Hepatocellular Carcinoma: Targeted Therapy and Multidisciplinary P4 potx

1 Epidemiology and Pathogenesis of Hepatocellular Carcinoma 15 51. Vineis P, Pirastu R (1997) Aromatic amines and cancer. Cancer Causes Control 8:346–355 52. Hecht SS (1998) Biochemistry, biology, and carcinogenicity of tobacco-specific N-nitrosamines. Chem Res Toxicol 11:559–603 53. Frei B, Forte TM, Ames BN, Cross CE (1991) Gas phase oxidants of cigarette smoke induce lipid peroxidation and changes in lipoprotein properties i n human blood plasma. Protective effects of ascorbic acid. Biochem J 277(Pt 1):133–138 54. Miro O, Alonso JR, Jarreta D, Casademont J, Urbano-Marquez A, Cardellach F (1999) Smoking disturbs mitochondrial respiratory chain function and enhances lipid peroxidation on human circulating lymphocytes. Carcinogenesis 20:1331–1336 55. Ueno Y (1985) The toxicology of mycotoxins. Crit Rev Toxicol 14:99–132 56. Guengerich FP, Shimada T (1991) Oxidation of toxic and carcinogenic chemicals by human cytochrome P-450 enzymes. Chem Res Toxicol 4:391–407 57. Guengerich FP, Shimada T, Iwasaki M, Butler MA, Kadlubar FF (1990) Activation of carcinogens by human liver cytochromes P-450. Basic Life Sci 53:381–396 58. Bulatao-Jayme J, Almero EM, Castro MC, Jardeleza MT, Salamat LA (1982) A case-control dietary study of primary liver cancer risk from aflatoxin exposure. Int J Epidemiol 11: 112–119 59. Yeh FS, Yu MC, Mo CC, Luo S, Tong MJ, Henderson BE (1989) Hepatitis B virus, aflatox- ins, and hepatocellular carcinoma in southern Guangxi, China. Cancer Res 49:2506–2509 60. Maheshwari S, Sarraj A, Kramer J, El-Serag HB (2007) Oral contraception and the risk of hepatocellular carcinoma. J Hepatol 47:506–513 61. De B, V, Welsh JA, Yu MC, Bennett WP (1996) p53 mutations in hepatocellular carcinoma related to oral contraceptive use. Carcinogenesis 17:145–149 62. Persson I, Yuen J, Bergkvist L, Schairer C (1996) Cancer incidence and mortality in women receiving estrogen and estrogen-progestin replacement therapy–long-term follow-up of a Swedish cohort. Int J Cancer 67:327–332 63. Fernandez E, Gallus S, Bosetti C, Franceschi S, Negri E, La VC (2003) Hormone replace- ment therapy and cancer risk: a systematic analysis from a network of case-control studies. Int J Cancer 105:408–412 64. Boffetta P, Matisane L, Mundt KA, Dell LD (2003) Meta-analysis of studies of occupational exposure to vinyl chloride in relation to cancer mortality. Scand J Work Environ Health 29:220–229 65. Dragani TA, Zocchetti C (2008) Occupational exposure to vinyl chloride and risk of hepatocellular carcinoma. Cancer Causes Control 19:1193–1200 66. El-Serag HB, Hampel H, Javadi F (2006) The association between diabetes and hepatocel- lular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 4:369–380 67. Bell DS, Allbright E (2007) The multifaceted associations of hepatobiliary disease and diabetes. Endocr Pract 13:300–312 68. Tolman KG, Fonseca V, Tan MH, Dalpiaz A (2004) Narrative review: hepatobiliary disease in type 2 diabetes mellitus. Ann Intern Med 141:946–956 69. Harrison SA (2006) Liver disease in patients with diabetes mellitus. J Clin Gastroenterol 40:68–76 70. Davila JA, Morgan RO, Shaib Y, McGlynn KA, El-Serag HB (2005) Diabetes increases the risk of hepatocellular carcinoma in the United States: a population based case control study. Gut 54:533–539 71. Veldt BJ, Chen W, Heathcote EJ, Wedemeyer H, Reichen J, Hofmann WP et al (2008) Increased risk of hepatocellular carcinoma among patients with hepatitis C cirrhosis and diabetes mellitus. Hepatology 47:1856–1862 72. Yuan JM, Govindarajan S, Arakawa K, Yu MC (2004) Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S. Cancer 101:1009–1017 16 M.M. Hassan and A.O. Kaseb 73. Yu MC, Tong MJ, Govindarajan S, Henderson BE (1991) Nonviral risk factors for hepatocel- lular carcinoma in a low-risk population, the non-Asians of Los Angeles County, California. J Natl Cancer Inst 83:1820–1826 74. El-Serag HB, Tran T, Everhart JE (2004) Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126:460–468 75. Chen CL, Yang HI, Yang WS, Liu CJ, Chen PJ, You SL et al (2008) Metabolic factors and risk of hepatocellular carcinoma by chronic hepatitis B/C infection: a follow-up study in Taiwan. Gastroenterology 135:111–121 76. Hassan MM, Hwang LY, Hatten CJ, Swaim M, Li D, Abbruzzese JL et al (2002) Risk factors for hepatocellular carcinoma: synergism of alcohol with viral hepatitis and diabetes mellitus. Hepatology 36:1206–1213 77. Komura T, Mizukoshi E, Kita Y, Sakurai M, Takata Y, Arai K et al (2007) Impact of dia- betes on recurrence of hepatocellular carcinoma after surgical treatment in patients with viral hepatitis. Am J Gastroenterol 102:1939–1946 78. Ikeda Y, Shimada M, Hasegawa H, Gion T, Kajiyama K, Shirabe K et al (1998) Prognosis of hepatocellular carcinoma with diabetes mellitus after hepatic resection. Hepatology 27:1567–1571 79. Dellon ES, Shaheen NJ (2005) Diabetes and hepatocellular carcinoma: associations, biologic plausibility, and clinical implications. Gastroenterology 129:1132–1134 80. Bugianesi E (2005) Review article: steatosis, the metabolic syndrome and cancer. Aliment Pharmacol Ther 22(Suppl 2):40–43 81. Moore MA, Park CB, Tsuda H (1998) Implications of the hyperinsulinaemia-diabetes- cancer link for preventive efforts. Eur J Cancer Prev 7:89–107 82. Alexia C, Fallot G, Lasfer M, Schweizer-Groyer G, Groyer A (2004) An evaluation of the role of insulin-like growth factors (IGF) and of type-I IGF receptor signalling in hepatocar- cinogenesis and in the resistance of hepatocarcinoma cells against drug-induced apoptosis. Biochem Pharmacol 68:1003–1015 83. Tanaka S, Mohr L, Schmidt EV, Sugimachi K, Wands JR (1997) Biological effects of human insulin receptor substrate-1 overexpression in hepatocytes. Hepatology 26:598–604 84. Tanaka S, Wands JR (1996) Insulin receptor substrate 1 overexpression in human hepatocel- lular carcinoma cells prevents transforming growth factor beta1-induced apoptosis. Cancer Res 56:3391–3394 85. Hu W, Feng Z, Eveleigh J, Iyer G, Pan J, Amin S et al (2002) The major lipid peroxida- tion product, trans-4-hydroxy-2-nonenal, preferentially forms DNA adducts at codon 249 of human p53 gene, a unique mutational hotspot in hepatocellular carcinoma. Carcinogenesis 23:1781–1789 86. Reddy JK, Rao MS (2006) Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol 290:G852–G858 87. Browning JD, Horton JD (2004) Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 114:147–152 88. Larsson SC, Wolk A (2007) Overweight, obesity and risk of liver cancer: a meta-analysis of cohort studies. Br J Cancer 97:1005–1008 89. Caldwell SH, Crespo DM, Kang HS, Al-Osaimi AM (2004) Obesity and hepatocellular carcinoma. Gastroenterology 127:S97–S103 90. Xu L, Han C, Lim K, Wu T (2006) Cross-talk between peroxisome proliferator-activated receptor delta and cytosolic phospholipase A(2)alpha/cyclooxygenase-2/prostaglandin E(2) signaling pathways in human hepatocellular carcinoma cells. Cancer Res 66:11859–11868 91. Bensinger SJ, Tontonoz P (2008) Integration of metabolism and inflammation by lipid- activated nuclear receptors. Nature 454:470–477 92. Pucci E, Chiovato L, Pinchera A (2000) Thyroid and lipid metabolism. Int J Obes Relat Metab Disord 24(Suppl 2):S109–S112 93. Krotkiewski M (2000) Thyroid hormones and treatment of obesity. Int J Obes Relat Metab Disord 24(Suppl 2):S116–S119 1 Epidemiology and Pathogenesis of Hepatocellular Carcinoma 17 94. Dimitriadis G, Parry-Billings M, Bevan S, Leighton B, Krause U, Piva T et al (1997) The effects of insulin on transport and metabolism of glucose in skeletal muscle from hyperthyroid and hypothyroid rats. Eur J Clin Invest 27:475–483 95. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK et al (2001) Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120:1183–1192 96. Liangpunsakul S, Chalasani N (2003) Is hypothyroidism a risk factor for non-alcoholic steatohepatitis? J Clin Gastroenterol 37:340–343 97. Reddy A, Dash C, Leerapun A, Mettler TA, Stadheim LM, Lazaridis KN et al (2007) Hypothyroidism: a possible risk factor for liver cancer in patients with no known underlying cause of liver disease. Clin Gastroenterol Hepatol 5:118–123 98. Hassan MM, Curley SA, Li D, Kaseb A, Davila M, Abdalla EK et al (2010) Duration of Diabetes and type of diabetes treatment, increase the risk of hepatocellular carcinoma. Cancer 116:1938–1946 99. Haffner SM (2000) Sex hormones, obesity, fat distribution, type 2 diabetes and insulin resis- tance: epidemiological and clinical correlation. Int J Obes Relat Metab Disord 24(Suppl 2):S56–S58 100. Hautanen A (2000) Synthesis and regulation of sex hormone-binding globulin in obesity. Int J Obes Relat Metab Disord 24(Suppl 2):S64–S70 101. Hampl R, Kancheva R, Hill M, Bicikova M, Vondra K (2003) Interpretation of sex hormone- binding globulin levels in thyroid disorders. Thyroid 13:755–760 102. Tanaka K, Sakai H, Hashizume M, Hirohata T (2000) Serum testosterone:estradiol ratio and the development of hepatocellular carcinoma among male cirrhotic patients. Cancer Res 60:5106–5110 103. Conte D, Fraquelli M, Fornari F, Lodi L, Bodini P, Buscarini L (1999) Close relation between cirrhosis and gallstones: cross-sectional and longitudinal survey. Arch Intern Med 159:49–52 104. Conte D, Barisani D, Mandelli C, Bodini P, Borzio M, Pistoso S et al (1991) Cholelithiasis in cirrhosis: analysis of 500 cases. Am J Gastroenterol 86:1629–1632 105. Fornari F, Civardi G, Buscarini E, Cavanna L, Imberti D, Rossi S et al (1990) Cirrhosis of the liver. A risk factor for development of cholelithiasis in males. Dig Dis Sci 35:1403–1408 106. Zhu JF, Shan LC, Chen WH (1994) [Changes in lipids, bilirubin and metal elements in the gallbladder bile in patients with cirrhosis of the liver]. Zhonghua Nei Ke Za Zhi 33:767–769 107. El-Serag HB, Engels EA, Landgren O, Chiao E, Henderson L, Amaratunge HC et al (2009) Risk of hepatobiliary and pancreatic cancers after hepatitis C virus infection: a population- based study of U.S. veterans. Hepatology 49:116–123 108. Gallus S, Bertuzzi M, Tavani A, Bosetti C, Negri E, La VC et al (2002) Does coffee protect against hepatocellular carcinoma? Br J Cancer 87:956–959 109. Gelatti U, Covolo L, Franceschini M, Pirali F, Tagger A, Ribero ML et al (2005) Coffee consumption reduces the risk of hepatocellular carcinoma independently of its aetiology: a case-control study. J Hepatol 42:528–534 110. Tanaka K, Hara M, Sakamoto T, Higaki Y, Mizuta T, Eguchi Y et al (2007) Inverse associa- tion between coffee drinking and the risk of hepatocellular carcinoma: a case-control study in Japan. Cancer Sci 98:214–218 111. Talamini R, Polesel J, Montella M, Dal ML, Crispo A, Tommasi LG et al (2006) Food groups and risk of hepatocellular carcinoma: a multicenter case-control study in Italy. Int J Cancer 119:2916–2921 112. Yu MW, Hsieh HH, Pan WH, Yang CS, Chen CJ (1995) Vegetable consumption, serum retinol level, and risk of hepatocellular carcinoma. Cancer Res 55:1301–1305 113. Demir G, Belentepe S, Ozguroglu M, Celik AF, Sayhan N, Tekin S et al (2002) Simultaneous presentation of hepatocellular carcinoma in identical twin brothers. Med Oncol 19:113–116 114. Cai RL, Meng W, Lu HY, Lin WY, Jiang F, Shen FM (2003) Segregation analysis of hepato- cellular carcinoma in a moderately high-incidence area of East China. World J Gastroenterol 9:2428–2432 18 M.M. Hassan and A.O. Kaseb 115. Zhang JY, Wang X, Han SG, Zhuang H (1998) A case-control study of risk fac- tors for hepatocellular carcinoma in Henan, China. Am J Trop Med Hyg 59: 947–951 116. Sun Z, Lu P, Gail MH, Pee D, Zhang Q, Ming L et al (1999) Increased risk of hepatocellu- lar carcinoma in male hepatitis B surface antigen carriers with chronic hepatitis who have detectable urinary aflatoxin metabolite M1. Hepatology 30:379–383 117. Yu MW, Chang HC, Liaw YF, Lin SM, Lee SD, Liu CJ et al (2000) Familial risk of hepato- cellular carcinoma among chronic hepatitis B carriers and their relatives. J Natl Cancer Inst 92:1159–1164 118. Chen CH, Huang GT, Lee HS, Yang PM, Chen DS, Sheu JC (1998) Clinical impact of screening first-degree relatives of patients with hepatocellular carcinoma. J Clin Gastroenterol 27:236–239 119. Yu MW, Chang HC, Chen PJ, Liu CJ, Liaw YF, Lin SM et al (2002) Increased risk for hepatitis B-related liver cirrhosis in relatives of patients with hepatocellular carcinoma in northern Taiwan. Int J Epidemiol 31:1008–1015 120. Donato F, Gelatti U, Chiesa R, Albertini A, Bucella E, Boffetta P et al (1999) A case-control study on family history of liver cancer as a risk factor for hepatocellular carcinoma in North Italy. Brescia HCC Study. Cancer Causes Control 10:417–421 121. Piperno A (1998) Classification and diagnosis of iron overload. Haematologica 83:447–455 122. Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A et al (1996) A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet 13:399–408 123. Beutler E, Gelbart T, West C, Lee P, Adams M, Blackstone R et al (1996) Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis 22:187–194 124. Bullen JJ, Rogers HJ, Griffiths E (1978) Role of iron in bacterial infection. Curr Top Microbiol Immunol 80:1–35 125. Bullen JJ, Ward CG, Rogers HJ (1991) The critical role of iron in some clinical infections. Eur J Clin Microbiol Infect Dis 10:613–617 126. Miller M, Crippin JS, Klintmalm G (1996) End stage liver disease in a 13-year old secondary to hepatitis C and hemochromatosis. Am J Gastroenterol 91:1427–1429 127. Hayashi H, Takikawa T, Nishimura N, Yano M (1995) Serum aminotransferase levels as an indicator of the effectiveness of venesection for chronic hepatitis C. J Hepatol 22: 268–271 128. Mazzella G, Accogli E, Sottili S, Festi D, Orsini M, Salzetta A et al (1996) Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis. J Hepatol 24:141–147 129. Bonkovsky HL, Banner BF, Rothman AL (1997) Iron and chronic viral hepatitis. Hepatology 25:759–768 130. Sifers RN, Finegold MJ, Woo SL (1992) Molecular biology and genetics of alpha 1- antitrypsin deficiency. Semin Liver Dis 12:301–310 131. Fabbretti G, Sergi C, Consales G, Faa G, Brisigotti M, Romeo G et al (1992) Genetic variants of alpha-1-antitrypsin (AAT). Liver 12:296–301 132. Eriksson S, Carlson J, Velez R (1986) Risk of cirrhosis and primary liver cancer in alpha 1-antitrypsin deficiency. N Engl J Med 314:736–739 133. Blenkinsopp WK, Haffenden GP (1977) Alpha-1-antitrypsin bodies in the liver. J Clin Pathol 30:132–137 134. Carlson J, Eriksson S (1985) Chronic ‘cryptogenic’ liver disease and malignant hepatoma in intermediate alpha 1-antitrypsin deficiency identified by a Pi Z-specific monoclonal antibody. Scand J Gastroenterol 20:835–842 135. Zhou H, Fischer HP (1998) Liver carcinoma in PiZ alpha-1-antitrypsin deficiency. Am J Surg Pathol 22:742–748 136. Teckman JH, Qu D, Perlmutter DH (1996) Molecular pathogenesis of liver disease in alpha1- antitrypsin deficiency. Hepatology 24:1504–1516 1 Epidemiology and Pathogenesis of Hepatocellular Carcinoma 19 137. Banner BF, Karamitsios N, Smith L, Bonkovsky HL (1998) Enhanced phenotypic expression of alpha-1-antitrypsin deficiency in an MZ heterozygote with chronic hepatitis C. Am J Gastroenterol 93:1541–1545 138. Bianchi L (1993) Glycogen storage disease I and hepatocellular tumours. Eur J Pediatr 152(Suppl 1):S63–S70 139. Siersema PD, ten Kate FJ, Mulder PG, Wilson JH (1992) Hepatocellular carcinoma in porphyria cutanea tarda: frequency and factors related to its occurrence. Liver 12:56–61 140. Cheng WS, Govindarajan S, Redeker AG (1992) Hepatocellular carcinoma in a case of Wilson’s disease. Liver 12:42–45 Chapter 2 Biology of Hepatocellular Carcinoma Maria Luisa Balmer and Jean-François Dufour Keywords Angiogenesis · Apoptosis · HCC · Metastasis · miRNA · Oncogene · Stem cells · Telomeres From Genotype to Phenotype – Or What a Cell Needs to Become a Cancer Cell Being a cancer cell is not easy. You have to maintain DNA replication and protein production under adverse conditions in the abnormal architecture of a tumour which often deprives you of oxygen and nutrients. Thus, survival requires a complete kit of stress response tools that you have to acquire before becoming a cancer cell. From a more scientific point of view, we can see tumorigenesis as fast-track evolution in miniature edition where genetic alterations drive the progressive trans- formation of normal human cells into highly malignant derivates that seem to be advantageous to their normal counterparts. Investigations have been conducted at different molecular levels including DNA level, RNA level and protein level, with regard to chromosomal imbalance and genetic instability, epigenetic alteration, gene expression and gene regulation and translation [1]. Whatever the level, can- cer cells need to acquire a combination of properties which typify their malignant phenotype in the end (Fig. 2.1). Six essential alterations in cell physiology that col- lectively dictate malignant growth have been proposed: self-sufficiency in growth signals, insensitivity to growth inhibition (antigrowth), evasion of programmed cell death (apoptosis), limitless replicative potential, sustained angiogenesis and tissue invasion and metastasis [2]. In this chapter we briefly discuss these six properties as they are common in most cancers, including HCC. J F. Dufour (B) Department of Clinical Pharmacology and Visceral Research, University of Bern, Bern, Switzerland 21 K.M. McMasters, J N. Vauthey (eds.), Hepatocellular Carcinoma, DOI 10.1007/978-1-60327-522-4_2, C  Springer Science+Business Media, LLC 2011 22 M.L. Balmer and J F. Dufour Fig. 2.1 The long and winding road to cancer Growth signals are essential to move a cell from its quiescent state into an active proliferative state. Cancer cells generate many of their own growth signals, thereby reducing their dependence on stimulation from their normal tissue environment. This can happen by synthesis of their own growth signals (autocrine stimula- tion), growth factor receptor overexpression, ligand-independent signalling through structural alteration of receptors and alterations in components of the downstream cytoplasmic circuitry that receives and processes the signals emitted by ligand- activated growth factor receptors and integrins. Tumour development is not only the result of selection of a genetically mutated population of cells with advanta- geous capabilities but rather the result of a tiny communication between the altered cancer cell and its unaltered neighbours such as fibroblasts, endothelial cells and inflammatory cells which maintain tumour growth. Within a normal tissue, multiple antiproliferative signals operate to maintain cel- lular quiescence and tissue homeostasis. These growth-inhibitory signals, like their positive counterparts, are received by transmembrane surface receptors coupled to intracellular signalling circuits. At the molecular level, many antiproliferative sig- nals are funnelled through the retinoblastoma protein (pRb) and its two relatives, p107 and p130, which block proliferation by inhibiting progression from G1- into S-phase of the cell cycle [3]. The pRb signalling circuit, as governed by TGFβ and other extrinsic factors, can be disrupted in a variety of ways: some cancer cells display mutant, dysfunctional receptors while others lose TGFβ responsiveness through downregulation of their TGFβ receptor. Apoptosis represents a physiological way to eliminate excess cells during both development and regeneration. Apoptosis can be triggered by an extrinsic pathway (death receptor associated) as well as an intrinsic pathway (mitochondria pathway), both of which might be inactivated during tumour development. Resistance to apop- tosis can be acquired by cancer cells through a variety of strategies. Surely, the most commonly occurring loss of a pro-apoptotic regulator through mutation involves the 2 Biology of Hepatocellular Carcinoma 23 p53 tumour suppressor gene. The resulting functional inactivation of its product, the p53 protein, is seen in greater than 50% of human cancers and results in the removal of a key component of the DNA damage sensor that can induce the apoptotic effector cascade [4]. Many and perhaps all types of mammalian cells carry an intrinsic, cell- autonomous program that limits their multiplication and stops their growth. Tumour cells have to exhaust their endowment of allowed doublings and breach the mortality barrier to acquire unlimited replicative potential. Telomeres, which are composed of several thousand repeats of a short six base-pair sequence element, and which are shortened in each cell doubling, limit one cell’s lifetime. Therefore, telomere maintenance either by upregulating expression of the telomerase enzyme [5]orby recombination-based interchromosomal exchanges of sequence information [6]is evident in virtually all types of malignant cells. By one or the other mechanism, telomeres are maintained at a length above a critical threshold, and this in turn permits unlimited multiplication of descendant cells. The oxygen and nutrients supplied by the vasculature are critical for cell func- tion and survival. Thus tumours need to induce blood vessel formation to maintain growth and viability. One common strategy is increased expression of angiogen- esis inducers as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) or downregulation of angiogenesis inhibitors as thrombospondin-1 or β-interferon. The development of cancer metastasis is a highly complex event, involving the generation of new blood and lymph vessels, growth, invasion with breakdown and cross talk of the host matrix, escape from immune surveillance, transport to other sites with adhesion, and subsequent invasion of the organ that hosts the metasta- sis. Several participants in this tightly orchestrated procedure are important, for instance cell-adhesion molecules, signalling pathways, immune cells, enzymes and receptors, acting all in concert to guide the tumour cell to its new home. To reach the six capabilities necessary for survival, you have to be highly selected as a cancer cell. Genomic instability, altered transcription and translation, deregulated protein synthesis all act in concert to equip you with the necessary armamentarium to reach the cancer phenotype. Biological Features of Liver Cancer – The Hallmark of Hepatocellular Carcinoma Usually, HCC arises as a consequence of underlying liver diseases such as viral hepatitis and liver cirrhosis. Highly variable clinical phenotypes in HCC patients indicate that HCC comprises several biologically distinctive patterns. Patients can be categorized in subgroups by different grades of differentiation, proliferation rates, ability to invade vessels, potential for metastasis, sensitivity to chemotherapeutic agents, etc. [7]. When the liver gets injured by factors like HBV/HCV, alcohol or aflatoxin B1, necrosis will appear in the liver accompanied by the subsequent 24 M.L. Balmer and J F. Dufour hepatocyte proliferation. After continuous cycles of destructive–regenerative process accumulate to some extent, the liver will suffer from cirrhosis. The main characteristic of cirrhosis is that abnormal nodules appear in the liver surrounded by collagens and scarring. Subsequently, the hyperplastic nodules will turn into dys- plastic nodules (DNs) inducing a high risk of developing HCC for those patients [8]. DNs are classified into low grade and high grade according to cytological and architectural atypia on microscopic examination [9]. One-third of high-grade DNs will progress to HCC in 2 years, and the rate increases to 81% in 5 years [10]. Coming back to the introduced route of cancer development, HCC phenotype can result as a consequence of different alterations on different molecular levels. The observed genetic aberrations associated with HCC include the amplification or deletion of chromosomal regions, copy number changes of genes and abnormal epi- genetic alterations. Chromosomal amplification regions often harbour oncogenes, whereas the chromosomal deletion regions often include tumour suppressor genes, both conferring a growth advantage for tumorigenesis in HCC [11]. These aber- rations can be caused by different environmental factors like virus infection and alcohol and/or aflatoxin consumption [12, 13]. Epigenetic modifications refer to changes in DNA/chromatin that do not involve changes in the DNA sequence, for instance DNA methylation or histone modifications. A number of studies have indi- cated that promoter hypermethylation may be a key mechanism involved in the inactivation of some tumour suppressor genes in HCC [1]. Changes in the expres- sion of many genes are also evident at both mRNA and protein levels. Such changes can be the consequences of the genetic aberrations and environmental interactions. As a complex disease, the genesis and development of HCC could not be decided by a single factor or a simple collection of single factors, but rather by interactions of multiple proteins, genes and miRNAs in biological pathways. Furthermore, signif- icant and complex cross talks among the different pathways exist and are involved in different aspects of HCC development and progression. These cross talks, largely not understood at the molecular level, could potentially account for the resistance to molecularly targeted drugs, which are able to hit pathways only at one or few sites [14]. In this section, we discuss the hallmarks of liver cancer which are important for diagnosis and treatment of the disease. Liver Stem Cells Stem cells are generally characterized by their capacity for self-renewal through asymmetrical cell division, multipotency for producing progeny in at least two lineages, long-term tissue reconstitution, and serial transplantability [15]. When mature hepatocytes and cholangiocytes are damaged or inhibited in their replication a reserve compartment of hepatic progenitor cells located within the intrahepatic bil- iary tree is activated [16]. The activation of this stem cell compartment is observed in circumstances of prolonged necrosis, cirrhosis and chronic inflammatory liver . Epidemiology and Pathogenesis of Hepatocellular Carcinoma 15 51. Vineis P, Pirastu R (1997) Aromatic amines and cancer. Cancer Causes Control 8:346–355 52. Hecht SS (1998) Biochemistry, biology, and carcinogenicity. aflatox- ins, and hepatocellular carcinoma in southern Guangxi, China. Cancer Res 49:2506–2509 60. Maheshwari S, Sarraj A, Kramer J, El-Serag HB (2007) Oral contraception and the risk of hepatocellular. Synergism of alcohol, diabetes, and viral hepatitis on the risk of hepatocellular carcinoma in blacks and whites in the U.S. Cancer 101:1009–1017 16 M.M. Hassan and A.O. Kaseb 73. Yu MC, Tong