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Primary Hepatocellular Carcinoma

  • Jean-François DufourEmail author
  • Caroline Hora
Chapter
Part of the Molecular Pathology Library book series (MPLB, volume 5)

Abstract

Hepatocellular carcinoma (HCC) is the main primary liver tumor, accounting for 85–90% of primary liver cancers diagnosed [1]. The prevalence and incidence vary greatly among the different regions of the world. High prevalence areas are Asia and Africa. Eastern Asia and sub-Saharan Africa account for over 80% of worldwide HCC cases, and more than half of the world’s cases occur in China [1, 2]. In these regions, the incidence ranges from 18.2 to 39.7/100,000 in men and 5.7 to 14.2/100,000 in women. North and South America, Europe, and Australia are considered as low-prevalence regions, with incidence rates ranging from 3.4 to 11.6/100,000 in men and from 1.7 to 4.0 in women; the highest incidence being recorded in countries of Southern Europe [1, 2].

Keywords

Vascular Endothelial Growth Factor Vasculogenic Mimicry Dysplastic Nodule Hepatic Progenitor Cell CTNNB1 Mutation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    El-Serag HB, Rudolph KL. Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology. 2007;132(7):2557–76.PubMedGoogle Scholar
  2. 2.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.PubMedGoogle Scholar
  3. 3.
    Sherman M. Hepatocellular carcinoma: epidemiology, risk factors, and screening. Semin Liver Dis. 2005;25(2):143–54.PubMedGoogle Scholar
  4. 4.
    Chang MH, Chen CJ, Lai MS, et al. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med. 1997;336(26):1855–9.PubMedGoogle Scholar
  5. 5.
    McGlynn KA, Tsao L, Hsing AW, Devesa SS, Fraumeni Jr JF. International trends and patterns of primary liver cancer. Int J Cancer. 2001;94(2):290–6.PubMedGoogle Scholar
  6. 6.
    El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med. 1999;340(10):745–50.PubMedGoogle Scholar
  7. 7.
    El-Serag HB. Hepatocellular carcinoma: an epidemiologic view. J Clin Gastroenterol. 2002;35(5 Suppl 2):S72–8.PubMedGoogle Scholar
  8. 8.
    El-Serag HB, Davila JA, Petersen NJ, McGlynn KA. The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med. 2003;139(10):817–23.PubMedGoogle Scholar
  9. 9.
    Hassan MM, Frome A, Patt YZ, El-Serag HB. Rising prevalence of hepatitis C virus infection among patients recently diagnosed with hepatocellular carcinoma in the United States. J Clin Gastroenterol. 2002;35(3):266–9.PubMedGoogle Scholar
  10. 10.
    Bosch FX, Ribes J, Diaz M, Cleries R. Primary liver cancer: worldwide incidence and trends. Gastroenterology. 2004;127(5 Suppl 1):S5–16.PubMedGoogle Scholar
  11. 11.
    Wong JB, McQuillan GM, McHutchison JG, Poynard T. Estimating future hepatitis C morbidity, mortality, and costs in the United States. Am J Public Health. 2000;90(10):1562–9.PubMedGoogle Scholar
  12. 12.
    Fattovich G, Giustina G, Schalm SW, et al. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis. Hepatology. 1995;21(1):77–82.PubMedGoogle Scholar
  13. 13.
    Hu KQ, Tong MJ. The long-term outcomes of patients with compensated hepatitis C virus-related cirrhosis and history of parenteral exposure in the United States. Hepatology. 1999;29(4):1311–6.PubMedGoogle Scholar
  14. 14.
    Freeman AJ, Dore GJ, Law MG, et al. Estimating progression to cirrhosis in chronic hepatitis C virus infection. Hepatology. 2001;34(4 Pt 1):809–16.PubMedGoogle Scholar
  15. 15.
    Donato F, Tagger A, Gelatti U, et al. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol. 2002;155(4):323–31.PubMedGoogle Scholar
  16. 16.
    Hassan MM, Hwang LY, Hatten CJ, et al. Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology. 2002;36(5):1206–13.PubMedGoogle Scholar
  17. 17.
    El-Serag HB, Richardson PA, Everhart JE. The role of diabetes in hepatocellular carcinoma: a case-control study among United States Veterans. Am J Gastroenterol. 2001;96(8):2462–7.PubMedGoogle Scholar
  18. 18.
    Lagiou P, Kuper H, Stuver SO, Tzonou A, Trichopoulos D, Adami HO. Role of diabetes mellitus in the etiology of hepatocellular carcinoma. J Natl Cancer Inst. 2000;92(13):1096–9.PubMedGoogle Scholar
  19. 19.
    Yu L, Sloane DA, Guo C, Howell CD. Risk factors for primary hepatocellular carcinoma in black and white Americans in 2000. Clin Gastroenterol Hepatol. 2006;4(3):355–60.PubMedGoogle Scholar
  20. 20.
    Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Over­weight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med. 2003;348(17):1625–38.PubMedGoogle Scholar
  21. 21.
    Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37(5):1202–19.PubMedGoogle Scholar
  22. 22.
    Elmberg M, Hultcrantz R, Ekbom A, et al. Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology. 2003;125(6):1733–41.PubMedGoogle Scholar
  23. 23.
    Fracanzani AL, Conte D, Fraquelli M, et al. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology. 2001;33(3):647–51.PubMedGoogle Scholar
  24. 24.
    Caballeria L, Pares A, Castells A, Gines A, Bru C, Rodes J. Hepatocellular carcinoma in primary biliary cirrhosis: similar incidence to that in hepatitis C virus-related cirrhosis. Am J Gastroenterol. 2001;96(4):1160–3.PubMedGoogle Scholar
  25. 25.
    Propst T, Propst A, Dietze O, Judmaier G, Braunsteiner H, Vogel W. Prevalence of hepatocellular carcinoma in alpha-1-antitrypsin deficiency. J Hepatol. 1994;21(6):1006–11.PubMedGoogle Scholar
  26. 26.
    Teufel A, Weinmann A, Centner C, et al. Hepatocellular carcinoma in patients with autoimmune hepatitis. World J Gastroenterol. 2009;15(5):578–82.PubMedGoogle Scholar
  27. 27.
    Wilkinson ML, Portmann B, Williams R. Wilson’s disease and hepatocellular carcinoma: possible protective role of copper. Gut. 1983;24(8):767–71.PubMedGoogle Scholar
  28. 28.
    Saito Y, Kanai Y, Sakamoto M, Saito H, Ishii H, Hirohashi S. Expression of mRNA for DNA methyltransferases and methyl-CpG-binding proteins and DNA methylation status on CpG islands and pericentromeric satellite regions during human hepatocarcinogenesis. Hepatology. 2001;33(3):561–8.PubMedGoogle Scholar
  29. 29.
    Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S. Genetic instability and aberrant DNA methylation in chronic hepatitis and cirrhosis – a comprehensive study of loss of heterozygosity and microsatellite instability at 39 loci and DNA hypermethylation on 8 CpG islands in microdissected specimens from patients with hepatocellular carcinoma. Hepatology. 2000;32(5):970–9.PubMedGoogle Scholar
  30. 30.
    Kawai H, Suda T, Aoyagi Y, et al. Quantitative evaluation of genomic instability as a possible predictor for development of hepatocellular carcinoma: comparison of loss of heterozygosity and replication error. Hepatology. 2000;31(6):1246–50.PubMedGoogle Scholar
  31. 31.
    Maggioni M, Coggi G, Cassani B, et al. Molecular changes in hepatocellular dysplastic nodules on microdissected liver biopsies. Hepatology. 2000;32(5):942–6.PubMedGoogle Scholar
  32. 32.
    Strauss BS. Frameshift mutation, microsatellites and mismatch repair. Mutat Res. 1999;437(3):195–203.PubMedGoogle Scholar
  33. 33.
    Roncalli M, Bianchi P, Grimaldi GC, et al. Fractional allelic loss in non-end-stage cirrhosis: correlations with hepatocellular carcinoma development during follow-up. Hepatology. 2000;31(4):846–50.PubMedGoogle Scholar
  34. 34.
    Kanai Y, Ushijima S, Tsuda H, Sakamoto M, Hirohashi S. Aberrant DNA methylation precedes loss of heterozygosity on chromosome 16 in chronic hepatitis and liver cirrhosis. Cancer Lett. 2000;148(1):73–80.PubMedGoogle Scholar
  35. 35.
    Boige V, Laurent-Puig P, Fouchet P, et al. Concerted nonsyntenic allelic losses in hyperploid hepatocellular carcinoma as determined by a high-resolution allelotype. Cancer Res. 1997;57(10):1986–90.PubMedGoogle Scholar
  36. 36.
    Laurent-Puig P, Legoix P, Bluteau O, et al. Genetic alterations associated with hepatocellular carcinomas define distinct pathways of hepatocarcinogenesis. Gastroenterology. 2001;120(7):1763–73.PubMedGoogle Scholar
  37. 37.
    Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocellular carcinoma. Nat Genet. 2002;31(4):339–46.PubMedGoogle Scholar
  38. 38.
    Marchio A, Meddeb M, Pineau P, et al. Recurrent chromosomal abnormalities in hepatocellular carcinoma detected by comparative genomic hybridization. Genes Chromosomes Cancer. 1997;18(1):59–65.PubMedGoogle Scholar
  39. 39.
    Nagai H, Pineau P, Tiollais P, Buendia MA, Dejean A. Comprehensive allelotyping of human hepatocellular carcinoma. Oncogene. 1997;14(24):2927–33.PubMedGoogle Scholar
  40. 40.
    Bressac B, Galvin KM, Liang TJ, Isselbacher KJ, Wands JR, Ozturk M. Abnormal structure and expression of p53 gene in human hepatocellular carcinoma. Proc Natl Acad Sci U S A. 1990;87(5):1973–7.PubMedGoogle Scholar
  41. 41.
    De La Coste A, Romagnolo B, Billuart P, et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci U S A. 1998;95(15):8847–51.PubMedGoogle Scholar
  42. 42.
    Miyoshi Y, Iwao K, Nagasawa Y, et al. Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res. 1998;58(12):2524–7.PubMedGoogle Scholar
  43. 43.
    Satoh S, Daigo Y, Furukawa Y, et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet. 2000;24(3):245–50.PubMedGoogle Scholar
  44. 44.
    Legoix P, Bluteau O, Bayer J, et al. Beta-catenin mutations in hepatocellular carcinoma correlate with a low rate of loss of heterozygosity. Oncogene. 1999;18(27):4044–6.PubMedGoogle Scholar
  45. 45.
    Ishizaki Y, Ikeda S, Fujimori M, et al. Immunohistochemical analysis and mutational analyses of beta-catenin, Axin family and APC genes in hepatocellular carcinomas. Int J Oncol. 2004;24(5):1077–83.PubMedGoogle Scholar
  46. 46.
    Taniguchi K, Roberts LR, Aderca IN, et al. Mutational spectrum of beta-catenin, AXIN1, and AXIN2 in hepatocellular carcinomas and hepatoblastomas. Oncogene. 2002;21(31):4863–71.PubMedGoogle Scholar
  47. 47.
    Roncalli M, Bianchi P, Bruni B, et al. Methylation framework of cell cycle gene inhibitors in cirrhosis and associated hepatocellular carcinoma. Hepatology. 2002;36(2):427–32.PubMedGoogle Scholar
  48. 48.
    Azechi H, Nishida N, Fukuda Y, et al. Disruption of the p16/cyclin D1/retinoblastoma protein pathway in the majority of human hepatocellular carcinomas. Oncology. 2001;60(4):346–54.PubMedGoogle Scholar
  49. 49.
    Zhang X, Xu HJ, Murakami Y, et al. Deletions of chromosome 13q, mutations in retinoblastoma 1, and retinoblastoma protein state in human hepatocellular carcinoma. Cancer Res. 1994;54(15):4177–82.PubMedGoogle Scholar
  50. 50.
    Higashitsuji H, Itoh K, Nagao T, et al. Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med. 2000;6(1):96–9.PubMedGoogle Scholar
  51. 51.
    De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL. M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat Genet. 1995;11(4):447–9.PubMedGoogle Scholar
  52. 52.
    Kawate S, Takenoshita S, Ohwada S, et al. Mutation analysis of transforming growth factor beta type II receptor, Smad2, and Smad4 in hepatocellular carcinoma. Int J Oncol. 1999;14(1):127–31.PubMedGoogle Scholar
  53. 53.
    Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M. Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene. 1999;18(34):4879–83.PubMedGoogle Scholar
  54. 54.
    Paterlini-Brechot P, Saigo K, Murakami Y, et al. Hepatitis B virus-related insertional mutagenesis occurs frequently in human liver cancers and recurrently targets human telomerase gene. Oncogene. 2003;22(25):3911–6.PubMedGoogle Scholar
  55. 55.
    Ferber MJ, Montoya DP, Yu C, et al. Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers. Oncogene. 2003;22(24):3813–20.PubMedGoogle Scholar
  56. 56.
    Horikawa I, Barrett JC. Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms. Carcinogenesis. 2003;24(7):1167–76.PubMedGoogle Scholar
  57. 57.
    Feitelson MA, Zhu M, Duan LX, London WT. Hepatitis B x antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. Oncogene. 1993;8(5):1109–17.PubMedGoogle Scholar
  58. 58.
    Essigmann JM, Croy RG, Nadzan AM, et al. Structural identification of the major DNA adduct formed by aflatoxin B1 in vitro. Proc Natl Acad Sci U S A. 1977;74(5):1870–4.PubMedGoogle Scholar
  59. 59.
    Martin CN, Garner RC. Aflatoxin B -oxide generated by chemical or enzymic oxidation of aflatoxin B1 causes guanine substitution in nucleic acids. Nature. 1977;267(5614):863–5.PubMedGoogle Scholar
  60. 60.
    Bressac B, Kew M, Wands J, Ozturk M. Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature. 1991;350(6317):429–31.PubMedGoogle Scholar
  61. 61.
    Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC. Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature. 1991;350(6317):427–8.PubMedGoogle Scholar
  62. 62.
    McGlynn KA, Rosvold EA, Lustbader ED, et al. Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1. Proc Natl Acad Sci U S A. 1995;92(6):2384–7.PubMedGoogle Scholar
  63. 63.
    Sun CA, Wang LY, Chen CJ, et al. Genetic polymorphisms of glutathione S-transferases M1 and T1 associated with susceptibility to aflatoxin-related hepatocarcinogenesis among chronic hepatitis B carriers: a nested case-control study in Taiwan. Carcinogenesis. 2001;22(8):1289–94.PubMedGoogle Scholar
  64. 64.
    Weihrauch M, Benicke M, Lehnert G, Wittekind C, Wrbitzky R, Tannapfel A. Frequent k-ras-2 mutations and p16(INK4A)methylation in hepatocellular carcinomas in workers exposed to vinyl chloride. Br J Cancer. 2001;84(7):982–9.PubMedGoogle Scholar
  65. 65.
    Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell. 2004;116(2):281–97.PubMedGoogle Scholar
  66. 66.
    Esquela-Kerscher A, Slack FJ. Oncomirs – microRNAs with a role in cancer. Nat Rev Cancer. 2006;6(4):259–69.PubMedGoogle Scholar
  67. 67.
    Gramantieri L, Fornari F, Callegari E, et al. MicroRNA involvement in hepatocellular carcinoma. J Cell Mol Med. 2008;12(6A):2189–204.PubMedGoogle Scholar
  68. 68.
    Fornari F, Gramantieri L, Ferracin M, et al. MiR-221 controls CDKN1C/p57 and CDKN1B/p27 expression in human hepatocellular carcinoma. Oncogene. 2008;27(43):5651–61.PubMedGoogle Scholar
  69. 69.
    le Sage C, Nagel R, Egan DA, et al. Regulation of the p27(Kip1) tumor suppressor by miR-221 and miR-222 promotes cancer cell proliferation. Embo J. 2007;26(15):3699–708.PubMedGoogle Scholar
  70. 70.
    Gramantieri L, Fornari F, Ferracin M, et al. MicroRNA-221 targets Bmf in hepatocellular carcinoma and correlates with tumor multifocality. Clin Cancer Res. 2009;15(16):5073–81.PubMedGoogle Scholar
  71. 71.
    Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133(2):647–58.PubMedGoogle Scholar
  72. 72.
    Gramantieri L, Ferracin M, Fornari F, et al. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res. 2007;67(13):6092–9.PubMedGoogle Scholar
  73. 73.
    Okamoto K, Li H, Jensen MR, et al. Cyclin G recruits PP2A to dephosphorylate Mdm2. Mol Cell. 2002;9(4):761–71.PubMedGoogle Scholar
  74. 74.
    Ohtsuka T, Jensen MR, Kim HG, Kim KT, Lee SW. The negative role of cyclin G in ATM-dependent p53 activation. Oncogene. 2004;23(31):5405–8.PubMedGoogle Scholar
  75. 75.
    Blackburn EH. Structure and function of telomeres. Nature. 1991;350(6319):569–73.PubMedGoogle Scholar
  76. 76.
    Vaziri H, Benchimol S. From telomere loss to p53 induction and activation of a DNA-damage pathway at senescence: the telomere loss/DNA damage model of cell aging. Exp Gerontol. 1996;31(1–2):295–301.PubMedGoogle Scholar
  77. 77.
    Chin L, Artandi SE, Shen Q, et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999;97(4):527–38.PubMedGoogle Scholar
  78. 78.
    Greider CW, Blackburn EH. A telomeric sequence in the RNA of tetrahymena telomerase required for telomere repeat synthesis. Nature. 1989;337(6205):331–7.PubMedGoogle Scholar
  79. 79.
    Harrington LA, Greider CW. Telomerase primer specificity and chromosome healing. Nature. 1991;353(6343):451–4.PubMedGoogle Scholar
  80. 80.
    Meyerson M, Counter CM, Eaton EN, et al. hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell. 1997;90(4):785–95.PubMedGoogle Scholar
  81. 81.
    Feng J, Funk WD, Wang SS, et al. The RNA component of human telomerase. Science. 1995;269(5228):1236–41.PubMedGoogle Scholar
  82. 82.
    Nakayama J, Tahara H, Tahara E, et al. Telomerase activation by hTRT in human normal fibroblasts and hepatocellular carcinomas. Nat Genet. 1998;18(1):65–8.PubMedGoogle Scholar
  83. 83.
    Miura N, Horikawa I, Nishimoto A, et al. Progressive telomere shortening and telomerase reactivation during hepatocellular carcinogenesis. Cancer Genet Cytogenet. 1997;93(1):56–62.PubMedGoogle Scholar
  84. 84.
    Takahashi S, Kitamoto M, Takaishi H, et al. Expression of telomerase component genes in hepatocellular carcinomas. Eur J Cancer. 2000;36(4):496–502.PubMedGoogle Scholar
  85. 85.
    Hytiroglou P, Kotoula V, Thung SN, Tsokos M, Fiel MI, Papadimitriou CS. Telomerase activity in precancerous hepatic nodules. Cancer. 1998;82(10):1831–8.PubMedGoogle Scholar
  86. 86.
    Oh BK, Jo Chae K, Park C, et al. Telomere shortening and telomerase reactivation in dysplastic nodules of human hepatocarcinogenesis. J Hepatol. 2003;39(5):786–92.PubMedGoogle Scholar
  87. 87.
    Kitada T, Seki S, Kawakita N, Kuroki T, Monna T. Telomere shortening in chronic liver diseases. Biochem Biophys Res Commun. 1995;211(1):33–9.PubMedGoogle Scholar
  88. 88.
    Urabe Y, Nouso K, Higashi T, et al. Telomere length in human liver diseases. Liver. 1996;16(5):293–7.PubMedGoogle Scholar
  89. 89.
    Wiemann SU, Satyanarayana A, Tsahuridu M, et al. Hepatocyte telomere shortening and senescence are general markers of human liver cirrhosis. Faseb J. 2002;16(9):935–42.PubMedGoogle Scholar
  90. 90.
    Plentz RR, Caselitz M, Bleck JS, et al. Hepatocellular telomere shortening correlates with chromosomal instability and the development of human hepatoma. Hepatology. 2004;40(1):80–6.PubMedGoogle Scholar
  91. 91.
    Farazi PA, Glickman J, Jiang S, Yu A, Rudolph KL, DePinho RA. Differential impact of telomere dysfunction on initiation and progression of hepatocellular carcinoma. Cancer Res. 2003;63(16):5021–7.PubMedGoogle Scholar
  92. 92.
    Lechel A, Holstege H, Begus Y, et al. Telomerase deletion limits progression of p53-mutant hepatocellular carcinoma with short telomeres in chronic liver disease. Gastroenterology. 2007;132(4):1465–75.PubMedGoogle Scholar
  93. 93.
    Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes to environment. Nat Rev Cancer. 2006;6(9):674–87.PubMedGoogle Scholar
  94. 94.
    Masutomi K, Possemato R, Wong JM, et al. The telomerase reverse transcriptase regulates chromatin state and DNA damage responses. Proc Natl Acad Sci U S A. 2005;102(23):8222–7.PubMedGoogle Scholar
  95. 95.
    Farazi PA, Glickman J, Horner J, Depinho RA. Cooperative interactions of p53 mutation, telomere dysfunction, and chronic liver damage in hepatocellular carcinoma progression. Cancer Res. 2006;66(9):4766–73.PubMedGoogle Scholar
  96. 96.
    Stiewe T. The p53 family in differentiation and tumorigenesis. Nat Rev Cancer. 2007;7(3):165–8.PubMedGoogle Scholar
  97. 97.
    Hu W, Feng Z, Atwal GS, Levine AJ. p53: a new player in reproduction. Cell Cycle. 2008;7(7):848–52.PubMedGoogle Scholar
  98. 98.
    Feng Z, Hu W, Rajagopal G, Levine AJ. The tumor suppressor p53: cancer and aging. Cell Cycle. 2008;7(7):842–7.PubMedGoogle Scholar
  99. 99.
    Bode AM, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer. 2004;4(10):793–805.PubMedGoogle Scholar
  100. 100.
    Joerger AC, Fersht AR. Structure-function-rescue: the diverse nature of common p53 cancer mutants. Oncogene. 2007;26(15):2226–42.PubMedGoogle Scholar
  101. 101.
    Nicholls CD, McLure KG, Shields MA, Lee PW. Biogenesis of p53 involves cotranslational dimerization of monomers and posttranslational dimerization of dimers. Implications on the dominant negative effect. J Biol Chem. 2002;277(15):12937–45.PubMedGoogle Scholar
  102. 102.
    Jeffrey PD, Gorina S, Pavletich NP. Crystal structure of the tetramerization domain of the p53 tumor suppressor at 1.7 angstroms. Science. 1995;267(5203):1498–502.PubMedGoogle Scholar
  103. 103.
    O’Keefe K, Li H, Zhang Y. Nucleocytoplasmic shuttling of p53 is essential for MDM2-mediated cytoplasmic degradation but not ubiquitination. Mol Cell Biol. 2003;23(18):6396–405.PubMedGoogle Scholar
  104. 104.
    Cann KL, Hicks GG. Regulation of the cellular DNA double-strand break response. Biochem Cell Biol. 2007;85(6):663–74.PubMedGoogle Scholar
  105. 105.
    Liebermann DA, Hoffman B, Vesely D. p53 induced growth arrest versus apoptosis and its modulation by survival cytokines. Cell Cycle. 2007;6(2):166–70.PubMedGoogle Scholar
  106. 106.
    Murray-Zmijewski F, Slee EA, Lu X. A complex barcode underlies the heterogeneous response of p53 to stress. Nat Rev Mol Cell Biol. 2008;9(9):702–12.PubMedGoogle Scholar
  107. 107.
    Lai PB, Chi TY, Chen GG. Different levels of p53 induced either apoptosis or cell cycle arrest in a doxycycline-regulated hepatocellular carcinoma cell line in vitro. Apoptosis. 2007;12(2):387–93.PubMedGoogle Scholar
  108. 108.
    Qian H, Wang T, Naumovski L, Lopez CD, Brachmann RK. Groups of p53 target genes involved in specific p53 downstream effects cluster into different classes of DNA binding sites. Oncogene. 2002;21(51):7901–11.PubMedGoogle Scholar
  109. 109.
    Weinberg RA. The biology of cancer. New York: Garland Science; 2006.Google Scholar
  110. 110.
    Liebermann DA, Hoffman B. Gadd45 in stress signaling. J Mol Signal. 2008;3:15.PubMedGoogle Scholar
  111. 111.
    Kastan MB, Zhan Q, Deiry WS, et al. A mammalian cell cycle checkpoint pathway utilizing p53 and GADD45 is defective in ataxia-telangiectasia. Cell. 1992;71(4):587–97.PubMedGoogle Scholar
  112. 112.
    Taylor WR, Stark GR. Regulation of the G2/M transition by p53. Oncogene. 2001;20(15):1803–15.PubMedGoogle Scholar
  113. 113.
    Zhou J, Ahn J, Wilson SH, Prives C. A role for p53 in base excision repair. Embo J. 2001;20(4):914–23.PubMedGoogle Scholar
  114. 114.
    Sengupta S, Harris CC. p53: traffic cop at the crossroads of DNA repair and recombination. Nat Rev Mol Cell Biol. 2005;6(1):44–55.PubMedGoogle Scholar
  115. 115.
    Hussain SP, Schwank J, Staib F, Wang XW, Harris CC. TP53 mutations and hepatocellular carcinoma: insights into the etiology and pathogenesis of liver cancer. Oncogene. 2007;26(15):2166–76.PubMedGoogle Scholar
  116. 116.
    Murphy ME, Leu JI, George DL. p53 moves to mitochondria: a turn on the path to apoptosis. Cell Cycle. 2004;3(7):836–9.PubMedGoogle Scholar
  117. 117.
    Palacios G, Crawford HC, Vaseva A, Moll UM. Mitochondrially targeted wild-type p53 induces apoptosis in a solid human tumor xenograft model. Cell Cycle. 2008;7(16):2584–90.PubMedGoogle Scholar
  118. 118.
    Wu X, Bayle JH, Olson D, Levine AJ. The p53-mdm-2 autoregulatory feedback loop. Genes Dev. 1993;7(7A):1126–32.PubMedGoogle Scholar
  119. 119.
    Piette J, Neel H, Marechal V. Mdm2: keeping p53 under control. Oncogene. 1997;15(9):1001–10.PubMedGoogle Scholar
  120. 120.
    Brooks CL, Gu W. p53 ubiquitination: Mdm2 and beyond. Mol Cell. 2006;21(3):307–15.PubMedGoogle Scholar
  121. 121.
    Wang XW, Forrester K, Yeh H, Feitelson MA, Gu JR, Harris CC. Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci U S A. 1994;91(6):2230–4.PubMedGoogle Scholar
  122. 122.
    Wang XW, Gibson MK, Vermeulen W, et al. Abrogation of p53-induced apoptosis by the hepatitis B virus X gene. Cancer Res. 1995;55(24):6012–6.PubMedGoogle Scholar
  123. 123.
    Chan DW, Ng IO. Knock-down of hepatitis B virus X protein reduces the tumorigenicity of hepatocellular carcinoma cells. J Pathol. 2006;208(3):372–80.PubMedGoogle Scholar
  124. 124.
    Lee SG, Rho HM. Transcriptional repression of the human p53 gene by hepatitis B viral X protein. Oncogene. 2000;19(3):468–71.PubMedGoogle Scholar
  125. 125.
    Jia L, Wang XW, Harris CC. Hepatitis B virus X protein inhibits nucleotide excision repair. Int J Cancer. 1999;80(6):875–9.PubMedGoogle Scholar
  126. 126.
    Schaeffer L, Roy R, Humbert S, et al. DNA repair helicase: a component of BTF2 (TFIIH) basic transcription factor. Science. 1993;260(5104):58–63.PubMedGoogle Scholar
  127. 127.
    Moon RT, Bowerman B, Boutros M, Perrimon N. The promise and perils of Wnt signaling through beta-catenin. Science. 2002;296(5573):1644–6.PubMedGoogle Scholar
  128. 128.
    Peifer M, Polakis P. Wnt signaling in oncogenesis and embryogenesis – a look outside the nucleus. Science. 2000;287(5458):1606–9.PubMedGoogle Scholar
  129. 129.
    Thompson MD, Monga SP. WNT/beta-catenin signaling in liver health and disease. Hepatology. 2007;45(5):1298–305.PubMedGoogle Scholar
  130. 130.
    Audard V, Grimber G, Elie C, et al. Cholestasis is a marker for hepatocellular carcinomas displaying beta-catenin mutations. J Pathol. 2007;212(3):345–52.PubMedGoogle Scholar
  131. 131.
    Lee HC, Kim M, Wands JR. Wnt/Frizzled signaling in hepatocellular carcinoma. Front Biosci. 2006;11:1901–15.PubMedGoogle Scholar
  132. 132.
    Tamai K, Semenov M, Kato Y, et al. LDL-receptor-related proteins in Wnt signal transduction. Nature. 2000;407(6803):530–5.PubMedGoogle Scholar
  133. 133.
    Wehrli M, Dougan ST, Caldwell K, et al. Arrow encodes an LDL-receptor-related protein essential for Wingless signaling. Nature. 2000;407(6803):527–30.PubMedGoogle Scholar
  134. 134.
    Bhanot P, Brink M, Samos CH, et al. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature. 1996;382(6588):225–30.PubMedGoogle Scholar
  135. 135.
    Brannon M, Gomperts M, Sumoy L, Moon RT, Kimelman D. A beta-catenin/XTcf-3 complex binds to the siamois promoter to regulate dorsal axis specification in Xenopus. Genes Dev. 1997;11(18):2359–70.PubMedGoogle Scholar
  136. 136.
    Riese J, Yu X, Munnerlyn A, et al. LEF-1, a nuclear factor coordinating signaling inputs from wingless and decapentaplegic. Cell. 1997;88(6):777–87.PubMedGoogle Scholar
  137. 137.
    Aberle H, Bauer A, Stappert J, Kispert A, Kemler R. Beta-catenin is a target for the ubiquitin-proteasome pathway. Embo J. 1997;16(13):3797–804.PubMedGoogle Scholar
  138. 138.
    Zucman-Rossi J, Benhamouche S, Godard C, et al. Differential effects of inactivated Axin1 and activated beta-catenin mutations in human hepatocellular carcinomas. Oncogene. 2007;26(5):774–80.PubMedGoogle Scholar
  139. 139.
    Salahshor S, Woodgett JR. The links between axin and carcinogenesis. J Clin Pathol. 2005;58(3):225–36.PubMedGoogle Scholar
  140. 140.
    Merle P, de la Monte S, Kim M, et al. Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology. 2004;127(4):1110–22.PubMedGoogle Scholar
  141. 141.
    Merle P, Kim M, Herrmann M, et al. Oncogenic role of the frizzled-7/beta-catenin pathway in hepatocellular carcinoma. J Hepatol. 2005;43(5):854–62.PubMedGoogle Scholar
  142. 142.
    Rattner A, Hsieh JC, Smallwood PM, et al. A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors. Proc Natl Acad Sci U S A. 1997;94(7):2859–63.PubMedGoogle Scholar
  143. 143.
    Takagi H, Sasaki S, Suzuki H, et al. Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma. J Gastroenterol. 2008;43(5):378–89.PubMedGoogle Scholar
  144. 144.
    Beachy PA, Karhadkar SS, Berman DM. Tissue repair and stem cell renewal in carcinogenesis. Nature. 2004;432(7015):324–31.PubMedGoogle Scholar
  145. 145.
    Ingham PW, McMahon AP. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 2001;15(23):3059–87.PubMedGoogle Scholar
  146. 146.
    van den Brink GR. Hedgehog signaling in development and homeostasis of the gastrointestinal tract. Physiol Rev. 2007;87(4):1343–75.PubMedGoogle Scholar
  147. 147.
    Ingham PW, Placzek M. Orchestrating ontogenesis: variations on a theme by sonic hedgehog. Nat Rev Genet. 2006;7(11):841–50.PubMedGoogle Scholar
  148. 148.
    Yoon JW, Kita Y, Frank DJ, et al. Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem. 2002;277(7):5548–55.PubMedGoogle Scholar
  149. 149.
    Lipinski RJ, Gipp JJ, Zhang J, Doles JD, Bushman W. Unique and complimentary activities of the Gli transcription factors in Hedgehog signaling. Exp Cell Res. 2006;312(11):1925–38.PubMedGoogle Scholar
  150. 150.
    Regl G, Kasper M, Schnidar H, et al. Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2. Cancer Res. 2004;64(21):7724–31.PubMedGoogle Scholar
  151. 151.
    Sicklick JK, Li YX, Jayaraman A, et al. Dysregulation of the Hedgehog pathway in human hepatocarcinogenesis. Carcinogenesis. 2006;27(4):748–57.PubMedGoogle Scholar
  152. 152.
    Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for Hedgehog ligand stimulation in growth of digestive tract tumours. Nature. 2003;425(6960):846–51.PubMedGoogle Scholar
  153. 153.
    Huang S, He J, Zhang X, et al. Activation of the hedgehog pathway in human hepatocellular carcinomas. Carcinogenesis. 2006;27(7):1334–40.PubMedGoogle Scholar
  154. 154.
    Tada M, Kanai F, Tanaka Y, et al. Down-regulation of hedgehog-interacting protein through genetic and epigenetic alterations in human hepatocellular carcinoma. Clin Cancer Res. 2008;14(12):3768–76.PubMedGoogle Scholar
  155. 155.
    Kim Y, Yoon JW, Xiao X, Dean NM, Monia BP, Marcusson EG. Selective down-regulation of glioma-associated oncogene 2 inhibits the proliferation of hepatocellular carcinoma cells. Cancer Res. 2007;67(8):3583–93.PubMedGoogle Scholar
  156. 156.
    Patil MA, Zhang J, Ho C, Cheung ST, Fan ST, Chen X. Hedgehog signaling in human hepatocellular carcinoma. Cancer Biol Ther. 2006;5(1):111–7.PubMedGoogle Scholar
  157. 157.
    Chuang PT, McMahon AP. Vertebrate Hedgehog signaling modulated by induction of a Hedgehog-binding protein. Nature. 1999;397(6720):617–21.PubMedGoogle Scholar
  158. 158.
    Bak M, Hansen C, Friis Henriksen K, Tommerup N. The human hedgehog-interacting protein gene: structure and chromosome mapping to 4q31.21→q31.3. Cytogenet Cell Genet. 2001;92(3–4):300–3.PubMedGoogle Scholar
  159. 159.
    Omenetti A, Diehl AM. Sonic hedghehog pathway. In: Dufour JF, Clavien PA, editors. Signaling pathways in liver diseases. Berlin: Springer; 2009.Google Scholar
  160. 160.
    Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA. Inflammation and liver cancer: new molecular links. Ann N Y Acad Sci. 2009;1155:206–21.PubMedGoogle Scholar
  161. 161.
    Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124(4):783–801.PubMedGoogle Scholar
  162. 162.
    Karin M, Lawrence T, Nizet V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell. 2006;124(4):823–35.PubMedGoogle Scholar
  163. 163.
    Chen CJ, Kono H, Golenbock D, Reed G, Akira S, Rock KL. Identification of a key pathway required for the sterile inflammatory response triggered by dying cells. Nat Med. 2007;13(7):851–6.PubMedGoogle Scholar
  164. 164.
    Zhang Z, Schluesener HJ. Mammalian toll-like receptors: from endogenous ligands to tissue regeneration. Cell Mol Life Sci. 2006;63(24):2901–7.PubMedGoogle Scholar
  165. 165.
    Luedde T, Trautwein C. NFkappaB. In: Dufour JF, Clavien PA, editors. Signaling pathways in liver diseases. Berlin: Springer; 2009.Google Scholar
  166. 166.
    Tai DI, Tsai SL, Chang YH, et al. Constitutive activation of nuclear factor kappaB in hepatocellular carcinoma. Cancer. 2000;89(11):2274–81.PubMedGoogle Scholar
  167. 167.
    Pikarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431(7007):461–6.PubMedGoogle Scholar
  168. 168.
    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):977–90.PubMedGoogle Scholar
  169. 169.
    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.PubMedGoogle Scholar
  170. 170.
    Boulanger MJ, Chow DC, Brevnova EE, Garcia KC. Hexameric structure and assembly of the interleukin-6/IL-6 alpha-receptor/gp130 complex. Science. 2003;300(5628):2101–4.PubMedGoogle Scholar
  171. 171.
    Ward LD, Howlett GJ, Discolo G, et al. High affinity interleukin-6 receptor is a hexameric complex consisting of two molecules each of interleukin-6, interleukin-6 receptor, and gp-130. J Biol Chem. 1994;269(37):23286–9.PubMedGoogle Scholar
  172. 172.
    Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol. 2007;7(1):41–51.PubMedGoogle Scholar
  173. 173.
    Yu H, Jove R. The STATs of cancer – new molecular targets come of age. Nat Rev Cancer. 2004;4(2):97–105.PubMedGoogle Scholar
  174. 174.
    Catlett-Falcone R, Landowski TH, Oshiro MM, et al. Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells. Immunity. 1999;10(1):105–15.PubMedGoogle Scholar
  175. 175.
    Yoshikawa H, Matsubara K, Qian GS, et al. SOCS-1, a negative regulator of the JAK/STAT pathway, is silenced by methylation in human hepatocellular carcinoma and shows growth-suppression activity. Nat Genet. 2001;28(1):29–35.PubMedGoogle Scholar
  176. 176.
    Calvisi DF, Ladu S, Gorden A, et al. Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology. 2006;130(4):1117–28.PubMedGoogle Scholar
  177. 177.
    Riehle KJ, Campbell JS, McMahan RS, et al. Regulation of liver regeneration and hepatocarcinogenesis by suppressor of cytokine signaling 3. J Exp Med. 2008;205(1):91–103.PubMedGoogle Scholar
  178. 178.
    Ogata H, Kobayashi T, Chinen T, et al. Deletion of the SOCS3 gene in liver parenchymal cells promotes hepatitis-induced hepatocarcinogenesis. Gastroenterology. 2006;131(1):179–93.PubMedGoogle Scholar
  179. 179.
    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):121–4.PubMedGoogle Scholar
  180. 180.
    Stein B, Yang MX. Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol Cell Biol. 1995;15(9):4971–9.PubMedGoogle Scholar
  181. 181.
    Cressman DE, Greenbaum LE, DeAngelis RA, et al. Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science. 1996;274(5291):1379–83.PubMedGoogle Scholar
  182. 182.
    Roskams TA, Theise ND, Balabaud C, et al. Nomenclature of the finer branches of the biliary tree: canals, ductules, and ductular reactions in human livers. Hepatology. 2004;39(6):1739–45.PubMedGoogle Scholar
  183. 183.
    Roskams T, Yang SQ, Koteish A, et al. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am J Pathol. 2003;163(4):1301–11.PubMedGoogle Scholar
  184. 184.
    Libbrecht L, Desmet V, Roskams T. Preneoplastic lesions in human hepatocarcinogenesis. Liver Int. 2005;25(1):16–27.PubMedGoogle Scholar
  185. 185.
    Roskams T. Liver stem cells and their implication in hepatocellular and cholangiocarcinoma. Oncogene. 2006;25(27):3818–22.PubMedGoogle Scholar
  186. 186.
    Wu PC, Lai VC, Fang JW, Gerber MA, Lai CL, Lau JY. Hepatocellular carcinoma expressing both hepatocellular and biliary markers also expresses cytokeratin 14, a marker of bipotential progenitor cells. J Hepatol. 1999;31(5):965–6.PubMedGoogle Scholar
  187. 187.
    Yoon DS, Jeong J, Park YN, et al. Expression of biliary antigen and its clinical significance in hepatocellular carcinoma. Yonsei Med J. 1999;40(5):472–7.PubMedGoogle Scholar
  188. 188.
    Van Eyken P, Sciot R, Paterson A, Callea F, Kew MC, Desmet VJ. Cytokeratin expression in hepatocellular carcinoma: an immunohistochemical study. Hum Pathol. 1988;19(5):562–8.PubMedGoogle Scholar
  189. 189.
    Hsia CC, Evarts RP, Nakatsukasa H, Marsden ER, Thorgeirsson SS. Occurrence of oval-type cells in hepatitis B virus-associated human hepatocarcinogenesis. Hepatology. 1992;16(6):1327–33.PubMedGoogle Scholar
  190. 190.
    Uenishi T, Kubo S, Yamamoto T, et al. Cytokeratin 19 expression in hepatocellular carcinoma predicts early postoperative recurrence. Cancer Sci. 2003;94(10):851–7.PubMedGoogle Scholar
  191. 191.
    Ding SJ, Li Y, Tan YX, et al. From proteomic analysis to clinical significance: overexpression of cytokeratin 19 correlates with hepatocellular carcinoma metastasis. Mol Cell Proteomics. 2004;3(1):73–81.PubMedGoogle Scholar
  192. 192.
    Weinstein M, Monga SP, Liu Y, et al. Smad proteins and hepatocyte growth factor control parallel regulatory pathways that converge on beta1-integrin to promote normal liver development. Mol Cell Biol. 2001;21(15):5122–31.PubMedGoogle Scholar
  193. 193.
    Kitisin K, Ganesan N, Tang Y, et al. Disruption of transforming growth factor-beta signaling through beta-spectrin ELF leads to hepatocellular cancer through cyclin D1 activation. Oncogene. 2007;26(50):7103–10.PubMedGoogle Scholar
  194. 194.
    Mishra L, Banker T, Murray J, et al. Liver stem cells and hepatocellular carcinoma. Hepatology. 2009;49(1):318–29.PubMedGoogle Scholar
  195. 195.
    Takami T, Kaposi-Novak P, Uchida K, et al. Loss of hepatocyte growth factor/c-Met signaling pathway accelerates early stages of N-nitrosodiethylamine induced hepatocarcinogenesis. Cancer Res. 2007;67(20):9844–51.PubMedGoogle Scholar
  196. 196.
    Marx-Stoelting P, Borowiak M, Knorpp T, Birchmeier C, Buchmann A, Schwarz M. Hepatocarcinogenesis in mice with a conditional knockout of the hepatocyte growth factor receptor c-Met. Int J Cancer. 2009;124(8):1767–72.PubMedGoogle Scholar
  197. 197.
    Boix L, Rosa JL, Ventura F, et al. c-met mRNA overexpression in human hepatocellular carcinoma. Hepatology. 1994;19(1):88–91.PubMedGoogle Scholar
  198. 198.
    Suzuki K, Hayashi N, Yamada Y, et al. Expression of the c-met protooncogene in human hepatocellular carcinoma. Hepatology. 1994;20(5):1231–6.PubMedGoogle Scholar
  199. 199.
    Kiss A, Wang NJ, Xie JP, Thorgeirsson SS. Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth Factor/c-met, TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res. 1997;3(7):1059–66.PubMedGoogle Scholar
  200. 200.
    Ueki T, Fujimoto J, Suzuki T, Yamamoto H, Okamoto E. Expression of hepatocyte growth factor and its receptor, the c-met proto-oncogene, in hepatocellular carcinoma. Hepatology. 1997;25(3):619–23.PubMedGoogle Scholar
  201. 201.
    Tavian D, De Petro G, Benetti A, Portolani N, Giulini SM, Barlati S. u-PA and c-MET mRNA expression is co-ordinately enhanced while hepatocyte growth factor mRNA is down-regulated in human hepatocellular carcinoma. Int J Cancer. 2000;87(5):644–9.PubMedGoogle Scholar
  202. 202.
    Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182–6.PubMedGoogle Scholar
  203. 203.
    Denekamp J. Vascular attack as a therapeutic strategy for cancer. Cancer Metastasis Rev. 1990;9(3):267–82.PubMedGoogle Scholar
  204. 204.
    Hanahan D, Folkman J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell. 1996;86(3):353–64.PubMedGoogle Scholar
  205. 205.
    Fonsatti E, Jekunen AP, Kairemo KJ, et al. Endoglin is a suitable target for efficient imaging of solid tumors: in vivo evidence in a canine mammary carcinoma model. Clin Cancer Res. 2000;6(5):2037–43.PubMedGoogle Scholar
  206. 206.
    Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275(5302):964–7.PubMedGoogle Scholar
  207. 207.
    Shaked Y, Ciarrocchi A, Franco M, et al. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science. 2006;313(5794):1785–7.PubMedGoogle Scholar
  208. 208.
    Kerbel RS. Tumor angiogenesis. N Engl J Med. 2008;358(19):2039–49.PubMedGoogle Scholar
  209. 209.
    Yu D, Sun X, Qiu Y, et al. Identification and clinical significance of mobilized endothelial progenitor cells in tumor vasculogenesis of hepatocellular carcinoma. Clin Cancer Res. 2007;13(13):3814–24.PubMedGoogle Scholar
  210. 210.
    Ho JW, Pang RW, Lau C, et al. Significance of circulating endothelial progenitor cells in hepatocellular carcinoma. Hepatology. 2006;44(4):836–43.PubMedGoogle Scholar
  211. 211.
    Saharinen P, Alitalo K. Double target for tumor mass destruction. J Clin Invest. 2003;111(9):1277–80.PubMedGoogle Scholar
  212. 212.
    Reinmuth N, Liu W, Jung YD, et al. Induction of VEGF in perivascular cells defines a potential paracrine mechanism for endothelial cell survival. Faseb J. 2001;15(7):1239–41.PubMedGoogle Scholar
  213. 213.
    Hellstrom M, Gerhardt H, Kalen M, et al. Lack of pericytes leads to endothelial hyperplasia and abnormal vascular morphogenesis. J Cell Biol. 2001;153(3):543–53.PubMedGoogle Scholar
  214. 214.
    Benjamin LE, Hemo I, Keshet E. A plasticity window for blood vessel remodeling is defined by pericyte coverage of the preformed endothelial network and is regulated by PDGF-B and VEGF. Development. 1998;125(9):1591–8.PubMedGoogle Scholar
  215. 215.
    Bergers G, Song S, Meyer-Morse N, Bergsland E, Hanahan D. Benefits of targeting both pericytes and endothelial cells in the tumor vasculature with kinase inhibitors. J Clin Invest. 2003;111(9):1287–95.PubMedGoogle Scholar
  216. 216.
    Italiano Jr JE, Richardson JL, Patel-Hett S, et al. Angiogenesis is regulated by a novel mechanism: pro- and antiangiogenic proteins are organized into separate platelet alpha granules and differentially released. Blood. 2008;111(3):1227–33.PubMedGoogle Scholar
  217. 217.
    Semela D. Pathogenesis and angiogenesis in hepatocellular carcinoma. EASL Annual Meeting. Copenhagen, Denmark; 2008.Google Scholar
  218. 218.
    Semela D, Piguet AC, Kolev M, et al. Vascular remodeling and antitumoral effects of mTOR inhibition in a rat model of hepatocellular carcinoma. J Hepatol. 2007;46(5):840–8.PubMedGoogle Scholar
  219. 219.
    Folberg R, Hendrix MJ, Maniotis AJ. Vasculogenic mimicry and tumor angiogenesis. Am J Pathol. 2000;156(2):361–81.PubMedGoogle Scholar
  220. 220.
    Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. Proc Natl Acad Sci U S A. 2000;97(26):14608–13.PubMedGoogle Scholar
  221. 221.
    Yamamoto T, Hirohashi K, Kaneda K, et al. Relationship of the microvascular type to the tumor size, arterialization and dedifferentiation of human hepatocellular carcinoma. Jpn J Cancer Res. 2001;92(11):1207–13.PubMedGoogle Scholar
  222. 222.
    Yang ZF, Poon RT. Vascular changes in hepatocellular carcinoma. Anat Rec (Hoboken). 2008;291(6):721–34.Google Scholar
  223. 223.
    Ueda K, Terada T, Nakanuma Y, Matsui O. Vascular supply in adenomatous hyperplasia of the liver and hepatocellular carcinoma: a morphometric study. Hum Pathol. 1992;23(6):619–26.PubMedGoogle Scholar
  224. 224.
    Himeno H, Enzan H, Saibara T, Onishi S, Yamamoto Y. Hitherto unrecognized arterioles within hepatocellular carcinoma. J Pathol. 1994;174(3):217–22.PubMedGoogle Scholar
  225. 225.
    Pang R, Poon RT. Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Lett. 2006;242(2):151–67.PubMedGoogle Scholar
  226. 226.
    Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol. 2004;41(5):864–80.PubMedGoogle Scholar
  227. 227.
    Schaffner F, Poper H. Capillarization of hepatic sinusoids in man. Gastroenterology. 1963;44:239–42.PubMedGoogle Scholar
  228. 228.
    Kin M, Torimura T, Ueno T, Inuzuka S, Tanikawa K. Sinusoidal capillarization in small hepatocellular carcinoma. Pathol Int. 1994;44(10–11):771–8.PubMedGoogle Scholar
  229. 229.
    Ferrara N. VEGF and the quest for tumour angiogenesis factors. Nat Rev Cancer. 2002;2(10):795–803.PubMedGoogle Scholar
  230. 230.
    Hicklin DJ, Ellis LM. Role of the vascular endothelial growth factor pathway in tumor growth and angiogenesis. J Clin Oncol. 2005;23(5):1011–27.PubMedGoogle Scholar
  231. 231.
    Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res. 2006;312(5):549–60.PubMedGoogle Scholar
  232. 232.
    Yamaguchi R, Yano H, Nakashima Y, et al. Expression and localization of vascular endothelial growth factor receptors in human hepatocellular carcinoma and non-HCC tissues. Oncol Rep. 2000;7(4):725–9.PubMedGoogle Scholar
  233. 233.
    Shimamura T, Saito S, Morita K, et al. Detection of vascular endothelial growth factor and its receptor expression in human hepatocellular carcinoma biopsy specimens. J Gastroenterol Hepatol. 2000;15(6):640–6.PubMedGoogle Scholar
  234. 234.
    Chiang DY, Villanueva A, Hoshida Y, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 2008;68(16):6779–88.PubMedGoogle Scholar
  235. 235.
    Harris AL. Hypoxia – a key regulatory factor in tumour growth. Nat Rev Cancer. 2002;2(1):38–47.PubMedGoogle Scholar
  236. 236.
    Fox SB, Gasparini G, Harris AL. Angiogenesis: pathological, prognostic, and growth-factor pathways and their link to trial design and anticancer drugs. Lancet Oncol. 2001;2(5):278–89.PubMedGoogle Scholar
  237. 237.
    Hanahan D. Signaling vascular morphogenesis and maintenance. Science. 1997;277(5322):48–50.PubMedGoogle Scholar
  238. 238.
    Oliner J, Min H, Leal J, et al. Suppression of angiogenesis and tumor growth by selective inhibition of angiopoietin-2. Cancer Cell. 2004;6(5):507–16.PubMedGoogle Scholar
  239. 239.
    Torimura T, Ueno T, Kin M, et al. Overexpression of angiopoietin-1 and angiopoietin-2 in hepatocellular carcinoma. J Hepatol. 2004;40(5):799–807.PubMedGoogle Scholar
  240. 240.
    Sugimachi K, Tanaka S, Taguchi K, Aishima S, Shimada M, Tsuneyoshi M. Angiopoietin switching regulates angiogenesis and progression of human hepatocellular carcinoma. J Clin Pathol. 2003;56(11):854–60.PubMedGoogle Scholar
  241. 241.
    Noguera-Troise I, Daly C, Papadopoulos NJ, et al. Blockade of D114 inhibits tumour growth by promoting non-productive angiogenesis. Nature. 2006;444(7122):1032–7.PubMedGoogle Scholar
  242. 242.
    Lobov IB, Renard RA, Papadopoulos N, et al. Delta-like ligand 4 (D114) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci U S A. 2007;104(9):3219–24.PubMedGoogle Scholar
  243. 243.
    Ridgway J, Zhang G, Wu Y, et al. Inhibition of D114 signaling inhibits tumour growth by deregulating angiogenesis. Nature. 2006;444(7122):1083–7.PubMedGoogle Scholar
  244. 244.
    Gale NW, Dominguez MG, Noguera I, et al. Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci U S A. 2004;101(45):15949–54.PubMedGoogle Scholar
  245. 245.
    Gao J, Song Z, Chen Y, et al. Deregulated expression of Notch receptors in human hepatocellular carcinoma. Dig Liver Dis. 2008;40(2):114–21.PubMedGoogle Scholar
  246. 246.
    Gramantieri L, Giovannini C, Lanzi A, et al. Aberrant Notch3 and Notch4 expression in human hepatocellular carcinoma. Liver Int. 2007;27(7):997–1007.PubMedGoogle Scholar
  247. 247.
    Vincent F, Bonnin P, Clemessy M, et al. Angiotensinogen delays angiogenesis and tumor growth of hepatocarcinoma in transgenic mice. Cancer Res. 2009;69(7):2853–60.PubMedGoogle Scholar
  248. 248.
    Sottile J. Regulation of angiogenesis by extracellular matrix. Biochim Biophys Acta. 2004;1654(1):13–22.PubMedGoogle Scholar
  249. 249.
    Kim JH, Kim TH, Jang JW, Jang YJ, Lee KH, Lee ST. Analysis of matrix metalloproteinase mRNAs expressed in hepatocellular carcinoma cell lines. Mol Cells. 2001;12(1):32–40.PubMedGoogle Scholar
  250. 250.
    Monvoisin A, Bisson C, Si-Tayeb K, Balabaud C, Desmouliere A, Rosenbaum J. Involvement of matrix metalloproteinase type-3 in hepatocyte growth factor-induced invasion of human hepatocellular carcinoma cells. Int J Cancer. 2002;97(2):157–62.PubMedGoogle Scholar
  251. 251.
    Giannelli G, Bergamini C, Fransvea E, Marinosci F, Quaranta V, Antonaci S. Human hepatocellular carcinoma (HCC) cells require both alpha3beta1 integrin and matrix metalloproteinases activity for migration and invasion. Lab Invest. 2001;81(4):613–27.PubMedGoogle Scholar
  252. 252.
    Martin DC, Sanchez-Sweatman OH, Ho AT, Inderdeo DS, Tsao MS, Khokha R. Transgenic TIMP-1 inhibits simian virus 40 T antigen-induced hepatocarcinogenesis by impairment of hepatocellular proliferation and tumor angiogenesis. Lab Invest. 1999;79(2):225–34.PubMedGoogle Scholar
  253. 253.
    Giannelli G, Bergamini C, Marinosci F, et al. Clinical role of MMP-2/TIMP-2 imbalance in hepatocellular carcinoma. Int J Cancer. 2002;97(4):425–31.PubMedGoogle Scholar
  254. 254.
    Arii S, Mise M, Harada T, et al. Overexpression of matrix metalloproteinase 9 gene in hepatocellular carcinoma with invasive potential. Hepatology. 1996;24(2):316–22.PubMedGoogle Scholar
  255. 255.
    Edmondson HA, Steiner PE. Primary carcinoma of the liver: a study of 100 cases among 48, 900 necropsies. Cancer. 1954;7(3):462–503.PubMedGoogle Scholar
  256. 256.
    Llovet JM, Bru C, Bruix J. Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis. 1999;19(3):329–38.PubMedGoogle Scholar
  257. 257.
    Llovet JM, Bustamante J, Castells A, et al. Natural history of untreated nonsurgical hepatocellular carcinoma: rationale for the design and evaluation of therapeutic trials. Hepatology. 1999;29(1):62–7.PubMedGoogle Scholar
  258. 258.
    Lee JS, Chu IS, Heo J, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40(3):667–76.PubMedGoogle Scholar
  259. 259.
    Boyault S, Rickman DS, de Reynies A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45(1):42–52.PubMedGoogle Scholar
  260. 260.
    Lee JS, Heo J, Libbrecht L, et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med. 2006;12(4):410–6.PubMedGoogle Scholar
  261. 261.
    Breuhahn K, Vreden S, Haddad R, et al. Molecular profiling of human hepatocellular carcinoma defines mutually exclusive interferon regulation and insulin-like growth factor II overexpression. Cancer Res. 2004;64(17):6058–64.PubMedGoogle Scholar
  262. 262.
    Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907–17.PubMedGoogle Scholar
  263. 263.
    Ye QH, Qin LX, Forgues M, et al. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat Med. 2003;9(4):416–23.PubMedGoogle Scholar
  264. 264.
    Iizuka N, Oka M, Yamada-Okabe H, et al. Oligonucleotide microarray for prediction of early intrahepatic recurrence of hepatocellular carcinoma after curative resection. Lancet. 2003;361(9361):923–9.PubMedGoogle Scholar
  265. 265.
    Wang SM, Ooi LL, Hui KM. Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma. Clin Cancer Res. 2007;13(21):6275–83.PubMedGoogle Scholar
  266. 266.
    Fidler IJ. Modulation of the organ microenvironment for treatment of cancer metastasis. J Natl Cancer Inst. 1995;87(21):1588–92.PubMedGoogle Scholar
  267. 267.
    Hunter KW. Host genetics and tumour metastasis. Br J Cancer. 2004;90(4):752–5.PubMedGoogle Scholar
  268. 268.
    Bernards R, Weinberg RA. A progression puzzle. Nature. 2002;418(6900):823.PubMedGoogle Scholar
  269. 269.
    Budhu A, Forgues M, Ye QH, et al. Prediction of venous metastases, recurrence, and prognosis in hepatocellular carcinoma based on a unique immune response signature of the liver microenvironment. Cancer Cell. 2006;10(2):99–111.PubMedGoogle Scholar
  270. 270.
    Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tissues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;359(19):1995–2004.PubMedGoogle Scholar
  271. 271.
    Imamura H, Matsuyama Y, Tanaka E, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. J Hepatol. 2003;38(2):200–7.PubMedGoogle Scholar
  272. 272.
    Calin GA, Croce CM. MicroRNA signatures in human cancers. Nat Rev Cancer. 2006;6(11):857–66.PubMedGoogle Scholar
  273. 273.
    Ladeiro Y, Couchy G, Balabaud C, et al. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 2008;47(6):1955–63.PubMedGoogle Scholar
  274. 274.
    Budhu A, Jia HL, Forgues M, et al. Identification of metastasis-related microRNAs in hepatocellular carcinoma. Hepatology. 2008;47(3):897–907.PubMedGoogle Scholar
  275. 275.
    Llovet JM, Ricci S, Mazzaferro V, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359(4):378–90.PubMedGoogle Scholar
  276. 276.
    Llovet JM, Bruix J. Molecular targeted therapies in hepatocellular carcinoma. Hepatology. 2008;48(4):1312–27.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Visceral MedicineUniversity of BerneBerneSwitzerland

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