Primary Liver Cancer: Chemical Carcinogenesis

Abstract

AbstractLiver cancer is an important form of cancer worldwide ranking in the top ten in both incidence and mortality (1). Over 200,000 new cases of primary hepatocellular carcinoma are diagnosed worldwide each year (1). The American Cancer Society predicts over 22,000 new cases of liver and bile duct cancer and that nearly 18,000 individuals will die of this disease in the year 2009 (2). In the United States and Europe, primary liver cancer is fairly rare, but in some parts of the world, it is the primary type of cancer observed (1). Environmental influences, including carcinogen exposure, are believed to contribute to its distinct geographical distribution pattern (3). Although rare genetic disorders can contribute to liver cancer development, ethanol and dietary factors are known to contribute to its incidence and progression (3). The prevalence of liver cancer and its high mortality rate indicates the need for appropriate animal models of this disease in order to develop treatment and intervention strategies. In addition, the liver is the primary site for cancer induction in the bioassays used for carcinogen testing indicating the necessity for extrapolation of neoplasms that arise at this site in animals to man. The utility of defining common biomarkers for the conversion of benign to malignant transition will assist in developing appropriate inter-species extrapolation for risk assessment. The inclusion of early lesions from preclinical models will permit assessment of the ability of methods to develop appropriate risk assessment. In addition, analysis of liver cancer development is a useful model for study of the carcinogenic process of solid tumors that arise in both humans and animals. The influence of genetic background and environmental factors on neoplastic development is readily studied in rodent models of this disease.While genetic factors can contribute to primary liver cancer development, environmental factors have an important role in human liver cancer development. The liver is exposed to ingested materials and has a high level of metabolism. The liver is susceptible to liver cancer development by chemicals and rodent liver has been used as a model to understand the role that chemicals play in liver cancer development and progression. In the human, cirrhosis is an important contributor to most primary liver cancer development. Viral hepatitis can lead to cirrhosis and certain chemical exposures to contribute to this baseline liver disease and can exacerbate the potential for liver cancer. These include aflatoxin, ethanol, and potentially other dietary constituents (limited antioxidant intake (selenium, Vitamin E), iron excess, and others). Ethanol and NASH can contribute to the development of cirrhosis and likewise can lead to HCC development. Chemicals that can increase the incidence of neoplasms in animals can be classified into genotoxic and nongenotoxic modes of action. The effects of agents with a carcinogenic potential are dose dependent. Understanding the biological basis of the changes that occur during the cancer induction and progression process, as well as the changes that chemicals induce in the liver will improve our knowledge of the steps and stages in the pathogenesis of primary liver cancer.Key WordsChemical carcinogensprimary liver cancerHCCgenotoxinsnongenotoxins