The incidence ranges from 10 cases per 100,000 population in North America and western Europe to 50-150 cases per 100,000 population in parts of Africa and Asia where HCC is responsible for a large proportion of cancer deaths. A rise in the incidence and mortality from HCC has recently been observed in most industrialized countries. 3 This likely reflects the increased prevalence of hepatitis C virus (HCV) infection. 4, 5 In addition, with the obesity epidemic and increased incidence of Type II diabetes and insulin resistance, the emergence of non-alcoholic steatohepatitis (NASH) has begun to assume a larger role in the pathogenesis due to the development of cirrhosis, a risk factor for HCC. Among health care professionals, there is widespread concern regarding the increase in HCC and the lack of optimal screening techniques that lead to delay in diagnosis and treatment. It is hoped that timely intervention may improve the prognosis of this almost uniformly fatal disease. The major etiologies of HCC are now well-defined and include chronic viral hepatitis B, C and D, toxins and drugs (eg, alcohol, aflatoxins, anabolic steroids), and metabolic liver diseases (eg, hereditary hemochromatosis, α1-antitrypsin deficiency). On a global scale, chronic hepatitis B (HBV) and C virus infection account for well over 90% of HCCs. 6 Indeed, the risk of the development of HCC is about 25-35 times higher among patients with chronic HBV infection compared to uninfected persons; coinfection with HBV and HCV increases this risk by 130-fold. 7 Another major clinical risk factor for HCC development is liver cirrhosis. In fact, 70% to 90% of HCCs develop in a liver with cirrhosis. 6 The HCC risk in patients with liver cirrhosis depends upon the activity, duration and etiology of the underlying liver disease. It is particularly high in cirrhosis resulting from chronic viral hepatitis and hemochromatosis, followed in descending order by alcoholic cirrhosis, autoimmune hepatitis, and primary biliary cirrhosis. The risk of HCC is low in Wilson’s disease. Coexistence of etiologies, such as HBV and HCV coinfection, HBV and aflatoxin B1, 3 or HCV and alcohol, increases the relative risk of developing HCC. 8 The molecular factors and interactions involved in hepatocarcinogenesis are still poorly understood. This is particularly true with respect to genomic mutations, as it has been difficult to identify common genetic changes in more than 20% to 30% of tumors. In fact, it is becoming clear that HCCs are genetically heterogenous tumors. Regardless of the etiology of liver disease, malignant transformation of hepatocytes may result from a sequence of increased liver cell turnover induced by chronic liver injury and regeneration in the context of inflammation and oxidative DNA damage. This raises the question as to what the processes are that regulate hepatocyte proliferation, migration, and survival. Advances in our understanding of the molecular pathogenesis of HCC has led to the identification of signal transduction pathways that are activated during hepatic transformation. 6 Two signal transduction cascades that appear to be very important are insulin/IGF-1/IRS-1/MAPK and Wnt/Frizzled/ß-catenin pathways as shown in Fig. 1. These pathways are activated early in over 90% of HCC tumors. This review will focus on the characteristics and biological consequences of enhanced activity of these pathways. We will present emerging evidence that HBV and HCV structural and non-structural proteins interact with and promote these cascades, ultimately leading to increased cell growth.

Abbreviations: HCC, hepatocellular carcinoma; HBV, hepatitis B virus; HCV, hepatitis C virus; NASH …