde M, Garcia-Irigoyen O, et al. Epidermal growth factor receptor (EGFR) crosstalks in liver cancer. Cancers. 2011;3:2444–61.PubMedCentralPubMed

32.

Yamashita M, Chattopadhyay S, Fensterl V, Saikia P, Wetzel JL, Sen GC. Epidermal growth factor receptor is essential for Toll-like receptor 3 signaling. Sci Signal. 2012;5:ra50.PubMedCentralPubMed

33.

Wilson KJ, Mill C, Lambert S, Buchman J, Wilson TR, Hernandez-Gordillo V, et al. EGFR ligands exhibit functional differences in models of paracrine and autocrine signaling. Growth Factors. 2012;30:107–16.PubMed

34.

Saito T, Okada S, Ohshima K, Yamada E, Sato M, Uehara Y, et al. Differential activation of epidermal growth factor (EGF) receptor downstream signaling pathways by betacellulin and EGF. Endocrinology. 2004;145:4232–43.PubMed

35.

Gilmore JL, Scott JA, Bouizar Z, Robling A, Pitfield SE, Riese DJ, et al. Amphiregulin-EGFR signaling regulates PTHrP gene expression in breast cancer cells. Breast Cancer Res Treat. 2008;110:493–505.PubMedCentralPubMed

36.

Stern KA, Place TL, Lill NL. EGF and amphiregulin differentially regulate Cbl recruitment to endosomes and EGF receptor fate. Biochem J. 2008;15(410):585–94.

37.

Nakakuki T, Birtwistle MR, Saeki Y, Yumoto N, Ide K, Nagashima T, et al. Ligand-specific c-Fos expression emerges from the spatiotemporal control of ErbB network dynamics. Cell. 2010;28(141):884–96.

38.

Lemos-González Y, Rodríguez-Berrocal FJ, Cordero OJ, Gómez C, Páez de la Cadena M. Alteration of the serum levels of the epidermal growth factor receptor and its ligands in patients with non-small cell lung cancer and head and neck carcinoma. Br J Cancer. 2007;21(96):1569–78.

39.

Révillion F, Lhotellier V, Hornez L, Bonneterre J, Peyrat J-P. ErbB/HER ligands in human breast cancer, and relationships with their receptors, the bio-pathological features and prognosis. Ann Oncol. 2008;19:73–80.PubMed

40.

Tanabe KK, Lemoine A, Finkelstein DM, Kawasaki H, Fujii T, Chung RT, et al. Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis. JAMA. 2008;2(299):53–60.

41.

Abu Dayyeh BK, Yang M, Fuchs BC, Karl DL, Yamada S, Sninsky JJ, et al. A functional polymorphism in the epidermal growth factor gene is associated with risk for hepatocellular carcinoma. Gastroenterology. 2011;141:141–9.PubMed

42.

Michalopoulos GK. Liver regeneration after partial hepatectomy: critical analysis of mechanistic dilemmas. Am J Pathol. 2010;176:2–13.PubMed

43.

Böhm F, Köhler UA, Speicher T, Werner S. Regulation of liver regeneration by growth factors and cytokines. EMBO Mol Med. 2010;22(2):294–305.

44.

Gilgenkrantz H, de l’Hortet AC. New insights into liver regeneration. Clin Res Hepatol Gastroenterol. 2011;35:623–9.PubMed

45.

Fausto N, Campbell JS, Riehle KJ. Liver regeneration. J Hepatol. 2012;57:692–4.PubMed

46.

Uriarte I, Fernández-Barrena MG, Monte MJ, Latasa MU, Chang HCY, Carotti S, et al. Identification of fibroblast growth factor 15 as a novel mediator of liver regeneration and its application in the prevention of post-resection liver failure in mice. Gut. 2013;62:899–910.PubMed

47.

Wang T, Takikawa Y, Tabuchi T, Satoh T, Kosaka K, Suzuki K. Carnosic acid (CA) prevents lipid accumulation in hepatocytes through the EGFR/MAPK pathway. J Gastroenterol. 2012;47:805–13.PubMed

48.

Carver RS, Stevenson MC, Scheving LA, Russell WE. Diverse expression of ErbB receptor proteins during rat liver development and regeneration. Gastroenterology. 2002;123:2017–27.PubMed

49.

Webber EM, FitzGerald MJ, Brown PI, Bartlett MH, Fausto N. Transforming growth factor-alpha expression during liver regeneration after partial hepatectomy and toxic injury, and potential interactions between transforming growth factor-alpha and hepatocyte growth factor. Hepatology. 1993;18:1422–31.PubMed

50.

Kiso S, Kawata S, Tamura S, Higashiyama S, Ito N, Tsushima H, et al. Role of heparin-binding epidermal growth factor-like growth factor as a hepatotrophic factor in rat liver regeneration after partial hepatectomy. Hepatology. 1995;22:1584–90.PubMed

51.

Stolz DB, Mars WM, Petersen BE, Kim TH, Michalopoulos GK. Growth factor signal transduction immediately after two-thirds partial hepatectomy in the rat. Cancer Res. 1999;15(59):3954–60.

52.

Lee D, Pearsall RS, Das S, Dey SK, Godfrey VL, Threadgill DW. Epiregulin is not essential for development of intestinal tumors but is required for protection from intestinal damage. Mol Cell Biol. 2004;24:8907–16.PubMedCentralPubMed

53.

Berasain C, García-Trevijano ER, Castillo J, Erroba E, Lee DC, Prieto J, et al. Amphiregulin: an early trigger of liver regeneration in mice. Gastroenterology. 2005;128:424–32.PubMed

54.

Lin X-M, Liu Y-B, Zhou F, Wu Y-L, Chen L, Fang H-Q. Expression of tumor necrosis factor-alpha converting enzyme in liver regeneration after partial hepatectomy. World J Gastroenterol. 2008;7(14):1353–7.

55.

Berasain C, García-Trevijano ER, Castillo J, Erroba E, Santamaría M, Lee DC, et al. Novel role for amphiregulin in protection from liver injury. J Biol Chem. 2005;13(280):19012–20.

56.

Michalopoulos GK. Liver regeneration. J Cell Physiol. 2007;213:286–300.PubMedCentralPubMed

57.

Berasain C, Castillo J, Prieto J, Avila MA. New molecular targets for hepatocellular carcinoma: the ErbB1 signaling system. Liver Int. 2007;27:174–85.PubMed

58.

Collin de L’hortet A, Gilgenkrantz H, Guidotti J-E. EGFR: a master piece in G1/S phase transition of liver regeneration. Int J Hepatol. 2012;2012:476910.PubMedCentralPubMed

59.

Natarajan A, Wagner B, Sibilia M. The EGF receptor is required for efficient liver regeneration. Proc Natl Acad Sci USA. 2007;23(104):17081–6.

60.

Paranjpe S, Bowen WC, Tseng GC, Luo J-H, Orr A, Michalopoulos GK. RNA interference against hepatic epidermal growth factor receptor has suppressive effects on liver regeneration in rats. Am J Pathol. 2010;25(176):2669–81.

61.

Zerrad-Saadi A, Lambert-Blot M, Mitchell C, Bretes H, Collin de L’hortet A, Baud V, et al. GH receptor plays a major role in liver regeneration through the control of EGFR and ERK1/2 activation. Endocrinology. 2011;152:2731–41.PubMed

62.

Tan X, Behari J, Cieply B, Michalopoulos GK, Monga SPS. Conditional deletion of beta-catenin reveals its role in liver growth and regeneration. Gastroenterology. 2006;131:1561–72.PubMed

63.

Murthy A, Defamie V, Smookler DS, Di Grappa MA, Horiuchi K, Federici M, et al. Ectodomain shedding of EGFR ligands and TNFR1 dictates hepatocyte apoptosis during fulminant hepatitis in mice. J Clin Investig. 2010;120:2731–44.PubMed

64.

Avila MA. Long distance calling for liver regeneration: identification of neuroendocrine signalling pathways activated after partial hepatectomy. J Hepatol. 2011;54:403–5.PubMed

65.

Russell WE, Kaufmann WK, Sitaric S, Luetteke NC, Lee DC. Liver regeneration and hepatocarcinogenesis in transforming growth factor-alpha-targeted mice. Mol Carcinog. 1996;15:183–9.PubMed

66.

Mitchell C, Nivison M, Jackson LF, Fox R, Lee DC, Campbell JS, et al. Heparin-binding epidermal growth factor-like growth factor links hepatocyte priming with cell cycle progression during liver regeneration. J Biol Chem. 2005;28(280):2562–8.

67.

Pardo-Saganta A, Pardo-Saganta A, Latasa MU, Latasa MU, Castillo J, Castillo J, et al. The epidermal growth factor receptor ligand amphiregulin is a negative regulator of hepatic acute-phase gene expression. J Hepatol. 2009;51:1010–20.PubMed

68.

Santamaría M, Pardo-Saganta A, Alvarez-Asiain L, Di Scala M, Qian C, Prieto J, et al. Nuclear α1-antichymotrypsin promotes chromatin condensation and inhibits proliferation of human hepatocellular carcinoma cells. Gastroenterology. 2013;144:818–28.PubMed

69.

Liu Q, Rehman H, Krishnasamy Y, Haque K, Schnellmann RG, Lemasters JJ, et al. Amphiregulin stimulates liver regeneration after small-for-size mouse liver transplantation. Am J Transplant. 2012;12(8):2052–61.PubMedCentralPubMed

70.

Sakuda S, Tamura S, Yamada A, Miyagawa J-I, Yamamoto K, Kiso S, et al. NF-kappaB activation in non-parenchymal liver cells after partial hepatectomy in rats: possible involvement in expression of heparin-binding epidermal growth factor-like growth factor. J Hepatol. 2002;36:527–33.PubMed

71.

El-Serag HB. Hepatocellular carcinoma. N Engl J Med. 2011;22(365):1118–27.

72.

White DL, Kanwal F, El-Serag HB. Association between nonalcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol. 2012;10:1342–59.PubMedCentralPubMed

73.

Mittal S, El-Serag HB. Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol. 2013;47(Suppl):S2–6.PubMed

74.

Avila MA, Berasain C, Torres L, Martin-Duce A, Corrales FJ, Yang H, et al. Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma. J Hepatol. 2000;33:907–14.PubMed

75.

Berasain C, Herrero J-I, García-Trevijano ER, Avila MA, Esteban JI, Mato JM, et al. Expression of Wilms’ tumor suppressor in the liver with cirrhosis: relation to hepatocyte nuclear factor 4 and hepatocellular function. Hepatology. 2003;38:148–57.PubMed

76.

Aravalli RN, Cressman ENK, Steer CJ. Cellular and molecular mechanisms of hepatocellular carcinoma: an update. Arch Toxicol. 2013;87:227–47.PubMed

77.

Gea VH, Toffanin S, Friedman SL, Llovet JM. Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology. 2013;144(3):512–27.

78.

Nikolaou K, Sarris M, Talianidis I. Molecular pathways: the complex roles of inflammation pathways in the development and treatment of liver cancer. Clin Cancer Res. 2013;1(19):2810–6.

79.

Capece D, Fischietti M, Verzella D, Gaggiano A, Cicciarelli G, Tessitore A, et al. The inflammatory microenvironment in hepatocellular carcinoma: a pivotal role for tumor-associated macrophages. Biomed Res Int. 2013;2013:187204.PubMedCentralPubMed

80.

Zhang DY, Friedman SL. Fibrosis-dependent mechanisms of hepatocarcinogenesis. Hepatology. 2012;56:769–75.PubMed

81.

Castillo J, Goñi S, Latasa MU, Perugorría MJ, Calvo A, Muntané J, et al. Amphiregulin induces the alternative splicing of p73 into its oncogenic isoform DeltaEx2p73 in human hepatocellular tumors. Gastroenterology. 2009;137:1805–15.PubMed

82.

Fujii T, Fuchs BC, Yamada S, Lauwers GY, Kulu Y, Goodwin JM, et al. Mouse model of carbon tetrachloride induced liver fibrosis: histopathological changes and expression of CD133 and epidermal growth factor. BMC Gastroenterol. 2010;10:79.PubMedCentralPubMed

83.

Pinzani M, Gesualdo L, Sabbah GM, Abboud HE. Effects of platelet-derived growth factor and other polypeptide mitogens on DNA synthesis and growth of cultured rat liver fat-storing cells. J Clin Investig. 1989;84:1786–93.PubMed

84.

Gressner AM. Cytokines and cellular crosstalk involved in the activation of fat-storing cells. J Hepatol. 1995;22:28–36.PubMed

85.

Yang C, Zeisberg M, Mosterman B, Sudhakar A, Yerramalla U, Holthaus K, et al. Liver fibrosis: insights into migration of hepatic stellate cells in response to extracellular matrix and growth factors. Gastroenterology. 2003;124:147–59.PubMed

86.

Perugorría MJ, Perugorría MJ, Latasa MU, Latasa MU, Nicou A, Nicou A, et al. The epidermal growth factor receptor ligand amphiregulin participates in the development of mouse liver fibrosis. Hepatology. 2008;48:1251–61.PubMed

87.

Zhou Y, Lee JY, Lee CM, Cho WK, Kang MJ, Koff JL, et al. Amphiregulin, an epidermal growth factor receptor ligand, plays an essential role in the pathogenesis of transforming growth factor-β-induced pulmonary fibrosis. J Biol Chem. 2012;7(287):41991–2000.

88.

Liu N, Guo J-K, Pang M, Tolbert E, Ponnusamy M, Gong R, et al. Genetic or pharmacologic blockade of EGFR inhibits renal fibrosis. J Am Soc Nephrol. 2012;23:854–67.PubMed

89.

Samarakoon R, Dobberfuhl AD, Cooley C, Overstreet JM, Patel S, Goldschmeding R, et al. Induction of renal fibrotic genes by TGF-β1 requires EGFR activation, p53 and reactive oxygen species. Cell Signal. 2013;25:2198–209.PubMed

90.

Tang J, Liu N, Tolbert E, Ponnusamy M, Ma L, Gong R, et al. Sustained activation of EGFR triggers renal fibrogenesis after acute kidney injury. Am J Pathol. 2013;183:160–72.PubMed

91.

Tzouvelekis A, Ntolios P, Karameris A, Vilaras G, Boglou P, Koulelidis A, et al. Increased expression of epidermal growth factor receptor (EGF-R) in patients with different forms of lung fibrosis. Biomed Res Int. 2013;2013:654354.PubMedCentralPubMed

92.

Takemura T, Yoshida Y, Kiso S, Kizu T, Furuta K, Ezaki H, et al. Conditional loss of heparin-binding EGF-like growth factor results in enhanced liver fibrosis after bile duct ligation in mice. Biochem Biophys Res Commun. 2013;26(437):185–91.

93.

Takemura T, Yoshida Y, Kiso S, Saji Y, Ezaki H, Hamano M, et al. Conditional knockout of heparin-binding epidermal growth factor-like growth factor in the liver accelerates carbon tetrachloride-induced liver injury in mice. Hepatol Res. 2013;43:384–93.PubMed

94.

Ito Y, Takeda T, Sakon M, Tsujimoto M, Higashiyama S, Noda K, et al. Expression and clinical significance of erb-B receptor family in hepatocellular carcinoma. Br J Cancer. 2001;18(84):1377–83.

95.

Buckley AF, Burgart LJ, Sahai V, Kakar S. Epidermal growth factor receptor expression and gene copy number in conventional hepatocellular carcinoma. Am J Clin Pathol. 2008;129:245–51.PubMed

96.

Kira S, Nakanishi T, Suemori S, Kitamoto M, Watanabe Y, Kajiyama G. Expression of transforming growth factor alpha and epidermal growth factor receptor in human hepatocellular carcinoma. Liver. 1997;17:177–82.PubMed

97.

Breuhahn K, Longerich T, Schirmacher P. Dysregulation of growth factor signaling in human hepatocellular carcinoma. Oncogene. 2006;26(25):3787–800.

98.

Keng VW, Sia D, Sarver AL, Tschida BR, Fan D, Alsinet C, et al. Sex bias occurrence of hepatocellular carcinoma in Poly7 molecular subclass is associated with EGFR. Hepatology. 2013;57:120–30.PubMedCentralPubMed

99.

Ou C, Wu F-X, Luo Y, Cao J, Zhao Y-N, Yuan W-P, et al. Expression and significance of epidermal growth factor receptor variant type III in hepatocellular carcinoma. Ai Zheng. 2005;24:166–9.PubMed

100.

Wang H, Jiang H, Zhou M, Xu Z, Liu S, Shi B, et al. Epidermal growth factor receptor vIII enhances tumorigenicity and resistance to 5-fluorouracil in human hepatocellular carcinoma. Cancer Lett. 2009;28(279):30–8.

101.

Zhou M, Gong B, Gu J, Li Z. EGFRvIII mRNA detection in the serum of patients with hepatocellular carcinoma. Liver Int. 2010;30:925–7.PubMed

102.

Hsieh S-Y, He J-R, Hsu C-Y, Chen W-J, Bera R, Lin K-Y, et al. Neuregulin/erythroblastic leukemia viral oncogene homolog 3 autocrine loop contributes to invasion and early recurrence of human hepatoma. Hepatology. 2011;53:504–16.PubMed

103.

Hsieh S-Y, He J-R, Yu M-C, Lee W-C, Chen T-C, Lo S-J, et al. Secreted ERBB3 isoforms are serum markers for early hepatoma in patients with chronic hepatitis and cirrhosis. J Proteome Res. 2011;7(10):4715–24.

104.

Harada K, Shiota G, Kawasaki H. Transforming growth factor-alpha and epidermal growth factor receptor in chronic liver disease and hepatocellular carcinoma. Liver. 1999;19:318–25.PubMed

105.

Kömüves LG, Feren A, Jones AL, Fodor E. Expression of epidermal growth factor and its receptor in cirrhotic liver disease. J Histochem Cytochem. 2000;48:821–30.PubMed

106.

Castillo J, Erroba E, Perugorría MJ, Santamaría M, Lee DC, Prieto J, et al. Amphiregulin contributes to the transformed phenotype of human hepatocellular carcinoma cells. Cancer Res. 2006;15(66):6129–38.

107.

Moon WS, Park HS, Yu KH, Park MY, Kim KR, Jang KY, et al. Expression of betacellulin and epidermal growth factor receptor in hepatocellular carcinoma: implications for angiogenesis. Hum Pathol. 2006;37:1324–32.PubMed

108.

Daveau M, Scotte M, François A, Coulouarn C, Ros G, Tallet Y, et al. Hepatocyte growth factor, transforming growth factor alpha, and their receptors as combined markers of prognosis in hepatocellular carcinoma. Mol Carcinog. 2003;36:130–41.PubMed

109.

Hoshida Y, Villanueva A, Kobayashi M, Peix J, Chiang DY, Camargo A, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;6(359):1995–2004.

110.

Berasain C, Castillo J, Perugorría MJ, Prieto J, Avila MA. Amphiregulin: a new growth factor in hepatocarcinogenesis. Cancer Lett. 2007;254:30–41.PubMed

111.

Ortiz C, Caja L, Sancho P, Bertran E, Fabregat I. Inhibition of the EGF receptor blocks autocrine growth and increases the cytotoxic effects of doxorubicin in rat hepatoma cells: role of reactive oxygen species production and glutathione depletion. Biochem Pharmacol. 2008;15(75):1935–45.

112.

Sancho P, Bertran E, Caja L, Carmona-Cuenca I, Murillo MM, Fabregat I. The inhibition of the epidermal growth factor (EGF) pathway enhances TGF-beta-induced apoptosis in rat hepatoma cells through inducing oxidative stress coincident with a change in the expression pattern of the NADPH oxidases (NOX) isoforms. Biochim Biophys Acta. 2009;1793:253–63.PubMed

113.

Mazzocca A, Fransvea E, Dituri F, Lupo L, Antonaci S, Giannelli G. Down-regulation of connective tissue growth factor by inhibition of transforming growth factor beta blocks the tumor-stroma cross-talk and tumor progression in hepatocellular carcinoma. Hepatology. 2010;51:523–34.PubMed

114.

Urtasun R, Urtasun R, Latasa MU, Latasa MU, Demartis MI, Demartis MI, et al. Connective tissue growth factor autocriny in human hepatocellular carcinoma: oncogenic role and regulation by epidermal growth factor receptor/yes-associated protein-mediated activation. Hepatology. 2011;54:2149–58.PubMed

115.

Latasa MU, Salis F, Urtasun R, Garcia-Irigoyen O, Elizalde M, Uriarte I, et al. Regulation of amphiregulin gene expression by β-catenin signaling in human hepatocellular carcinoma cells: a novel crosstalk between FGF19 and the EGFR system. PLoS ONE. 2012;7:e52711.PubMedCentralPubMed

116.

Reschke M, Ferby I, Stepniak E, Seitzer N, Horst D, Wagner EF, et al. Mitogen-inducible gene-6 is a negative regulator of epidermal growth factor receptor signaling in hepatocytes and human hepatocellular carcinoma. Hepatology. 2010;51:1383–90.PubMed

117.

Wang R-Y, Chen L, Chen H-Y, Hu L, Li L, Sun H-Y, et al. MUC15 inhibits dimerization of EGFR and PI3K–AKT signaling and is associated with aggressive hepatocellular carcinomas in patients. Gastroenterology. 2013.

118.

Avila MA, Berasain C, Sangro B, Prieto J. New therapies for hepatocellular carcinoma. Oncogene. 2006;26(25):3866–84.

119.

Villanueva A, Llovet JM. Targeted therapies for hepatocellular carcinoma. Gastroenterology. 2011;140:1410–26.PubMedCentralPubMed

120.

Tebbutt N, Pedersen MW, Johns TG. Targeting the ERBB family in cancer: couples therapy. Nat Rev Cancer. 2013;13:663–73.PubMed

121.

Matsuo M, Sakurai H, Saiki I. ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, shows antimetastatic activity using a hepatocellular carcinoma model. Mol Cancer Ther. 2003;2:557–61.PubMed

122.

Huether A, Höpfner M, Baradari V, Schuppan D, Scherübl H. EGFR blockade by cetuximab alone or as combination therapy for growth control of hepatocellular cancer. Biochem Pharmacol. 2005;25(70):1568–78.

123.

Huether A, Höpfner M, Sutter AP, Schuppan D, Scherübl H. Erlotinib induces cell cycle arrest and apoptosis in hepatocellular cancer cells and enhances chemosensitivity towards cytostatics. J Hepatol. 2005;43:661–9.PubMed

124.

Liu Y, Poon RTP, Shao W, Sun X, Chen H, Kok TW, et al. Blockage of epidermal growth factor receptor by quinazoline tyrosine kinase inhibitors suppresses growth of human hepatocellular carcinoma. Cancer Lett. 2007;8(248):32–40.

125.

Giannelli G, Sgarra C, Porcelli L, Azzariti A, Antonaci S, Paradiso A. EGFR and VEGFR as potential target for biological therapies in HCC cells. Cancer Lett. 2008;18(262):257–64.

126.

Fuchs BC, Fujii T, Dorfman JD, Goodwin JM, Zhu AX, Lanuti M, et al. Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Res. 2008;1(68):2391–9.

127.

Villanueva A, Chiang DY, Newell P, Peix J, Thung S, Alsinet C, et al. Pivotal role of mTOR signaling in hepatocellular carcinoma. Gastroenterology. 2008;135:1972–83.

128.

Schiffer E, Housset C, Cacheux W, Wendum D, Desbois-Mouthon C, Rey C, et al. Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis. Hepatology. 2005;41:307–14.PubMed

129.

Zhu AX. New agents on the horizon in hepatocellular carcinoma. Ther Adv Med Oncol. 2013;5:41–50.PubMedCentralPubMed

130.

Asnacios A, Fartoux L, Romano O, Tesmoingt C, Louafi SS, Mansoubakht T, et al. Gemcitabine plus oxaliplatin (GEMOX) combined with cetuximab in patients with progressive advanced stage hepatocellular carcinoma: results of a multicenter phase 2 study. Cancer. 2008;15(112):2733–9.

131.

Ramanathan RK, Belani CP, Singh DA, Tanaka M, Lenz H-J, Yen Y, et al. A phase II study of lapatinib in patients with advanced biliary tree and hepatocellular cancer. Cancer Chemother Pharmacol. 2009;64:777–83.PubMed

132.

Philip PA, Mahoney MR, Allmer C, Thomas J, Pitot HC, Kim G, et al. Phase II study of Erlotinib (OSI-774) in patients with advanced hepatocellular cancer. J Clin Oncol. 2005;20(23):6657–63.

133.

Thomas MB, Chadha R, Glover K, Wang X, Morris J, Brown T, et al. Phase 2 study of erlotinib in patients with unresectable hepatocellular carcinoma. Cancer. 2007;1(110):1059–67.

134.

Thomas MB, Morris JS, Chadha R, Iwasaki M, Kaur H, Lin E, et al. Phase II trial of the combination of bevacizumab and erlotinib in patients who have advanced hepatocellular carcinoma. J Clin Oncol. 2009;20(27):843–50.

135.

Hsu C-H, Kang YK, Yang T-S, Shun C-T, Shao Y–Y, Su W-C, et al. Bevacizumab with erlotinib as first-line therapy in Asian patients with advanced hepatocellular carcinoma: a multicenter phase II study. Oncology. 2013;85:44–52.PubMed

136.

Philip PA, Mahoney MR, Holen KD, Northfelt DW, Pitot HC, Picus J, et al. Phase 2 study of bevacizumab plus erlotinib in patients with advanced hepatocellular cancer. Cancer. 2012;1(118):2424–30.

137.

Dekervel J, van Pelt J, Verslype C. Advanced unresectable hepatocellular carcinoma: new biologics as fresh ammunition or clues to disease understanding? Curr Opin Oncol. 2013;25:409–16.PubMed

138.

Finn RS. Emerging targeted strategies in advanced hepatocellular carcinoma. Semin Liver Dis. 2013;33(Suppl 1):S11–9.PubMed

139.

Ratushny V, Astsaturov I, Burtness BA, Golemis EA, Silverman JS. Targeting EGFR resistance networks in head and neck cancer. Cell Signal. 2009;21:1255–68.PubMedCentralPubMed

140.

Wheeler DL, Dunn EF, Harari PM. Understanding resistance to EGFR inhibitors-impact on future treatment strategies. Nat Rev Clin Oncol. 2010;7:493–507.PubMedCentralPubMed

141.

Brand TM, Iida M, Wheeler DL. Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab. Cancer Biol Ther. 2011;1(11):777–92.

142.

Yamaguchi H, Chang S–S, Hsu JL, Hung M-C. Signaling cross-talk in the resistance to HER family receptor targeted therapy. Oncogene. 2013.

143.

Desbois-Mouthon C, Cacheux W, Blivet-Van Eggelpoël M-J, Barbu V, Fartoux L, Poupon R, et al. Impact of IGF-1R/EGFR cross-talks on hepatoma cell sensitivity to gefitinib. Int J Cancer. 2006;1(119):2557–66.

144.

Desbois-Mouthon C, Baron A, Blivet-Van Eggelpoël M-J, Fartoux L, Venot C, Bladt F, et al. Insulin-like growth factor-1 receptor inhibition induces a resistance mechanism via the epidermal growth factor receptor/HER3/AKT signaling pathway: rational basis for cotargeting insulin-like growth factor-1 receptor and epidermal growth factor receptor in hepatocellular carcinoma. Clin Cancer Res. 2009;1(15):5445–56.

145.

Giordano S, Columbano A. Met as a therapeutic target in HCC: facts and hopes. J Hepatol. 2013.

146.

Karamouzis MV, Konstantinopoulos PA, Papavassiliou AG. Targeting MET as a strategy to overcome crosstalk-related resistance to EGFR inhibitors. Lancet Oncol. 2009;10:709–17.PubMed

147.

Jo M, Stolz DB, Esplen JE, Dorko K, Michalopoulos GK, Strom SC. Cross-talk between epidermal growth factor receptor and c-Met signal pathways in transformed cells. J Biol Chem. 2000;24(275):8806–11.

148.

Gusenbauer S, Vlaicu P, Ullrich A. HGF induces novel EGFR functions involved in resistance formation to tyrosine kinase inhibitors. Oncogene. 2013;15(32):3846–56.

149.

Lisabeth EM, Falivelli G, Pasquale EB. Eph receptor signaling and ephrins. Cold Spring Harbor Perspect Biol. 2013;5(9):1–20.

150.

Vermeer PD, Colbert PL, Wieking BG, Vermeer DW, Lee JH. Targeting ERBB receptors shifts their partners and triggers persistent ERK signaling through a novel ERBB/EFNB1 complex. Cancer Res. 2013;15(73):5787–97.

151.

Yeh S-H, Wu D-C, Tsai C-Y, Kuo T-J, Yu W-C, Chang Y-S, et al. Genetic characterization of fas-associated phosphatase-1 as a putative tumor suppressor gene on chromosome 4q21.3 in hepatocellular carcinoma. Clin Cancer Res. 2006;15(12):1097–108.

152.

Sawai Y, Tamura S, Fukui K, Ito N, Imanaka K, Saeki A, et al. Expression of ephrin-B1 in hepatocellular carcinoma: possible involvement in neovascularization. J Hepatol. 2003;39:991–6.PubMed

153.

Han W, Lo H-W. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett. 2012;28(318):124–34.

154.

Brand TM, Iida M, Luthar N, Starr MM, Huppert EJ, Wheeler DL. Nuclear EGFR as a molecular target in cancer. Radiother Oncol. 2013.

155.

Raper SE, Burwen SJ, Barker ME, Jones AL. Translocation of epidermal growth factor to the hepatocyte nucleus during rat liver regeneration. Gastroenterology. 1987;92:1243–50.PubMed

156.

Marti U, Burwen SJ, Wells A, Barker ME, Huling S, Feren AM, et al. Localization of epidermal growth factor receptor in hepatocyte nuclei. Hepatology. 1991;13:15–20.PubMed

157.

Schausberger E, Eferl R, Parzefall W, Chabicovsky M, Breit P, Wagner EF, et al. Induction of DNA synthesis in primary mouse hepatocytes is associated with nuclear pro-transforming growth factor alpha and erbb-1 and is independent of c-jun. Carcinogenesis. 2003;24:835–41.PubMed

158.

Giannelli G, Azzariti A, Fransvea E, Porcelli L, Antonaci S, Paradiso A. Laminin-5 offsets the efficacy of gefitinib (“Iressa”) in hepatocellular carcinoma cells. Br J Cancer. 2004;29(91):1964–9.

159.

Chan J, Ko FCF, Yeung Y-S, Ng IO-L, Yam JWP. Integrin-linked kinase overexpression and its oncogenic role in promoting tumorigenicity of hepatocellular carcinoma. PLoS ONE. 2011;6:e16984.PubMedCentralPubMed

160.

Bergamini C, Sgarra C, Trerotoli P, Lupo L, Azzariti A, Antonaci S, et al. Laminin-5 stimulates hepatocellular carcinoma growth through a different function of alpha6beta4 and alpha3beta1 integrins. Hepatology. 2007;46:1801–9.PubMed

161.

Losert A, Lötsch D, Lackner A, Koppensteiner H, Peter-Vörösmarty B, Steiner E, et al. The major vault protein mediates resistance to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Lett. 2012;28(319):164–72.

162.

Yu H-C, Chen H-J, Chang Y-L, Liu C-Y, Shiau C-W, Cheng A-L, et al. Inhibition of CIP2A determines erlotinib-induced apoptosis in hepatocellular carcinoma. Biochem Pharmacol. 2013;1(85):356–66.

163.

Calvisi DF, Ladu S, Gorden A, Farina M, Conner EA, Lee J-S, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006;130:1117–28.PubMed

164.

Huang S, Li C, Armstrong EA, Peet CR, Saker J, Amler LC, et al. Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation. Cancer Res. 2013;15(73):824–33.

165.

Blivet-Van Eggelpoël MJ, Chettouh H, Fartoux L, Aoudjehane L, Barbu V, Rey C, et al. Epidermal growth factor receptor and HER-3 restrict cell response to sorafenib in hepatocellular carcinoma cells. J Hepatol. 2012;57(1):108–15.PubMed

166.

Sok JC, Coppelli FM, Thomas SM, Lango MN, Xi S, Hunt JL, et al. Mutant epidermal growth factor receptor (EGFRvIII) contributes to head and neck cancer growth and resistance to EGFR targeting. Clin Cancer Res. 2006;1(12):5064–73.

167.

Jiang H, Wang H, Tan Z, Hu S, Wang H, Shi B, et al. Growth suppression of human hepatocellular carcinoma xenografts by a monoclonal antibody CH12 directed to epidermal growth factor receptor variant III. J Biol Chem. 2011;18(286):5913–20.

168.

Yang Y, Jiang H, Gao H, Kong J, Zhang P, Hu S, et al. The monoclonal antibody CH12 enhances the sorafenib-mediated growth inhibition of hepatocellular carcinoma xenografts expressing epidermal growth factor receptor variant III. Neoplasia. 2012;14:509–18.PubMedCentralPubMed

169.

Jiang H, Dong Q, Luo X, Shi B, Wang H, Gao H, et al. The monoclonal antibody CH12 augments 5-fluorouracil-induced growth suppression of hepatocellular carcinoma xenografts expressing epidermal growth factor receptor variant III. Cancer Lett. 2013.

170.

Miyamoto S, Fukami T, Yagi H, Kuroki M, Yotsumoto F. Potential for molecularly targeted therapy against epidermal growth factor receptor ligands. Anticancer Res. 2009;29:823–30.PubMed

171.

Busser B, Sancey L, Brambilla E, Coll J-L, Hurbin A. The multiple roles of amphiregulin in human cancer. Biochim Biophys Acta. 2011;1816:119–31.PubMed

172.

Busser B, Sancey L, Josserand V, Niang C, Favrot MC, Coll J-L, et al. Amphiregulin promotes BAX inhibition and resistance to gefitinib in non-small-cell lung cancers. Mol Ther. 2010;18:528–35.PubMed

173.

Zaiss DMW, van Loosdregt J, Gorlani A, Bekker CPJ, Gröne A, Sibilia M, et al. Amphiregulin enhances regulatory T cell-suppressive function via the epidermal growth factor receptor. Immunity. 2013;38:275–84.PubMed

174.

Hoshida Y, Fuchs BC, Tanabe KK. Prevention of hepatocellular carcinoma: potential targets, experimental models, and clinical challenges. Curr Cancer Drug Targets. 2012;1(12):1129–59.

175.

Pardee AD, Butterfield LH. Immunotherapy of hepatocellular carcinoma: unique challenges and clinical opportunities. Oncoimmunology. 2012;1(1):48–55.PubMedCentralPubMed

176.

Villanueva A. Rethinking future development of molecular therapies in hepatocellular carcinoma: a bottom-up approach. J Hepatol. 2013;59:392–5.PubMed

Title: The EGFR signalling system in the liver: from hepatoprotection to hepatocarcinogenesis
Authors: Carmen Berasain
Matías A. Avila
Publication date: 01-01-2014
Publisher: Springer Japan
Published in: Journal of Gastroenterology / Issue 1/2014
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI: https://doi.org/10.1007/s00535-013-0907-x

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2014

Current status of bariatric surgery in Japan and effectiveness in obesity and diabetes

Impact of hospital volume on outcomes in acute pancreatitis: a study using a nationwide administrative database

Roadmap to eliminate gastric cancer with Helicobacter pylori eradication and consecutive surveillance in Japan

Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives

Clinical utility of newly developed immunoassays for serum concentrations of adalimumab and anti-adalimumab antibodies in patients with Crohn’s disease

C-ERC/mesothelin provokes lymphatic invasion of colorectal adenocarcinoma

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

At a glance: The STEP trials