Molecular therapy and prevention of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in some areas of the worldwith an extremely poor prognosis. The major etiologic risk factors for HCC development include hepatitis Bvirus (HBV) and hepatitis C virus (HCV) infection, toxins (alcohol, aflatoxin BI) and variousinherited metabolic liver diseases, such as hemochromatosis and alpha-1-antitrypsin deficiency. Central to the molecular pathogenesis of HCC are mutations of various genes and genetic/chromosomalinstability that result from chronic liver disease and the associated enhanced liver cell regeneration andmitotic activity. Alterations in the structure or expression of several tumor suppressor genes and oncogeneshave been described. In addition, mechanisms leading to genetic instability due to mismatch repairdeficiency or chromosomal instability and aneuploidy due to defective chromosomal segregation appear tobe involved. The prognosis of HCC patients is generally very poor. Most studies have shown a five-year survivalrate of less than 5% in symptomatic patients. HCC has been found to be quite resistant to radio- orchemotherapy. Investigations of the natural history and clinical course of HCC revealed a long-termsurvival of patients only with small asymptomatic HCC that could be treated surgically or nonsurgically.For patients with advanced symptomatic HCC, novel therapeutic strategies such as gene therapy areurgently needed. Apart from exploring and refining new HCC treatment strategies, the implementation of the existingmeasures or the development of novel measures to prevent HCC is most important. Primary HCCprevention could have a major impact on the incidence of HCC. Further, secondary prevention of a localrecurrence or of new HCC lesions in patients after successful surgical or nonsurgical HCC treatment is ofparamount importance and is expected to significantly improve disease-free and overall survival rates ofpatients. Based on rapid scientific advances, molecular diagnosis, gene therapy and molecular prevention arebecoming increasingly part of our patient management and will eventually complement or in part replacethe existing diagnostic, therapeutic and preventive strategies. Overall, this should result in a reducedHCC incidence and an improved clinical outcome for patients with HCC, one of the most devastatingmalignancies worldwide.