Chemopreventive strategies in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer. The incidence and mortality of HCC are increasing in most Western countries as a result of an ageing cohort infected with chronic hepatitis C, and are expected to continue to rise as a consequence of the obesity epidemic. Chemopreventive strategies aimed at decreasing the risk or delaying the onset of HCC are needed. Universal immunization against HBV and antiviral therapy against HBV and HCV in patients with established disease has consistently been associated with reduced HCC risk, especially in patients who achieve sustained virologic response. However, the cost-effectiveness of antiviral therapy for primary HCC prevention is not known. Several commonly prescribed medications seem promising as chemopreventive agents against HCC, including statins, antidiabetic medications and aspirin. Dietary agents such as coffee, vitamin E and fish oil as well as phytochemicals might also be associated with reduced risk of HCC. Though randomized controlled trials are ideally needed to firmly establish efficacy, such chemoprevention trials are logistically and ethically challenging. Well-designed, prospective, population-based cohort studies might provide the best evidence for chemopreventive efficacy of these agents.

Figure 1

Pathogenesis of HCC and targets for chemopreventive agents. Receptor tyrosine kinase pathways induce MAPK and PI3K–Akt kinase signalling pathways in >50% of HCCs. Activation of the PI3K–Akt kinase signalling pathway results in disruption of the mTOR pathway, which is seen in 40–50% of cases of HCC, leading to inactivation of tumour suppressors such as PTEN, and promoting carcinogenesis. Statins prevent post-translational prenylation of signalling Ras/ Raf proteins, inhibit the activation of the proteasome pathway, limiting the degradation of the cyclin-dependent kinase inhibitors p21 and p27, and block Myc phosphorylation and activation, suppressing tumour initiation and growth. Metformin activates AMPK, which inhibits the mTOR pathway. Thiazolidinediones also exert anticancer effects through inhibition of the ubiquitin-proteasome system and extracellular signal-regulated kinase pathway. Antiplatelet agents, such as aspirin, decrease T-cell-mediated inflammation through inhibition of cyclo-oxygenase-2, decreasing severity of fibrosis and progression to HCC. Insulin and sulphonylureas might promote hepatocarcinogenesis by increasing IGFR1 activity, resulting in abnormal stimulation of multiple cellular signalling cascades, enhancing growth-factor-dependent cell proliferation and affecting cell metabolism. Cirrhotic-stage HCV and HBV infection leaves the liver prone to the development of activating mutations in oncogenes and inactivating genetic and epigenetic suppression of tumour suppressor genes. Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; HCC, hepatocellular carcinoma; IGFR1, insulin-like growth factor receptor 1; IR, insulin receptor; MAPK, Ras mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; PPAR-γ, peroxisome proliferator activated receptor γ.

Figure 2

Proposed algorithm for chemoprevention in patients at risk of hepatocellular carcinoma. *On the basis of AASLD guidelines;^{, ‡}on the basis of ATP III guidelines for management of hyperlipidaemia; ^§on the basis of USPSTF guidelines for prevention of cardiovascular disease. Abbreviations: AASLD, American Association for the Study of Liver Diseases; ATP III, Adult Treatment Panel III; TZD, thiazolidinediones; USPSTF, United States Preventive Services Task Force.