Advertisement

Hepatozelluläres Karzinom

  • Darius Moradpour
  • Hans-Peter Allgaier
  • Heinz G. Linhart
  • Hubert E. Blum
Chapter
Part of the Molekulare Medizin book series (MOLMED)

Zusammenfassung

Tumoren der Leber können benigne oder maligne Läsionen sein. Maligne Neoplasien der Leber sind primär hepatisch oder sekundär metastatisch. In westlichen Ländern überwiegen metastatische Läsionen, während in Asien und Teilen Afrikas primäre Lebermalignome häufiger sind. Die primären Lebertumoren sind entweder epithelialen Ursprungs und gehen von Hepatozyten bzw. Gallengangsepithelzellen aus oder sie sind mesenchymaler, seltener auch gemischtzelliger Herkunft. Das hepatozelluläre Karzinom (HCC) ist klinisch ein hoch maligner Tumor mit rascher Progredienz und limitierten therapeutischen Möglichkeiten (Wands u. Blum 1991, Blum 1995, Okuda 2000). Im Folgenden werden epidemiologische, klinische, pathogenetische, diagnostische und therapeutische Aspekte des HCC besprochen.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. Aghi M, Chou TC, Suling K, Breakefield XO, Chiocca EA(1999) Multimodal cancer treatment mediated by a replicating oncolytic virus that delivers the oxazaphosphorine/rat cytochrome P450 2B1 and ganeiclovir/herpes simplex virus thymidine kinase gene Therapics. Cancer Res 59:3861–3865PubMedGoogle Scholar
  2. Aguilar F, Hussain SP, Cerutti P (1993) Aflatoxin B1 induces the transversion of G → T in codon 249 of the p53 tumor suppressor gene in human hepatocytes. Proc Natl Acad Sci USA 90:8586–8590PubMedCentralPubMedGoogle Scholar
  3. Allgaier HP, Deibert P, Olschewski M et al. (1998a) Survival benefit of patients with inoperable hepatocellular careinoma treated by a combination of transarterial chemoembolization and percutaneous ethanol injection-a single-center analysis including 132 patients. Int J Cancer 79:601–605PubMedGoogle Scholar
  4. Allgaier HP, Deibert P, Zuber I, Blum HE (1998b) Perkutane Behandlung von Lebertumoren durch interstitielle Radiofrequenzthermoablation. Dtsch Med Wochensehr 123:907–911Google Scholar
  5. Allgaier HP, Deibert P, Zuber I, Olschewski M, Blum HE (1999) Percutaneous radiofrequency interstitial thermal ablation of small hepatocellular carcinoma. Lancet 353:1676–1677PubMedGoogle Scholar
  6. Alter MJ (1997) Epidemiology of hepatitis C. Hepatology [Suppl 1] 26:62S–65SPubMedGoogle Scholar
  7. Beasley RP, Hwang L-Y, Lin C-C, Chien C-S (1981) Hepatocellular carcinoma and hepatitis B virus-a prospective study of 22707 men in Taiwan. Lancet II:1129–1133Google Scholar
  8. Becker SA, Lee T-H, Butel JS, Slagle BL (1998) Hepatitis B virus X protein interferes with cellular DNA repair. J Vir-ol 72:266–272Google Scholar
  9. Benn J, Schneider RJ (1994) Hepatitis B virus X protein activates Ras-GTP complex formation and establishes aRas, Raf, MAP kinase signaling cascade. Proc Natl Acad Sci USA 91:10350–10354PubMedCentralPubMedGoogle Scholar
  10. Bischoff JR, Kirn DH, Williams A et al. (1996) An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274:373–376PubMedGoogle Scholar
  11. Blum HE (1994) Does hepatitis C virus cause hepatocellular carcinoma? Hepatology 19:251–255PubMedGoogle Scholar
  12. Blum HE (1995) Tumoren der Leber und des biliären Systems. In: Gerok W, Blum HE (Hrsg) Hepatologie. Urban & Schwarzenberg, München Wien Baltimore, S 635–650Google Scholar
  13. Blum HE, Liang TJ, Galun E, Wands JR (1991) Persistence of hepatitis B viral DNA after serological recovery from hepatitis B virus infection. Hepatology 14:56–62PubMedGoogle Scholar
  14. Bosch FX, Ribes J, Borras J (1999) Epidemiology of primary liver cancer. Semin Liver Dis 19:271–285PubMedGoogle Scholar
  15. Brand N, Petkovich M, Krust A et al. (1988) Identification of a second human retinoic acid receptor. Nature 332:850–853PubMedGoogle Scholar
  16. Bréchot C, Degos F, Lugassy C et al. (1985) Hepatitis B virus DNA in patients with chronic liver disease and negativetests for hepatitis B surface antigen. N Engl J Med 312:270–276PubMedGoogle Scholar
  17. Bressac B, Kew M, Wands J, Ozturk M (1991) Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350:429–431PubMedGoogle Scholar
  18. Buendia MA (1994) Animal models for hepatitis B virus and liver cancer. In: Brechot C (ed) Primary liver cancer: etiological and progression factors. CRC Press, Boca Raton, FLGoogle Scholar
  19. Bui LA, Butterfield LH, Kim JY et al. (1997) In vivo therapy of hepatocelluIar carcinoma with a tumor-specific adeno-viral vector expressing interleukin-2. Hum Gene Ther 8:2173–2182PubMedGoogle Scholar
  20. Cao G, Kuriyama S, Du P et al. (1997) Complete regression of established murine hepatocellular carcinoma by in vivo tumor necrosis factor alpha gene transfer. Gastroenterology 112:501–510PubMedGoogle Scholar
  21. Cariani E, Lasserre C, Kemeny F, Franeo D, Bréchot C (1991) Expression of insulin-like growth factor 11, a-fetoprotein, and hepatitis B virus transcripts in human primary liver cancer. Hepatology 13:644–649PubMedGoogle Scholar
  22. Caselmann WH, Koshy R (1998) Transactivators of HBV, signal transduction and tumorigenesis. In: Caselmann WH, Koshy R (eds) Hepatitis B virus. Imperial College Press, LondonGoogle Scholar
  23. Caselmann WH, Meyer M, Kekulé AS, Lauer U, Hofschneider PH, Koshy R (1990) A trans-activator function is generated by integration of hepatitis B virus preS/S sequences in human hepatocellular carcinoma DNA. Proc Natl Acad Sci USA 87:2970–2974PubMedCentralPubMedGoogle Scholar
  24. Castells A, Bruix J, Bru C et al. (1993) Treatment of small hepatocellular carcinoma in cirrhotic patients: a cohort study comparing surgical resection and percutaneous ethanol injection. Hepatology 18:1121–1126PubMedGoogle Scholar
  25. Chang M-H, Chen C-J, Lai M-S et al. (1997) Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. N Engl J Med 336:1855–1859PubMedGoogle Scholar
  26. Chang J, Yang S-H, Cho Y-G, Hwang SB, Hahn YS, Sung YC (1998) Hepatitis C virus core from two different genotypes has an oncogenic potential but is not sufficient for transforming primary rat embryo fibroblasts in co operation with the H-ras oncogene. J Virol 72:3060–3065PubMedCentralPubMedGoogle Scholar
  27. Chen QR, Kumar D, Stass SA, Mixson AJ (1999) Liposomes complexed to plasmids encoding angiostatin and endostatin inhibit breast cancer in nude mice. Cancer Res 59:3308–3312PubMedGoogle Scholar
  28. Chisari FV (1995) Hepatitis B virus transgenie mice: insights into the virus and the disease. Hepatology 22:1316–1325PubMedGoogle Scholar
  29. Chisari FV, Filippi P, McLachlan A et al. (1986) Expression of hepatitis B virus large envelope polypeptide inhibits hepatitis B surface antigen secretion in transgenic mice. J Virol 60:880–887PubMedCentralPubMedGoogle Scholar
  30. Chisari FV, Filippi P, Buras J et al. (1987) Structural and pathological effects of synthesis of hepatitis B virus large envelope polypeptide in transgenic mice. Proc Natl Acad Sci USA 84:6909–6913PubMedCentralPubMedGoogle Scholar
  31. Choo Q-L, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M (1989) Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244:359–362PubMedGoogle Scholar
  32. CLIP Group (Cancer of the Liver Italian Programme) (1998) Tamoxifen in treatment of hepatocellular carcinoma: a randomised controlled trial. Lancet 352:17–20Google Scholar
  33. Coffin CS, Michalak TI (1999) Persistence of infectious hepadnavirus in the offspring of woodchuck mothers recovered from viral hepatitis. J Clin Invest 104:203–212PubMedCentralPubMedGoogle Scholar
  34. Colombo M, Cambieri R, Rumi MG, Ronchi G, Ninno E del, Franchis R de (1983) Long-term delta superinfection in hepatitis B surface antigen carriers and its relationship to the course of chronic hepatitis. Gastroenterology 85:235–239PubMedGoogle Scholar
  35. Compagnon B, Moradpour D, Alford DR et al. (1997) Enhanced gene delivery and expression in human hepatocellular carcinoma cells by cationic immunoliposomes. J Liposome Res 7:127–141Google Scholar
  36. Cross M, Dexter TM (1991) Growth factors in development, transformation, and tumorigenesis. Cell 64:271–280PubMedGoogle Scholar
  37. Dejean A, de Thé H (1990) Hepatitis B virus as an insertional mutagene in a human hepatocellular carcinoma. Mol Biol Med 7:213–222PubMedGoogle Scholar
  38. Dejean A, Sonigo P, Wain-Hobson S, Tiollais P (1984) Specific hepatitis B virus integration in hepatocellular carcinoma DNA through a viral 11-base-pair direct repeat. Proc Natl Acad Sci USA 81:5350–5354PubMedCentralPubMedGoogle Scholar
  39. Dejean A, Bougueleret L, Grzeschik K-H, Tiollais P (1986) Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma. Nature 322:70–72PubMedGoogle Scholar
  40. De la Coste A, Romagnolo B, Billuart P et al. (1998) Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc Natl Acad Sci USA 95:8847–8851PubMedCentralGoogle Scholar
  41. Derynck R, Zhang Y, Feng XH (1998) Smads: transcriptional activators of TGF-beta responses. Cell 95:737–740PubMedGoogle Scholar
  42. De Souza AT, Hankins GR, Washington MK, Orton TC, Jirtle RL (1995) M6P/IGF2R gene is mutated in human hepatocellular carcinomas with loss of heterozygosity. Nat Genet11:447–449PubMedGoogle Scholar
  43. De Thé H, Marchio A, Tiollais P, Dejean A (1987) A novel steroid thyroid hormone receptor-related gene inappropriately expressed in human hepatocellular carcinoma. Nature 330:667–670PubMedGoogle Scholar
  44. Deuffic S, Poynard T, Buffat L, Valleron AJ (1998) Trends in primary liver cancer. Lancet 351:214–215PubMedGoogle Scholar
  45. Di Bisceglie AM (1997) Hepatitis C and hepatocellular carcinoma.Hepatology [Suppl 1] 26:34S–38SPubMedGoogle Scholar
  46. Dienstag JL (1997) Sexual and perinatal transmission of hepatitis C. Hepatology 26:66S–70SPubMedGoogle Scholar
  47. Donnelly JJ, Ulmer JB, Shiver JW, Liu MA (1997) DNA vaccines. Annu Rev Immunol 15:617–648PubMedGoogle Scholar
  48. Douglas JT, Rogers BE, Rosenfeld ME, Michael SI, Feng M, Curiel DT (1996) Targeted gene delivery by tropism-modified adenoviral vectors. Nat Biotechnol 14:1574–1578PubMedGoogle Scholar
  49. Dunsford HA, Sell S, Chisari FV (1990) Hepatocarcinogenesis due to chronic liver cell injury in hepatitis B virus transgenic mice. Cancer Res 50:3400–3407PubMedGoogle Scholar
  50. El-Serag HB, Mason AC (1999) Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 340:745–750PubMedGoogle Scholar
  51. Encell LP, Landis DM, Loeb LA (1999) Improving enzymes for cancer gene therapy. Nat Biotechnol 17:143–147PubMedGoogle Scholar
  52. Fausto N (1999) Mouse liver tumorigenesis: models, mechanisms, and relevance to human disease. Semin Liver Dis 19:243–252PubMedGoogle Scholar
  53. Fausto N, Webber EM (1993) Mechanisms of growth regulation in liver regeneration and hepatic carcinogenesis. In: Boyer JL, Ockner RK (eds) Progress in liver diseases. Saunders, Philadelphia, pp 115–137Google Scholar
  54. Feitelson MA, Zhu M, Duan L-X, London WT (1993) Hepatitis B x antigen and p53 are associated in vitro and in liver tissues from patients with primary hepatocellular carcinoma. Oncogene 8:1109–1117PubMedGoogle Scholar
  55. Ferry N, Heard JM (1998) Liver-directed gene transfer vectors. Hum Gene Ther 9:1975–1981PubMedGoogle Scholar
  56. Fourel G, Trepo C, Bougueleret L et al. (1990) Frequent activation of N-myc genes by hepadnavirus insertion in woodchuck liver tumors. Nature 347:294–298PubMedGoogle Scholar
  57. Fourel G, Couturier J, Wei Y, Apiou F, Tiollais P, Buendia MA (1994) Evidence for long-range oncogene activation by hepadnavirus insertion. EMBO J 13:2526–2534PubMedCentralPubMedGoogle Scholar
  58. Fujimoto Y, Hampton LL, Wirth PJ, Wang NJ, Xie JP, Thorgeirsson SS (1994) Alterations of tumor suppressor genes and allelic losses in human hepatocellular carcinomas in China. Cancer Res 54:281–285PubMedGoogle Scholar
  59. Gale M Jr, Korth MJ, Tang NM et al. (1997) Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5 A protein. Virology 230:217–227PubMedGoogle Scholar
  60. Gale M Jr, Blakely CM, Kwieciszewski B et al. (1998) Control of PKR protein kinase by hepatitis C virus nonstructural 5A protein: molecular mechanisms of kinase regulation. Mol Cell Biol 18:5208–5218PubMedCentralPubMedGoogle Scholar
  61. Gale M Jr, Kwieciszewski B, Dossett M, Nakao H, Katze MG (1999) Antiapoptotic and oncogenic potentials of hepatitis virus are linked to interferon resistance by viral repression of the PKR protein kinase. J Virol 73:6506–6516PubMedCentralPubMedGoogle Scholar
  62. Graef E, Caselmann WH, Wells J, Koshy R (1994) Insertional activation of mevalonate kin ase by hepatitis B virus DNA in a human hepatoma cell line. Oncogene 9:81–87PubMedGoogle Scholar
  63. Graef E, Caselmann WH, Hofschneider PH, Koshy R (1995) Enzymatic properties of overexpressed HBV-mevalonate kinase fusion proteins and mevalonate kinase proteins in the human hepatoma cell line PLC/PRF/5. Virology 208:696–703PubMedGoogle Scholar
  64. Haber DA (1995) Telomeres, cancer, and immortality. N Engl J Med 332:955–956PubMedGoogle Scholar
  65. Habib NA, Hodgson HJ, Lemoine N, Pignatelli M (1999) A phase IIII study of hepatic artery infusion with wtp53-CMV-Ad in metastatic malignant liver tumours. Hum Gene Ther 10:2019–2034PubMedGoogle Scholar
  66. Hallenbeck PL, Chang YN, Hay C et al. (1999) A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma. Hum Gene Ther 10:1721–1733PubMedGoogle Scholar
  67. Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis.Cell 86:353–364PubMedGoogle Scholar
  68. Hanahan D, Weinberg RA (2000) The hallmarks of cancer.Cell 100:57–70PubMedGoogle Scholar
  69. Hansen LJ, Tennant BC, Seeger C, Ganem D (1993) Differential activation of myc gene family members in hepatic carcinogenesis by closely related hepatitis B viruses. Mol Cell Biol 13:659–667PubMedCentralPubMedGoogle Scholar
  70. Harvey CJ, Blomley MJK, Eckersley RJ, Heckemann RA, Butler-Barnes J, Cosgrove DO (2000) Pulse-inversion mode imaging of liver specific microbubbles: improved detection of subcentimetre metastases. Lancet 355:807–808PubMedGoogle Scholar
  71. He TC, Zhou S, Costa da LT, Yu J, Kinzier KW, Vogelstein B (1998) A simplified system for generating recombinant adenoviruses. Proc Natl Acad Sci USA 95:2509–2514PubMedCentralPubMedGoogle Scholar
  72. Heintges T, Wands JR (1997) Hepatitis C virus: epidemiology and transmission. Hepatology 26:521–526PubMedGoogle Scholar
  73. Heise CC, Williams AM, Xue S, Propst M, Kirn DH (1999) Intravenous administration of ONYX-DIS, a selectively replicating adenovirus, induces antitumoral efficacy. Cancer Res 59:2623–2628PubMedGoogle Scholar
  74. Henry SH, Bosch FX, Troxell TC, Bolger PM (1999) Reducing liver cancer-global control of aflatoxin. Science 286:2453–2454PubMedGoogle Scholar
  75. Higashitsuji H, Itoh K, Nagao T et al. (2000) Reduced stability of retinoblastoma pro tein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas. Nat Med 6:96–99PubMedGoogle Scholar
  76. Hock H, Dorsch M, Kunzendorf U et al. (1993) Vaceinations with tumor cells genetically engineered to produce different cytokines: effectivity not superior to a classical adjuvant. Cancer Res 53:714–716PubMedGoogle Scholar
  77. Höhne M, Schaefer S, Seifer M, Feitelson MA, Paul D, Gerlich WH (1990) Malignant transformation of immortalized transgenic hepatocytes after transfection with hepatitis B virus DNA. EMBO J 9:1137–1145PubMedCentralPubMedGoogle Scholar
  78. Hoofnagle JH (1997) Hepatitis C: the clinical spectrum of disease. Hepatology [Suppl 1] 26:15S–20SPubMedGoogle Scholar
  79. Hsu T-Y, Möröy T, Etiemble T et al. (1988) Activation of c-myc by woodchuck hepatitis virus insertion in hepatocellular carcinoma. Cell 55:627–635PubMedGoogle Scholar
  80. Hsu IC, Metcalf RA, Sun T, Welsh JA, Wang NJ, Harris CC (1991) Mutational hotspot in the p53 gene in human hepatocellular carcinomas. Nature 350:427–428PubMedGoogle Scholar
  81. Huang H, Chen SH, Kosai K, Finegold MJ, Woo SL (1996) Gene therapy for hepatocellular carcinoma: long-term remission of primary and metastatic tumors in mice by interleukin-2 gene therapy in vivo. Gene Ther 3:980–987PubMedGoogle Scholar
  82. Im SA, Gomez-Manzano C, Fueyo J et al. (1999) Antiangiogenesis treatment for gliomas: transfer of antisense-vascular endothelial growth factor inhibits tumor growth in vivo. Cancer Res 59:895–900PubMedGoogle Scholar
  83. Ishikawa H, Nakata K, Mawatari F et al. (1999) Utilization of variant-type of human alpha-fetoprotein promoter in gene therapy targeting for hepatocellular carcinoma. Gene Ther 6:465–470PubMedGoogle Scholar
  84. Isokawa O, Suda T, Aoyagi Y et al. (1999) Reduction of telomeric repeats as a possible predictor for development of hepatocellular carcinoma: convenient evaluation by slot-blot analysis. Hepatology 30:408–412PubMedGoogle Scholar
  85. Ito T, Sasaki Y, Wands JR (1996) Overexpression of human insulin receptor substrate 1 induces cellular transformation with activation of mitogen-activated protein kinases. Mol Cell Biol 16:943–951PubMedCentralPubMedGoogle Scholar
  86. Kafri T, Blomer U, Peterson DA, Gage FH, Verma IM (1997) Sustained expression of genes delivered directly into liver and muscle by lentiviral vectors. Nat Genet 17:314–317PubMedGoogle Scholar
  87. Kanai F, Lan KH, Shiratori Y et al. (1997) In vivo gene therapy for alpha-fetoprotein-producing hepatocellular carcinoma by adenovirus-mediated transfer of cytosine deaminase gene. Cancer Res 57:461–465PubMedGoogle Scholar
  88. Kekulé AS, Lauer U, Meyer M, Caselmann WH, Hofschneider PH, Koshy R (1990) The preS2/S region of integrated hepatitis B virus DNA encodes a transcriptional transactivator. Nature 343:457–461PubMedGoogle Scholar
  89. Kekulé AS, Lauer U, Weiss L, Luber B, Hofschneider PH (1993) Hepatitis B virus transactivator HBx uses a tumour promoter signalling pathway. Nature 361:742–745PubMedGoogle Scholar
  90. Kim C-M, Koike R, Saito I, Miyamura T, Jay G (1991) HBx gene of hepatitis B virus induces liver cancer in transgenic mice. Nature 351:317–320PubMedGoogle Scholar
  91. Kim NW, Piatyszek MA, Prowse KR et al. (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015PubMedGoogle Scholar
  92. Kinzier KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170Google Scholar
  93. Kita R, Nishida N, Fukuda Y et al. (1996) Infrequent alterations of the p16INK4A gene in liver cancer. Int J Cancer 67:176–180PubMedGoogle Scholar
  94. Kiyosawa K, Sodeyama T, Tanaka E et al. (1990) Interrelationship of blood transfusion, non-A, non-B hepatitis and hepatocellular carcinoma: analysis by detection of antibody to hepatitis C virus. Hepatology 12:671–675PubMedGoogle Scholar
  95. Kojima H, Yokosuka O, Imazeki F, Saisho H, Omata M (1997) Telomerase activity and telomere length in hepatocellular carcinoma and chronic liver disease. Gastroenterology 112:493–500PubMedGoogle Scholar
  96. Kojima H, Yokosuka O, Kato N et al. (1999) Quantitative evaluation of telomerase activity in small liver tumors: analysis of ultrasonography-guided liver biopsy specimens. J Hepatol 31:514–520PubMedGoogle Scholar
  97. Kondo Y, Kanai Y, Sakamoto M, Mizokami M, Ueda R, Hirohashi S (1999) Microsatellite instability associated with hepatocarcinogenesis. J Hepatol 31:529–536PubMedGoogle Scholar
  98. Korba BE, Wells FV, Baldwin B et al. (1989) Hepatocellular carcinoma in woodchuck hepatitis virus-infected woodchucks: presence of viral DNA in tumor tissue from chronic carriers and animals serologically recovered from acute infection. Hepatology 9:461–470PubMedGoogle Scholar
  99. Kouroumalis E, Skordilis P, Thermos K, Vasilaki A, Moschandrea J, Manousos ON (1998) Treatment of hepatocellular carcinoma with octreotide: a randomised controlled study. Gut 42:442–447PubMedCentralPubMedGoogle Scholar
  100. Kuo G, Choo Q-L, Alter HJ et al. (1989) An assay for circulating antibodies to a major etiologic virus of human non-A, non-B hepatitis. Science 244:362–364PubMedGoogle Scholar
  101. Kuriyama S, Masui K, Kikukawa M et al. (1999) Complete cure of established murine hepatocellular carcinoma is achievable by repeated injections of retroviruses carrying the herpes simplex virus thymidine kinase gene. Gene Ther 6:525–533PubMedGoogle Scholar
  102. Livraghi T, Bolondi L, Lazzaroni S et al. (1992) Percutaneous ethanol injection in the treatment of hepatocellular carcinoma in cirrhosis. A study on 207 patients. Cancer 69:925–929PubMedGoogle Scholar
  103. Livraghi T, Giorgio A, Marin G et al. (1995) Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 197:101–108PubMedGoogle Scholar
  104. Lukacs KV, Porter CD, Pardo OE et al. (1999) In vivo transfer of bacterial marker genes results in differing levels of gene expression and tumor progression in immunocompetent and immunodeficient mice. Hum Gene Ther 10: 2373–2379PubMedGoogle Scholar
  105. Macdonald GA, Greenson JK, Saito K, Cherian SP, Appelman H.D., Boland CR (1998) Microsatellite instability and loss of heterozygosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis. Hepatology 28:90–97PubMedGoogle Scholar
  106. Martin LA, Vile R, Lemoine NR, Sikora K, Pandha HS (1997) Genetic prodrug activation therapy. Lancet 350:1793–1794PubMedGoogle Scholar
  107. Matsubara K, Tokino T (1990) Integration of hepatitis B virus DNA and its implications for hepatocarcinogenesis. Mol Biol Med 7:243–260PubMedGoogle Scholar
  108. Mazzaferro V, Regalia E, Doci R et al. (1996) Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med 334:693–699PubMedGoogle Scholar
  109. Michalak TI, Pasquinelli C, Guilhot S, Chisari FV (1994) Hepatitis B virus persistence after recovery from acute viral hepatitis. J Clin Invest 93:230–239PubMedCentralPubMedGoogle Scholar
  110. Michalak TI, Pardoe I.U., Coffin CS et al. (1999) Occult life-long persistence of infectious hepadnavirus and residual liver inflammation in woodchucks convalescent from acute viral hepatitis. Hepatology 29:928–938PubMedGoogle Scholar
  111. Miller JF, Morahan G (1992) Peripheral T cell tolerance. Annu Rev Immunol 10:51–69PubMedGoogle Scholar
  112. Mise M, Arii S, Higashituji H et al. (1996) Clinical significance of vascular endothelial growth factor and basic fibroblast growth factor gene expression in liver tumor. Hepatology 23:455–464PubMedGoogle Scholar
  113. Miyoshi Y, Iwao K, Nagasawa Y et al. (1998) Activation of the beta-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res 58:2524–2527PubMedGoogle Scholar
  114. Mohr L, Schauer JI, Boutin RH, Moradpour D, Wands JR (1999) Targeted gene transfer to hepatocellular carcinoma cells in vitro using a novel monodonal antibody-based gene delivery system. Hepatology 29:82–89PubMedGoogle Scholar
  115. Moradpour D, Blum HE (1999) Current and evolving Therapics for hepatitis C. Eur J Gastroenterol Hepatol 11:1199–1202PubMedGoogle Scholar
  116. Morel A, De la Coste A, Fernandez N et al. (1998) Does preventive vaccination with engineered tumor cells work in cancer-prone transgenic mice? Cancer Gene Ther 5:92–100PubMedGoogle Scholar
  117. Moriya K, Fujie H, Shintani Y et al. (1998) The core protein of hepatitis C virus induces hepatocellular carcinoma in transgenic mice. Nat Med 4:1065–1067PubMedGoogle Scholar
  118. Möröy T, Marchio A, Etiemble J, Trépo C, Tiollais P, Buendia M-A (1986) Rearrangement and enhanced expression of c-myc in hepatocellular carcinoma of hepatitis virus infected woodchucks. Nature 324:276–279PubMedGoogle Scholar
  119. Moscow JA, Huang H, Carter C et al. (1999) Engraftment of MDR1 and NeoR gene-transduced hematopoietic cells after breast cancer chemotherapy. Blood 94:52–61PubMedGoogle Scholar
  120. Murakami Y, Hayashi K, Hirohashi S, Sekiya T (1991) Aber-rations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas. Cancer Res 51:5520–5525PubMedGoogle Scholar
  121. Nabel GJ (1999) Development of optimized vectors for gene therapy. Proc Natl Acad Sci USA 96:324–326PubMedCentralPubMedGoogle Scholar
  122. Nagaya T, Nakamura T, Tokino T et al. (1987) The mode of hepatitis B virus DNA integration in chromosomes of human hepatocellular carcinoma. Genes Dev 1:773–782PubMedGoogle Scholar
  123. Nakamoto Y, Guidotti LC, Kuhlen CV, Fowler P, Chisari FV (1998) Immune pathogenesis of hepatocellular carcinoma. J Exp Med 188:341–350PubMedCentralPubMedGoogle Scholar
  124. Nassal M (1996) Hepatitis B virus morphogenesis. Curr Top Microbiol Immunol 214:297–337PubMedGoogle Scholar
  125. Nassal M (1999) Hepatitis B virus replication: novel roles for virus-host interactions. Intervirology 42:100–116PubMedGoogle Scholar
  126. Nishida N, Fukuda Y, Komeda T et al. (1994) Amplification and overexpression of the cydin D1 gene in aggressive human hepatocellular carcinoma. Cancer Res 54:3107–3110PubMedGoogle Scholar
  127. Nishiyama M, Wands JR (1992) Cloning and increased expression of an insulin receptor substrate-1-like gene in human hepatocellular carcinoma. Biochem Biophys Res Commun 183:280–285PubMedGoogle Scholar
  128. Nurse P (2000) A long twentieth century of the cell cycle and beyond. Cell 100:71–78PubMedGoogle Scholar
  129. Oda H, Imai Y, Nakatsuru Y, Hata J, Ishikawa T (1996) Somatic mutations of the APC gene in sporadic hepatoblastomas. Cancer Res 56:3320–3323PubMedGoogle Scholar
  130. Ogata N, Kamimura T, Asakura H (1991) Point mutation, allelic loss and increased methylation of c-Ha-Ras gene in human hepatocellular carcinoma. Hepatology 13:31–37PubMedGoogle Scholar
  131. Ohguchi S, Nakatsukasa H, Higashi T et al. (1998) Expression of alpha-fetoprotein and albumin genes in human hepatocellular carcinomas: limitations in the application of the genes for targeting human hepatocellular carcinoma in gene therapy. Hepatology 27:599–607PubMedGoogle Scholar
  132. Ohto H, Terazawa S, Sasaki N et al. (1994) Transmission of hepatitis C virus from mothers to infants. N Engl J Med 330:744–750PubMedGoogle Scholar
  133. Ohwada A, Hirschowitz EA, Crystal RG (1996) Regional delivery of an adenovirus vector containing the Escherichia cali cytosine deaminase gene to provide local activation of 5-fluorocytosine to suppress the growth of colon carcinoma metastatic to liver. Hum Gene Ther 7:1567–1576PubMedGoogle Scholar
  134. Okada S, Shimada K, Yamamoto J et al. (1994) Predictive factors for postoperative recurrence of hepatocellular carcinoma. Gastroenterology 106:1618–1624PubMedGoogle Scholar
  135. Okuda K (2000) Hepatocellular carcinoma. J Hepatol [Suppl1] 32:225–237PubMedGoogle Scholar
  136. Ozturk M (1999) Genetic aspects of hepatocellular carcinogenesis.Semin Liver Dis 19:235–242PubMedGoogle Scholar
  137. Park JS, Yang JM, Min MK (2000) Hepatitis C virus nonstructural protein NS4B transforms NIH3T3 cells in cooperation with the Ha-ras oncogene. Biochem Biophys Res Commun 267:581–587PubMedGoogle Scholar
  138. Pasquinelli C, Bhavani K, Chisari FV (1992) Multiple oncogenes and tumor suppressor genes are structurally and functionally intact during hepatocarcinogenesis in hepatitis B virus transgenic mice. Cancer Res 52:2823–2829PubMedGoogle Scholar
  139. Paterlini P, Gerken G, Nakajima E et al. (1990) Polymerase chain reaction to detect hepatitis B virus DNA and RNA sequences in primary liver cancers from patients negative for hepatitis B surface antigen. N Engl J Med 323:80–85PubMedGoogle Scholar
  140. Pileri P, Uematsu Y, Campagnoli S et al. (1998) Binding of hepatitis C virus to CD81. Science 282:938–941PubMedGoogle Scholar
  141. Pineau P, Marchio A, Terris B et al. (1996) A t(3;8) chromosomal translocation associated with hepatitis B virus integration involves the carboxypeptidase N locus. J Virol 70:7280–7284PubMedCentralPubMedGoogle Scholar
  142. Pitot HC (1990) Proto-oncogene activation in multistage murine hepatocarcinogenesis. Prog Clin Biol Res 331: 311–324PubMedGoogle Scholar
  143. Puisieux A, Lim S, Groopman J, Ozturk M (1991) Selective targeting of p53 gene mutational hotspots in human cancers by etiologically defined carcinogens. Cancer Res 51:6185–6189PubMedGoogle Scholar
  144. Puisieux A, Ji J, Guillot C et al. (1995) p53-mediated cellular response to DNA damage in cells with replicative hepatitis B virus. Proc Natl Acad Sci USA 92:1342–1346PubMedCentralPubMedGoogle Scholar
  145. Qian C, Idoate M, Bilbao R et al. (1997) Gene transfer and therapy with adenoviral vector in rats with diethylnitrosamine-induced hepatocellular carcinoma. Hum Gene Ther 8:349–358PubMedGoogle Scholar
  146. Qian C, Drozdzik M, Caselmann WH, Prieto J (2000) The potential of gene therapy in the treatment of hepatocellular carcinoma. J Hepatol 32:344–351PubMedGoogle Scholar
  147. Ray RB, Lagging LM, Meyer K, Ray R (1996) Hepatitis C virus core protein cooperates with ras and transforms primary rat embryo fibroblasts to tumorigenic phenotype. J Virol 70:4438–4443PubMedCentralPubMedGoogle Scholar
  148. Ray RB, Steele R, Meyer K, Ray R (1997) Transcriptional repression of p53 promoter by hepatitis C virus core protein. J Biol Chem 272:10983–10986PubMedGoogle Scholar
  149. Ray RB, Steele R, Meyer K, Ray R (1998) Hepatitis C virus core protein represses p21 WAF1/Cip1/Sid1 promoter activity. Gene 208:331–336PubMedGoogle Scholar
  150. Reed KE, Rice CM (2000) Overview of hepatitis C virus genome structure, polyprotein processing, and protein properties. Curr Top Microbiol Immunol 242:55–84PubMedGoogle Scholar
  151. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV (1996) The hepatitis B virus persists for decades after patients’ recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med 2:1104–1108PubMedGoogle Scholar
  152. Rice CM (1996) Flaviviridae: the viruses and their replication. In: Fields B.N., Knipe DM, Howley PM (eds) Fields virology. Lippincott-Raven, Philadelphia, pp 931–959Google Scholar
  153. Ross RK, Yuan JM, Yu MC et al. (1992) Urinary aflatoxin biomarkers and risk of hepatocellular carcinoma. Lancet 339:943–946PubMedGoogle Scholar
  154. Rossi S, Buscarini E, Garbagnati F et al. (1998) Percutaneous treatment of small hepatic tumors by an expandable RF needle electrode. AJR Am J Roentgenol 170:1015–1022PubMedGoogle Scholar
  155. Sakamuro D, Furukawa T, Takegami T (1995) Hepatitis C virus nonstructural protein NS3 transforms NIH 3T3 cells. J Virol 69:3893–3896PubMedCentralPubMedGoogle Scholar
  156. Santoni-Rugiu E, Preisegger KH, Kiss A et al. (1996) Inhibition of neoplastic development in the liver by hepatocyte growth factor in a transgenic mouse model. Proc Natl Acad Sci USA 93:9577–9582PubMedCentralPubMedGoogle Scholar
  157. Schreiber GB, Busch MP, Kleinman SH et al. (1996) The risk of transfusion-transmitted viral infections. N Engl J Med 334:1685–1690PubMedGoogle Scholar
  158. Seeff LB (1997) Natural history of hepatitis C. Hepatology [Suppl 1] 26:21S–28SPubMedGoogle Scholar
  159. Shih C, Burke K, Chou M-J et al. (1987) Tight clustering of human hepatitis B virus integration sites in hepatomas near a triple-stranded region. J Virol 61:3491–3498PubMedCentralPubMedGoogle Scholar
  160. Shiota G, Rhoads DB, Wang TC, Nakamura T, Schmidt EV (1992) Hepatocyte growth factor inhibits growth of hepatocellular carcinoma cells. Proc Natl Acad Sci USA 89:373–377PubMedCentralPubMedGoogle Scholar
  161. Shiota G, Wang TC, Nakamura T, Schmidt EV (1994) Hepatic growth factor in transgenic mice: effect on hepatocyte growth, liver regeneration and gene expression. Hepatology 19:962–972PubMedGoogle Scholar
  162. Slagle B, Zhou Y-Z, Birchmeier W, Scorsone KA (1993) Deletion of the E-cadherin gene in hepatitis B virus-positive Chinese hepatocellular carcinomas. Hepatology 18:757–762PubMedGoogle Scholar
  163. Stroffolini T, Andreone P, Andriulli A et al. (1998) Characteristics of hepatocellular carcinoma in Italy. J Hepatol 29:944–952PubMedGoogle Scholar
  164. Sun Z, Lu P, Gail MH et al. (1999) Increased risk of hepatocellular carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. Hepatology 30:379–383PubMedGoogle Scholar
  165. Tada M, Omata M, Ohto M (1990) Analysis of ras gene mutations in human hepatic malignant tumors by polymerase chain reaction and direct sequencing. Cancer Res 50:1121–1124PubMedGoogle Scholar
  166. Tahara H, Nakanishi T, Kitamoto M et al. (1995) Telomerase activity in human liver tissues: comparison between chronic liver disease and hepatocellular carcinomas. Cancer Res 55:2734–2736PubMedGoogle Scholar
  167. Tan SL, Nakao H, He Y et al. (1999) NS5A, a nonstructural protein of hepatitis C virus, binds growth factor receptor-bound protein 2 adaptor protein in a Src homolgy 3 domain/ligand-dependent manner and perturbs mitogenic signaling. Proc Natl Acad Sci USA 96:5533–5538PubMedCentralPubMedGoogle Scholar
  168. Tanaka S, Mori M, Sakamoto Y, Makuchi M, Sugimachi K, Wands JR (1999) Biologic significance of angiopoietin-2 expression in human hepatocellular carcinoma. J Clin Invest 103:341–345PubMedCentralPubMedGoogle Scholar
  169. Tatsumi T, Takehara T, Kanto T et al. (1999) B7-1 (CD80)gene transfer combined with interleukin-12 administration elicits protective and therapeutic immunity against mouse hepatocellular carcinoma. Hepatology 30:422–429PubMedGoogle Scholar
  170. Taylor-Robinson SD, Foster GR, Arora S, Hargreaves S, Thomas HC (1997) Increase in primary liver cancer in the UK, 1979-94. Lancet 350:1142–1143Google Scholar
  171. Tennant BC (1992) Hepatocarcinogenesis in experimental woodchuck hepatitis virus infection. In: Sirica AE (ed) The role of cell types in hepatocarcinogenesis. CRC Press, Boca Raton, FL, pp 323–349Google Scholar
  172. Tobe T, Arii S (1992) Improving survival after resection of hepatocellular carcinoma: characteristics and current status of surgical treatment of primary liver cancer in Japan. In: Tobe T, Kaneda H, Okudaira M, Ohto M, Endo Y (eds) Primary liver cancer in Japan. Springer, Berlin Heidelberg New YorkGoogle Scholar
  173. Torimura T, Sata M, Ueno T et al. (1998) Increased expression of vascular endothelial growth factor is associated with tumor progression in hepatocellular carcinoma. Hum Pathol 29:986–991PubMedGoogle Scholar
  174. Torzilli G, Minagawa M, Takayama T et al. (1999) Accurate preoperative evaluation of liver mass lesions without fine-needle biopsy. Hepatology 30:889–893PubMedGoogle Scholar
  175. Ueda H, Ullrich SJ, Gangemi JD et al. (1995) Functional inactivation but not structural mutation of p53 causes liver cancer. Nat Genet 9:41–47PubMedGoogle Scholar
  176. Vollmer CM Jr, Eilber FC, Butterfield LH et al. (1999) Alphafetoprotein-specific genetic immunotherapy for hepatocellular carcinoma. Cancer Res 59:3064–3067PubMedGoogle Scholar
  177. Wands JR, Blum HE (1991) Primary hepatocellular carcinoma. N Engl J Med 325:729–731PubMedGoogle Scholar
  178. Wands JR, Liang TJ, Blum HE, Shafritz DA (1992) Molecular pathogenesis of liver disease during persistent hepatitis B virus infection. Semin Liver Dis 12:252–264PubMedGoogle Scholar
  179. Wang H-P, Rogler CE (1991) Topoisomerase I-mediated integration of hepadnavirus DNA in vitro. J Virol 65:2381–2392PubMedCentralPubMedGoogle Scholar
  180. Wang J, Chenivesse X, Henglein B, Bréchot C (1990) Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma. Nature 343:555–557PubMedGoogle Scholar
  181. Wang J, Zindy F, Chenivesse X, Lamas E, Henglein B, Bréchot C (1992) Modification of cyclin A expression by hepatitis B virus DNA integration in a hepatocellular carcinoma. Oncogene 7:1653–1656PubMedGoogle Scholar
  182. Wang X.W., Forrester K, Yeh H, Feitelson MA, Gu J-R, Harris CC (1994) Hepatitis B virus X protein inhibits p53 sequence-specific DNA binding, transcriptional activity, and association with transcription factor ERCC3. Proc Natl Acad Sci USA 91:2230–2234PubMedCentralPubMedGoogle Scholar
  183. Watanabe S, Yamasaki S, Tanae A, Hibi I, Honna T (1994) Three cases of hepatocellular carcinoma among cyproterone users.Ad hoc Committee on Androcur Users. Lancet344:1567–1568PubMedGoogle Scholar
  184. Wei Y, Fourel G, Ponzetto A, Silvestro M, Tiollais P, Buendia M-A (1992) Hepadnavirus integration: mechanisms of activation of the N-myc2 retrotransposon in woodchuck liver tumors. J Virol 66:5265–5276PubMedCentralPubMedGoogle Scholar
  185. Xu GW, Sun ZT, Forrester K, Wang X.W., Coursen J, Harris CC (1996) Tissue-specific growth suppression and chemosensitivity promotion in human hepatocellular carcinoma cells by retroviral-mediated transfer of the wildtype p53 gene. Hepatology 24:1264–1268PubMedGoogle Scholar
  186. Yakicier MC, Irmak MB, Romano A, Kew M, Ozturk M (1999) Smad2 and Smad4 gene mutations in hepatocellular carcinoma. Oncogene 18:4879–4883PubMedGoogle Scholar
  187. Yamada T, De Souza AT, Finkelstein S, Jirtle RL (1997) Loss of the gene encoding mannose 6-phosphate/insulin-like growth factor II receptor is an early event in liver carcinogenesis.Proc Natl Acad Sci USA 94:10351–10355PubMedCentralPubMedGoogle Scholar
  188. Yamaguchi R, Yano H, Lemura A, Ogasawara S, Haramaki M, Kojiro M (1998) Expression of vascular endothelial growth factor in human hepatocellular carecinoma. Hepatology 28:68–77PubMedGoogle Scholar
  189. Yang Y, Nunes FA, Berencsi K, Furth EE, Gonczol E, Wilson JM (1994) Cellular immunity to viral antigens limits E1-deleted adenoviruses for gene therapy. Proc Natl Acad Sci USA 91:4407–4411PubMedCentralPubMedGoogle Scholar
  190. Yano M, Asahara T, Dohi K, Mizuno T, Iwamoto KS, Seyama T (1999) Close correlation between a p53 or hMSH2 gene mutation in the tumor and survival of hepatocellular carcinoma patients. Int J Oncol 14:447–451PubMedGoogle Scholar
  191. Yoshiji H, Kuriyama S, Yoshii J et al. (1998) Vascular endothelial growth factor tightly regulates in vivo development of murine hepatocellular carcinoma cells. Hepatology 28:1489–1496PubMedGoogle Scholar
  192. Zanetti AR, Tanzi E, Paccagnini S et al. (1995) Mother-to-infant transmission of hepatitis C virus. Lancet 345:289–291PubMedGoogle Scholar
  193. Zhang X-K, Huang DP, Qiu DK, Chiu JF (1990) The expression of c-myc and c-N-ras in human cirrhotic livers, hepatocellular carcinomas and liver tissue surrounding the tumors. Oncogene 5:909–914PubMedGoogle Scholar
  194. Zhang X-K, Egan J.O., Huang D-P, Sun Z-L, Chien V.KY, Chiu J-F (1992) Hepatitis B virus DNA integration and expression of an erb B-like gene in human hepatocellular carcinoma. Biochem Biophys Res Commun 188:344–351PubMedGoogle Scholar
  195. Zhang Y-J, Hang W, Chen CJ et al. (1993) Amplification and overexpression of cyclin D1 in human hepatocellular carcinoma. Biochem Biophys Res Commun 196:1010–1016PubMedGoogle Scholar
  196. Zhang X-K, Xu H-J, Murakami Y et al. (1994) Deletions of chromosome 13q, mutations in RB1 and RB protein state in human hepatocellular carcinoma. Cancer Res 54:4177–4182PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • Darius Moradpour
  • Hans-Peter Allgaier
  • Heinz G. Linhart
  • Hubert E. Blum

There are no affiliations available

Personalised recommendations