Skip to main navigation menu Skip to main content Skip to site footer

Review article: Biomedical intelligence

Vol. 141 No. 1920 (2011)

Chronic liver inflammation and hepatocellular carcinoma: persistence matters

  • YT Boege
  • F Reisinger
  • M Heikenwalder
Cite this as:
Swiss Med Wkly. 2011;141:w13197


Inflammatory responses in the liver – a central constituent of hepatic wound healing – can be self-limited or persistent depending on the aetiology, liver health state, concentration of toxins or pathogens, and the time frame of exposure to toxins or infection. In case the immune system eradicates a pathogen or in case toxin-exposure is transient, acute hepatitis resolves and the affected liver tissue regenerates ad integrum. However, in many cases liver damage remains chronic. Irrespective of the aetiology, chronic liver damage drives chronic hepatitis and hepatocyte death as well as compensatory proliferation, reflecting liver regeneration. Over time this potentially promotes further hepatic damage, fibrosis, cirrhosis and liver cancer. Here, we review the current knowledge on how chronic liver injury and inflammation is triggered and maintained, and how inflammation is linked to liver cancer. We also discuss the most frequently used animal models for damage or inflammation induced liver cancer and their suitability for conducting clinically relevant research.


Hepatitis can be elicited in response to a plethora of diverse insults to the liver. Chronic inflammation is associated with persistent liver damage and consecutive regeneration, potentially leading to fibrosis and cirrhosis and the development of HCC. Human HCC, even of the same aetiology, reveal a broad clinical, morphological and molecular spectrum, however, they generally have a bad prognosis. The efficiency of drugs is currently limited, but might be improved by the identification of specific molecular targets. Several mouse models are available which are used to recapitulate different aetiologies of human hepatocarcinogenesis. It is now of paramount importance to determine how these models are transferable to human HCC and how they can be thus exploited for interventional studies.

Acknowledgments: We thank Jay Tracy, Barbara Zadnich, Sukumar Namineni, Dr. Nicole Simonavicius and Dr. Barbara Stecher for reading the manuscript and for valuable input. We are thankful to all members of our laboratory for discussions and apologise to those authors whose contributions were not cited due to space limitations.


  1. Burt A, Portmann B, Ferrell L. MacSween’s pathology of the liver. 2006.
  2. Bostan N, Mahmood T. An overview about hepatitis C: a devastating virus. Crit Rev Microbiol. 2010;36(2):91–133.
  3. Dienstag JL. Hepatitis B virus infection. N Engl J Med. 2008;359(14):1486–500.
  4. Wedemeyer H, Manns Epidemiology MP. pathogenesis and management of hepatitis D: update and challenges ahead. Nature Rev Gastroenterol Hepatol 2010;7(1):31–40.
  5. Krawitt EL. Autoimmune hepatitis. N Engl J Med. 2006;354(1):54–66.
  6. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353(12):1261–73.
  7. Lucey MR, Mathurin P, Morgan TR. Alcoholic hepatitis. N Engl J Med. 2009;360(26):2758–69.
  8. Tujios, S. and R.J. Fontana Mechanisms of drug-induced liver injury: from bedside to bench. Nature reviews. Gastroenterology & hepatology. 2011;
  9. Riehle KJ, Dan YY, Campbell JS, Fausto N. New concepts in liver regeneration. J Gastroenterol Hepatol. 2011;26(Suppl 1):203–212.
  10. Friedmann S, Dantes A, Amsterdam A. Ovarian transcriptomes as a tool for a global approach of genes modulated by gonadotropic hormones in human ovarian granulosa cells. Endocrine. 2005;26(3):259–65.
  11. Yeoman AD, Al-Chalabi T, Karani JB, et al. Evaluation of risk factors in the development of hepatocellular carcinoma in autoimmune hepatitis: Implications for follow-up and screening. Hepatology. 2008;48(3):863–70.
  12. Cavazza A, Caballería L, Floreani A, et al. Incidence, risk factors, and survival of hepatocellular carcinoma in primary biliary cirrhosis: comparative analysis from two centers. Hepatology. 2009;50(4):1162–1168.
  13. Virchow R. An Address on the Value of Pathological Experiments. Br Med J. 1881;2(1075):198–203.
  14. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–45.
  15. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.
  16. Demaria S, Pikarsky E, Karin M, et al. Cancer and inflammation: promise for biologic therapy. J Immunother. 2010;33(4):335–51.
  17. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44.
  18. Colotta F, Allavena P, Sica A, Garlanda C, Mantovani A. Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability. Carcinogenesis. 2009;30(7):1073–1081.
  19. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674.
  20. Llovet JM, Beaugrand M. Hepatocellular carcinoma: present status and future prospects. J Hepatol. 2003;38(Suppl 1):136–149.
  21. Cover TL, Blaser MJ. Helicobacter pylori in health and disease. Gastroenterology. 2009;136(6):1863–1873.
  22. Mostafa MH, Sheweita SA, O’Connor PJ. Relationship between schistosomiasis and bladder cancer. Clin Microbiol Rev. 1999;12(1):97–111.
  23. Nishiyama R, Kanai T, Abe J, et al. Hepatocellular carcinoma associated with autoimmune hepatitis. J Hepatobiliary Pancreat Surg. 2004;11(3):215–9.
  24. Pohl C, Hombach A, Kruis W. Chronic inflammatory bowel disease and cancer. Hepatogastroenterology. 2000;47(31):57–70.
  25. Maggs JR, Chapman RW. An update on primary sclerosing cholangitis. Curr Opin Gastroenterol. 2008;24(3):377–83.
  26. Fan JG, Farrell GC. Epidemiology of non-alcoholic fatty liver disease in China. J Hepatol. 2009;50(1):204–10.
  27. Park EJ, Lee JH, Yu GY, et al. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010;140(2):197–208.
  28. Legakis I, Syrigos K. Obesity modulation - the role in carcinogenesis. Anticancer Agents Med Chem. 2010;10(6):481–490.
  29. Wolf MJ, Seleznik GM, Zeller N, Heikenwalder M. The unexpected role of lymphotoxin beta receptor signaling in carcinogenesis: from lymphoid tissue formation to liver and prostate cancer development. Oncogene. 2010;29(36):5006–18.
  30. Lukashev M, LePage D, Wilson C, et al. Targeting the lymphotoxin-beta receptor with agonist antibodies as a potential cancer therapy. Cancer Res. 2006;66(19):9617–24.
  31. Vucur M, Roderburg C, Bettermann K, et al. Mouse models of hepatocarcinogenesis: what can we learn for the prevention of human hepatocellular carcinoma? Oncotarget. 2010;1(5):373–8.
  32. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883–99.
  33. Coley WB. The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop Relat Res. 1991;(262):3–11.
  34. Sylvester RJ. Bacillus Calmette-Guerin treatment of non-muscle invasive bladder cancer. International journal of urology: official journal of the Japanese Urological Association. 2011; 18(2):113–20.
  35. Wolf MJ, Seleznik GM, Heikenwalder M. Lymphotoxin’s link to carcinogenesis: friend or foe? from lymphoid neogenesis to hepatocellular carcinoma and prostate cancer. Adv Exp Med Biol. 2011;691:231–249.
  36. El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557–2576.
  37. Sherman M. Epidemiology of hepatocellular carcinoma. Oncology. 2010;78(Suppl 1):7–10.
  38. Dutkowski P, et al. Current and future trends in liver transplantation in Europe. Gastroenterology. 2010; 138(3):802–9 e1–4.
  39. Llovet JM, Ricci S, Mazzaferro V, et al; SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.
  40. Cheng AL, Kang YK, Chen Z, et al. 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. Lancet Oncol. 2009;10(1):25–34.
  41. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907–7.
  42. De Flora S, Bonanni P. The prevention of infection-associated cancers. Carcinogenesis. 2011
  43. Luedde T, Schwabe RF. NF-kappaB in the liver – linking injury, fibrosis and hepatocellular carcinoma. Nature Rev Gastroenterol Hepatol. 2011;8(2):108–118.
  44. Nakamoto Y, Guidotti LG, Kuhlen CV, Fowler P, Chisari FV. Immune pathogenesis of hepatocellular carcinoma. J Exp Med. 1998;188(2):341–350.
  45. Lim IK. Spectrum of molecular changes during hepatocarcinogenesis induced by DEN and other chemicals in Fischer 344 male rats. Mech Ageing Dev. 2002;123(12):1665–1680.
  46. Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88–dependent IL-6 production. Science. 2007;317(5834):121–124.
  47. Autrup H, Wakhisi J. Detection of exposure to aflatoxin in an African population. IARC Sci Publ. 1988;(89):63–66.
  48. Wang Q., Z.Y. Lin, and X.L. Feng Alterations in metastatic properties of hepatocellular carcinoma cell following H-ras oncogene transfection. World journal of gastroenterology: WJG. 2001;7(3):335–9.
  49. Pikarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431(7007):461–466.
  50. Vainer GW, Pikarsky E, Ben-Neriah Y. Contradictory functions of NF-kappaB in liver physiology and cancer. Cancer Lett. 2008;267(2):182–188.
  51. Maeda S, Kamata H, Luo JL, Leffert H, Karin M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell. 2005;121(7):977–990.
  52. Browning JL, French LE. Visualization of lymphotoxin-beta and lymphotoxin-beta receptor expression in mouse embryos. J Immunol. 2002;168(10):5079–5087.
  53. Haybaeck J, Zeller N, Wolf MJ, et al. A lymphotoxin-driven pathway to hepatocellular carcinoma. Cancer Cell. 2009;16(4):295–308.
  54. Lo JC, Wang Y, Tumanov AV, et al. Lymphotoxin beta receptor-dependent control of lipid homeostasis. Science. 2007;316(5822):285–288.
  55. Tumanov AV, et al. T cell-derived lymphotoxin regulates liver regeneration. Gastroenterology. 2009;136(2):694–704 e4.
  56. Ruddell RG, Knight B, Tirnitz-Parker JE, et al. Lymphotoxin-beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury. Hepatology. 2009;49(1):227–239.
  57. Haybaeck J, Heikenwalder M, Klevenz B, et al. Aerosols transmit prions to immunocompetent and immunodeficient mice. PLoS Pathog. 2011;7(1):e1001257.
  58. Luedde T, Beraza N, Kotsikoris V, et al. Deletion of NEMO/IKKgamma in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma. Cancer Cell. 2007;11(2):119–32.
  59. Bettermann K, Vucur M, Haybaeck J, et al. TAK1 suppresses a NEMO-dependent but NF-kappaB-independent pathway to liver cancer. Cancer Cell. 2010;17(5):481–496.
  60. Vick B, Weber A, Urbanik T, et al. Knockout of myeloid cell leukemia-1 induces liver damage and increases apoptosis susceptibility of murine hepatocytes. Hepatology. 2009;49(2):627–36.
  61. Weber A, Boger R, Vick B, et al. Hepatocyte-specific deletion of the antiapoptotic protein myeloid cell leukemia-1 triggers proliferation and hepatocarcinogenesis in mice. Hepatology. 2010;51(4):1226–36.
  62. Weng SY, Yang CY, Li CC, et al. Synergism between p53 and Mcl-1 in protecting from hepatic injury, fibrosis and cancer. J Hepatol. 2011;54(4):685–694.
  63. Han J, Goldstein LA, Gastman BR, Rabinowich H. Interrelated roles for Mcl-1 and BIM in regulation of TRAIL-mediated mitochondrial apoptosis. J Biol Chem. 2006;281(15):10153–63.
  64. Jost PJ, Kaufmann T. Cancer caused by too much apoptosis – an intriguing contradiction? Hepatology. 2010;51(4):1110–112.
  65. Zhou D, Conrad C, Xia F, et al. Mst1 and Mst2 maintain hepato-cyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell. 2009;16(5):425–438.
  66. Wu S, Huang J, Dong J, Pan D. hippo encodes a Ste-20 family protein kinase that restricts cell proliferation and promotes apoptosis in conjunction with salvador and warts. Cell. 2003;114(4):445–56.
  67. Udan RS, Kango-Singh M, Nolo R, Tao C, Halder G. Hippo promotes proliferation arrest and apoptosis in the Salvador/Warts pathway. Nat Cell Biol. 2003;5(10):914–20.
  68. Möröy T, Marchio A, Etiemble J, Trépo C, Tiollais P, Buendia MA. Rearrangement and enhanced expression of c-myc in hepatocellular carcinoma of hepatitis virus infected woodchucks. Nature. 1986;324(6094):276–9.
  69. Santoni-Rugiu E, Preisegger KH, Kiss A, et al. Inhibition of neoplastic development in the liver by hepatocyte growth factor in a transgenic mouse model. Proc Natl Acad Sci U S A. 1996;93(18):9577–82.
  70. Santoni-Rugiu E, Nagy P, Jensen MR, Factor VM, Thorgeirsson SS. Evolution of neoplastic development in the liver of transgenic mice co-expressing c-myc and transforming growth factor-alpha. Am J Pathol. 1996;149(2):407–28.
  71. Terradillos O, Billet O, Renard CA, et al. The hepatitis B virus X gene potentiates c-myc-induced liver oncogenesis in transgenic mice. Oncogene. 1997;14(4):395–404.
  72. Sekine S, Ogawa R, Mcmanus MT, Kanai Y, Hebrok M. Dicer is required for proper liver zonation. J Pathol. 2009;219(3):365–72.
  73. Thorgeirsson SS, Santoni-Rugiu E. Transgenic mouse models in carcinogenesis: interaction of c-myc with transforming growth factor alpha and hepatocyte growth factor in hepatocarcinogenesis. Br J Clin Pharmacol. 1996;42(1):43–52.
  74. Murakami H, Sanderson ND, Nagy P, Marino PA, Merlino G, Thorgeirsson SS. Transgenic mouse model for synergistic effects of nuclear oncogenes and growth factors in tumorigenesis: interaction of c-myc and transforming growth factor alpha in hepatic oncogenesis. Cancer Res. 1993;53(8):1719–23.
  75. Jhappan C, Stahle C, Harkins RN, Fausto N, Smith GH, Merlino GT. TGF alpha overexpression in transgenic mice induces liver neoplasia and abnormal development of the mammary gland and pancreas. Cell. 1990;61(6):1137–46.
  76. Lee GH, Merlino G, Fausto N. Development of liver tumors in transforming growth factor alpha transgenic mice. Cancer Res. 1992;52(19):5162–70.
  77. Lakhtakia R, Kumar V, Reddi H, Mathur M, Dattagupta S, Panda SK. Hepatocellular carcinoma in a hepatitis B “x” transgenic mouse model: A sequential pathological evaluation. J Gastroenterol Hepatol. 2003;18(1):80–91.
  78. Chisari FV, Klopchin K, Moriyama T, et al. Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell. 1989;59(6):1145–56.
  79. Kim CM, Koike K, Saito I, Miyamura T, Jay G. HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature. 1991;351(6324):317–320.
  80. Moriya K, Fujie H, Shintani Y, et al. The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med. 1998;4(9):1065–1067.
  81. Sepulveda AR, Finegold MJ, Smith B, et al. Development of a transgenic mouse system for the analysis of stages in liver carcinogenesis using tissue-specific expression of SV40 large T-antigen controlled by regulatory elements of the human alpha-1–antitrypsin gene. Cancer Res. 1989;49(21):6108–17.
  82. DuBois, G.C., E. Appella, and L.W. Law Isolation of a tumor-associated transplantation antigen (TATA) from an SV40–induced sarcoma. Resemblance to the TATA of chemically induced neoplasms. International journal of cancer. Journal international du cancer. 1984;34(4):561–6.
  83. Mauad TH, van Nieuwkerk CM, Dingemans KP, et al. Mice with homozygous disruption of the mdr2 P-glycoprotein gene. A novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am J Pathol. 1994;145(5):1237–45.
  84. Ghebranious N, Sell S. Hepatitis B injury, male gender, aflatoxin, and p53 expression each contribute to hepatocarcinogenesis in transgenic mice. Hepatology. 1998;27(2):383–391.
  85. McGlynn KA, Hunter K, LeVoyer T, et al. Susceptibility to aflatoxin B1 – related primary hepatocellular carcinoma in mice and humans. Cancer Res. 2003;63(15):4594–601.
  86. Tarsetti F, Lenzi R, Salvi R, et al. Liver carcinogenesis associated with feeding of ethionine in a choline-free diet: evidence against a role of oval cells in the emergence of hepatocellular carcinoma. Hepatology. 1993;18(3):596–603.
  87. Sun FX, et al. Establishment of a metastatic model of human hepatocellular carcinoma in nude mice via orthotopic implantation of histologically intact tissues. International journal of cancer. Journal international du cancer. 1996;66(2):239–43.