Biology of Hepatocellular Carcinoma

  • Maria Luisa Balmer
  • Jean-François Dufour


Being a cancer cell is not easy. You have to maintain DNA replication and protein production under adverse conditions in the abnormal architecture of a tumour which often deprives you of oxygen and nutrients. Thus, survival requires a complete kit of stress response tools that you have to acquire before becoming a cancer cell.


Angiogenesis Apoptosis HCC Metastasis miRNA Oncogene Stem cells Telomeres 


  1. 1.
    Pei Y, Zhang T, Renault V, Zhang X (2009) An overview of hepatocellular carcinoma study by omics-based methods. Acta Biochim Biophys Sin (Shanghai) 41:1–15CrossRefGoogle Scholar
  2. 2.
    Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70CrossRefPubMedGoogle Scholar
  3. 3.
    Weinberg RA (1996) The retinoblastoma protein and cell cycle control. Cell 81:323–330CrossRefGoogle Scholar
  4. 4.
    Harris CC (1996) p53 tumor suppressor gene: from the basic research laboratory to the clinic—an abridged historical perspective. Carcinogenesis 17:1187–1198Google Scholar
  5. 5.
    Bryan TM, Cech TR (1999) Telomerase and the maintenance of chromosome ends. Curr Opin Cell Biol 11:318–324CrossRefPubMedGoogle Scholar
  6. 6.
    Bryan TM, Englezou A, Gupta J, Bacchetti S, Reddel RR (1995) Telomere elongation in immortal human cells without detectable telomerase activity. EMBO J 14:4240–4248PubMedGoogle Scholar
  7. 7.
    Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, Mikaelyan A, et al (2006) A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12:410–416CrossRefPubMedGoogle Scholar
  8. 8.
    Farazi PA, DePinho RA (2006) Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer 6:674–687CrossRefPubMedGoogle Scholar
  9. 9.
    Borzio M, Bruno S, Roncalli M, Mels GC, Ramella G, Borzio F, Leandro G, et al (1995) Liver cell dysplasia is a major risk factor for hepatocellular carcinoma in cirrhosis: a prospective study. Gastroenterology 108:812–817CrossRefPubMedGoogle Scholar
  10. 10.
    Nakamoto Y, Kaneko S, Fan H, Momoi T, Tsutsui H, Nakanishi K, Kobayashi K, et al (2002) Prevention of hepatocellular carcinoma development associated with chronic hepatitis by anti-fas ligand antibody therapy. J Exp Med 196:1105–1111CrossRefPubMedGoogle Scholar
  11. 11.
    Huang J, Sheng HH, Shen T, Hu YJ, Xiao HS, Zhang Q, Zhang QH, et al (2006) Correlation between genomic DNA copy number alterations and transcriptional expression in hepatitis B virus-associated hepatocellular carcinoma. FEBS Lett 580:3571–3581CrossRefPubMedGoogle Scholar
  12. 12.
    Pineau P, Marchio A, Battiston C, Cordina E, Russo A, Terris B, Qin LX, et al (2008) Chromosome instability in human hepatocellular carcinoma depends on p53 status and aflatoxin exposure. Mutat Res 653:6–13PubMedGoogle Scholar
  13. 13.
    Saigo K, Yoshida K, Ikeda R, Sakamoto Y, Murakami Y, Urashima T, Asano T, et al (2008) Integration of hepatitis B virus DNA into the myeloid/lymphoid or mixed-lineage leukemia (MLL4) gene and rearrangements of MLL4 in human hepatocellular carcinoma. Hum Mutat 29:703–708CrossRefPubMedGoogle Scholar
  14. 14.
    Gramantieri L, Fornari F, Callegari E, Sabbioni S, Lanza G, Croce CM, Bolondi L, et al (2008) MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med 12:2189–2204CrossRefPubMedGoogle Scholar
  15. 15.
    Morrison SJ, Kimble J (2006) Asymmetric and symmetric stem-cell divisions in development and cancer. Nature 441:1068–1074CrossRefPubMedGoogle Scholar
  16. 16.
    Roskams T, Yang SQ, Koteish A, Durnez A, DeVos R, Huang X, Achten R, et al (2003) Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol 163:1301–1311PubMedGoogle Scholar
  17. 17.
    Sell S (2001) Heterogeneity and plasticity of hepatocyte lineage cells. Hepatology 33:738–750CrossRefPubMedGoogle Scholar
  18. 18.
    Alison MR, Islam S, Lim S (2009) Stem cells in liver regeneration, fibrosis and cancer: the good, the bad and the ugly. J Pathol 217:282–298Google Scholar
  19. 19.
    Mishra L, Banker T, Murray J, Byers S, Thenappan A, He AR, Shetty K, et al (2009) Liver stem cells and hepatocellular carcinoma. Hepatology 49:318–329CrossRefPubMedGoogle Scholar
  20. 20.
    Pardal R, Clarke MF, Morrison SJ (2003) Applying the principles of stem-cell biology to cancer. Nat Rev Cancer 3:895–902CrossRefPubMedGoogle Scholar
  21. 21.
    Poon RT, Ng IO, Lau C, Zhu LX, Yu WC, Lo CM, Fan ST, et al (2001) Serum vascular endothelial growth factor predicts venous invasion in hepatocellular carcinoma: a prospective study. Ann Surg 233:227–235CrossRefPubMedGoogle Scholar
  22. 22.
    Asahara T, Masuda H, Takahashi T, Kalka C, Pastore C, Silver M, Kearne M, et al (1999) Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res 85:221–228PubMedGoogle Scholar
  23. 23.
    Shi Q, Rafii S, Wu MH, Wijelath ES, Yu C, Ishida A, Fujita Y, et al (1998) Evidence for circulating bone marrow-derived endothelial cells. Blood 92:362–367PubMedGoogle Scholar
  24. 24.
    Ribatti D, Vacca A, Dammacco F (2003) New non-angiogenesis dependent pathways for tumour growth. Eur J Cancer 39:1835–1841CrossRefPubMedGoogle Scholar
  25. 25.
    Kieser A, Weich HA, Brandner G, Marme D, Kolch W (1994) Mutant p53 potentiates protein kinase C induction of vascular endothelial growth factor expression. Oncogene 9:963–969PubMedGoogle Scholar
  26. 26.
    Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, Kerbel RS (1995) Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res 55:4575–4580PubMedGoogle Scholar
  27. 27.
    North S, Moenner M, Bikfalvi A (2005) Recent developments in the regulation of the angiogenic switch by cellular stress factors in tumors. Cancer Lett 218:1–14CrossRefPubMedGoogle Scholar
  28. 28.
    Dvorak HF, Nagy JA, Berse B, Brown LF, Yeo KT, Yeo TK, Dvorak AM, et al (1992) Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma formation. Ann N Y Acad Sci 667:101–111CrossRefPubMedGoogle Scholar
  29. 29.
    El-Assal ON, Yamanoi A, Soda Y, Yamaguchi M, Igarashi M, Yamamoto A, Nabika T, et al (1998) Clinical significance of microvessel density and vascular endothelial growth factor expression in hepatocellular carcinoma and surrounding liver: possible involvement of vascular endothelial growth factor in the angiogenesis of cirrhotic liver. Hepatology 27:1554–1562CrossRefPubMedGoogle Scholar
  30. 30.
    Sugimachi K, Tanaka S, Taguchi K, Aishima S, Shimada M, Tsuneyoshi M (2003) Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma. J Clin Pathol 56:854–860CrossRefPubMedGoogle Scholar
  31. 31.
    Yasuda S, Arii S, Mori A, Isobe N, Yang W, Oe H, Fujimoto A, et al (2004) Hexokinase II and VEGF expression in liver tumors: correlation with hypoxia-inducible factor 1 alpha and its significance. J Hepatol 40:117–123CrossRefPubMedGoogle Scholar
  32. 32.
    von Marschall Z, Cramer T, Hocker M, Finkenzeller G, Wiedenmann B, Rosewicz S (2001) Dual mechanism of vascular endothelial growth factor upregulation by hypoxia in human hepatocellular carcinoma. Gut 48:87–96CrossRefGoogle Scholar
  33. 33.
    Lee SW, Lee YM, Bae SK, Murakami S, Yun Y, Kim KW (2000) Human hepatitis B virus X protein is a possible mediator of hypoxia-induced angiogenesis in hepatocarcinogenesis. Biochem Biophys Res Commun 268:456–461CrossRefPubMedGoogle Scholar
  34. 34.
    Tsukamoto A, Kaneko Y, Yoshida T, Ichinose M, Kimura S (1999) Regulation of angiogenesis in human hepatomas: possible involvement of p53-inducible inhibitor of vascular endothelial cell proliferation. Cancer Lett 141:79–84CrossRefPubMedGoogle Scholar
  35. 35.
    Pang R, Poon RT (2006) Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Lett 242:151–167CrossRefPubMedGoogle Scholar
  36. 36.
    Yoshiji H, Kuriyama S, Yoshii J, Ikenaka Y, Noguchi R, Hicklin DJ, Huber J, et al (2002) Synergistic effect of basic fibroblast growth factor and vascular endothelial growth factor in murine hepatocellular carcinoma. Hepatology 35:834–842CrossRefPubMedGoogle Scholar
  37. 37.
    Kin M, Sata M, Ueno T, Torimura T, Inuzuka S, Tsuji R, Sujaku K, et al (1997) Basic fibroblast growth factor regulates proliferation and motility of human hepatoma cells by an autocrine mechanism. J Hepatol 27:677–687CrossRefPubMedGoogle Scholar
  38. 38.
    Mitsuhashi N, Shimizu H, Ohtsuka M, Wakabayashi Y, Ito H, Kimura F, Yoshidome H, et al (2003) Angiopoietins and Tie-2 expression in angiogenesis and proliferation of human hepatocellular carcinoma. Hepatology 37:1105–1113CrossRefPubMedGoogle Scholar
  39. 39.
    Morinaga S, Yamamoto Y, Noguchi Y, Imada T, Rino Y, Akaike M, Sugimasa Y, et al (2003) Platelet-derived endothelial cell growth factor (PD-ECGF) is up-regulated in human hepatocellular carcinoma (HCC) and the corresponding hepatitis liver. Hepatogastroenterology 50:1521–1526PubMedGoogle Scholar
  40. 40.
    Poon RT, Lau CP, Ho JW, Yu WC, Fan ST, Wong J (2003) Tissue factor expression correlates with tumor angiogenesis and invasiveness in human hepatocellular carcinoma. Clin Cancer Res 9:5339–5345PubMedGoogle Scholar
  41. 41.
    Tang TC, Poon RT, Lau CP, Xie D, Fan ST (2005) Tumor cyclooxygenase-2 levels correlate with tumor invasiveness in human hepatocellular carcinoma. World J Gastroenterol 11:1896–1902PubMedGoogle Scholar
  42. 42.
    Hisai H, Kato J, Kobune M, Murakami T, Miyanishi K, Takahashi M, Yoshizaki N, et al (2003) Increased expression of angiogenin in hepatocellular carcinoma in correlation with tumor vascularity. Clin Cancer Res 9:4852–4859PubMedGoogle Scholar
  43. 43.
    Erlitzki R, Minuk GY (1999) Telomeres, telomerase and HCC: the long and the short of it. J Hepatol 31:939–945CrossRefPubMedGoogle Scholar
  44. 44.
    Plentz RR, Park YN, Lechel A, Kim H, Nellessen F, Langkopf BH, Wilkens L, et al (2007) Telomere shortening and inactivation of cell cycle checkpoints characterize human hepatocarcinogenesis. Hepatology 45:968–976CrossRefPubMedGoogle Scholar
  45. 45.
    Begus-Nahrmann Y, Lechel A, Obenauf AC, Nalapareddy K, Peit E, Hoffmann E, Schlaudraff F, et al.(2009) p53 deletion impairs clearance of chromosomal-instable stem cells in aging telomere-dysfunctional mice. Nat Genet 41:1138–1143CrossRefPubMedGoogle Scholar
  46. 46.
    Lechel A, Holstege H, Begus Y, Schienke A, Kamino K, Lehmann U, Kubicka S, et al (2007) Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology 132:1465–1475CrossRefPubMedGoogle Scholar
  47. 47.
    Nzeako UC, Goodman ZD, Ishak KG (1996) Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-histopathologic study of 804 North American patients. Am J Clin Pathol 105:65–75PubMedGoogle Scholar
  48. 48.
    Okuda K, Nakashima T, Kojiro M, Kondo Y, Wada K (1989) Hepatocellular carcinoma without cirrhosis in Japanese patients. Gastroenterology 97:140–146PubMedGoogle Scholar
  49. 49.
    Regimbeau JM, Colombat M, Mognol P, Durand F, Abdalla E, Degott C, Degos F, et al (2004) Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl 10:S69–S73Google Scholar
  50. 50.
    Trevisani F, D’Intino PE, Caraceni P, Pizzo M, Stefanini GF, Mazziotti A, Grazi GL, et al (1995) Etiologic factors and clinical presentation of hepatocellular carcinoma. Differences between cirrhotic and noncirrhotic Italian patients. Cancer 75:2220–2232CrossRefPubMedGoogle Scholar
  51. 51.
    Okuda K (1997) Liver cancer. Churchill Livingstone, LondonGoogle Scholar
  52. 52.
    Zhou H, Ortiz-Pallardo ME, Ko Y, Fischer HP (2000) Is heterozygous alpha-1-antitrypsin deficiency type PIZ a risk factor for primary liver carcinoma? Cancer 88:2668–2676CrossRefPubMedGoogle Scholar
  53. 53.
    Bianchi L (1993) Glycogen storage disease I and hepatocellular tumours. Eur J Pediatr 152(Suppl 1):S63–S70Google Scholar
  54. 54.
    Kowdley KV (2004) Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology 127:S79–S86Google Scholar
  55. 55.
    Turlin B, Juguet F, Moirand R, Le Quilleuc D, Loreal O, Campion JP, Launois B, et al (1995) Increased liver iron stores in patients with hepatocellular carcinoma developed on a noncirrhotic liver. Hepatology 22:446–450PubMedGoogle Scholar
  56. 56.
    Lok AS (2009) Hepatitis B: liver fibrosis and hepatocellular carcinoma. Gastroenterol Clin Biol 33:911–915CrossRefPubMedGoogle Scholar
  57. 57.
    But DY, Lai CL, Yuen MF (2008) Natural history of hepatitis-related hepatocellular carcinoma. World J Gastroenterol 14:1652–1656CrossRefPubMedGoogle Scholar
  58. 58.
    Park NH, Song IH, Chung YH (2006) Chronic hepatitis B in hepatocarcinogenesis. Postgrad Med J 82:507–515CrossRefPubMedGoogle Scholar
  59. 59.
    Terasaki S, Kaneko S, Kobayashi K, Nonomura A, Nakanuma Y (1998) Histological features predicting malignant transformation of nonmalignant hepatocellular nodules: a prospective study. Gastroenterology 115:1216–1222CrossRefPubMedGoogle Scholar
  60. 60.
    Watanabe S, Horie Y, Kataoka E, Sato W, Dohmen T, Ohshima S, Goto T, et al (2007) Non-alcoholic steatohepatitis and hepatocellular carcinoma: lessons from hepatocyte-specific phosphatase and tensin homolog (PTEN)-deficient mice. J Gastroenterol Hepatol 22(Suppl 1):S96–S100Google Scholar
  61. 61.
    Caldwell S, Park SH (2009) The epidemiology of hepatocellular cancer: from the perspectives of public health problem to tumor biology. J Gastroenterol 44(Suppl 19):96–101CrossRefPubMedGoogle Scholar
  62. 62.
    Takuma Y, Nouso K, Makino Y, Saito S, Takayama H, Takahara M, Takahashi H, et al (2007) Hepatic steatosis correlates with the postoperative recurrence of hepatitis C virus-associated hepatocellular carcinoma. Liver Int 27:620–626CrossRefPubMedGoogle Scholar
  63. 63.
    Lagiou P, Kuper H, Stuver SO, Tzonou A, Trichopoulos D, Adami HO (2000) Role of diabetes mellitus in the etiology of hepatocellular carcinoma. J Natl Cancer Inst 92:1096–1099CrossRefPubMedGoogle Scholar
  64. 64.
    Paradis V, Zalinski S, Chelbi E, Guedj N, Degos F, Vilgrain V, Bedossa P, et al (2009) Hepatocellular carcinomas in patients with metabolic syndrome often develop without significant liver fibrosis: a pathological analysis. Hepatology 49:851–859CrossRefPubMedGoogle Scholar
  65. 65.
    Closset J, Veys I, Peny MO, Braude P, Van Gansbeke D, Lambilliotte JP, Gelin M (2000) Retrospective analysis of 29 patients surgically treated for hepatocellular adenoma or focal nodular hyperplasia. Hepatogastroenterology 47:1382–1384PubMedGoogle Scholar
  66. 66.
    Ferrell LD (1993) Hepatocellular carcinoma arising in a focus of multilobular adenoma. A case report. Am J Surg Pathol 17:525–529Google Scholar
  67. 67.
    Foster JH, Berman MM (1994) The malignant transformation of liver cell adenomas. Arch Surg 129:712–717PubMedGoogle Scholar
  68. 68.
    Bioulac-Sage P, Laumonier H, Couchy G, Le Bail B, Sa Cunha A, Rullier A, Laurent C, et al (2009) Hepatocellular adenoma management and phenotypic classification: the Bordeaux experience. Hepatology 50:481–489CrossRefPubMedGoogle Scholar
  69. 69.
    Plopper H, Schaffner F (1957) Primary hepatic carcinomas. McGraw-Hill, New York, pp. 593–612Google Scholar
  70. 70.
    Nakano S, Haratake J, Okamoto K, Takeda S (1994) Investigation of resected multinodular hepatocellular carcinoma: assessment of unicentric or multicentric genesis from histological and prognostic viewpoint. Am J Gastroenterol 89:189–193PubMedGoogle Scholar
  71. 71.
    Yasui M, Harada A, Nonami T, Takeuchi Y, Taniguchi K, Nakao A, Takagi H (1997) Potentially multicentric hepatocellular carcinoma: clinicopathologic characteristics and postoperative prognosis. World J Surg 21:860–865CrossRefPubMedGoogle Scholar
  72. 72.
    Ng IO, Guan XY, Poon RT, Fan ST, Lee JM (2003) Determination of the molecular relationship between multiple tumour nodules in hepatocellular carcinoma differentiates multicentric origin from intrahepatic metastasis. J Pathol 199:345–353CrossRefPubMedGoogle Scholar
  73. 73.
    Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659CrossRefPubMedGoogle Scholar
  74. 74.
    Itoh T, Shiro T, Seki T, Nakagawa T, Wakabayashi M, Inoue K, Okamura A (2000) Relationship between p53 overexpression and the proliferative activity in hepatocellular carcinoma. Int J Mol Med 6:137–142PubMedGoogle Scholar
  75. 75.
    Jeng KS, Sheen IS, Chen BF, Wu JY (2000) Is the p53 gene mutation of prognostic value in hepatocellular carcinoma after resection? Arch Surg 135:1329–1333CrossRefPubMedGoogle Scholar
  76. 76.
    Guo K, Liu Y, Zhou H, Dai Z, Zhang J, Sun R, Chen J, et al (2008) Involvement of protein kinase C beta-extracellular signal-regulating kinase 1/2/p38 mitogen-activated protein kinase-heat shock protein 27 activation in hepatocellular carcinoma cell motility and invasion. Cancer Sci 99:486–496CrossRefPubMedGoogle Scholar
  77. 77.
    Song PM, Zhang Y, He YF, Bao HM, Luo JH, Liu YK, Yang PY, et al (2008) Bioinformatics analysis of metastasis-related proteins in hepatocellular carcinoma. World J Gastroenterol 14:5816–5822CrossRefPubMedGoogle Scholar
  78. 78.
    Chambers AF, Wilson SM, Kerkvliet N, O’Malley FP, Harris JF, Casson AG (1996) Osteopontin expression in lung cancer. Lung Cancer 15:311–323CrossRefPubMedGoogle Scholar
  79. 79.
    Al-Mehdi AB, Tozawa K, Fisher AB, Shientag L, Lee A, Muschel RJ (2000) Intravascular origin of metastasis from the proliferation of endothelium-attached tumor cells: a new model for metastasis. Nat Med 6:100–102CrossRefPubMedGoogle Scholar
  80. 80.
    Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe’er J, Trent JM, et al (1999) Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am J Pathol 155:739–752PubMedGoogle Scholar
  81. 81.
    Sugino T, Yamaguchi T, Hoshi N, Kusakabe T, Ogura G, Goodison S, Suzuki T (2008) Sinusoidal tumor angiogenesis is a key component in hepatocellular carcinoma metastasis. Clin Exp Metastasis 25:835–841CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Maria Luisa Balmer
    • 1
  • Jean-François Dufour
    • 1
  1. 1.Department of Clinical Pharmacology and Visceral ResearchUniversity of BernBernSwitzerland

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