Mechanisms of liver tumor promotion

Publisher Summary Hepatocellular carcinomas (HCC) are among the most common malignancies in the world with tumor incidence approaching 150 per 100,000 per year in areas, such as China. Although the incidence of liver cancer is lower in the United States, 60% of the chemicals determined by the National Toxicology Program to be carcinogens, give rise to liver tumors in rats and mice. A number of these agents appear to function through tumor promoting rather than initiating mechanisms. Consequently, to appropriately assess the risk these xenobiotic agents pose to humans, it is necessary to determine the molecular events by which liver tumor promoters enhance the formation of HCC. This chapter provides evidence that liver tumor promotion by phenobarbital (PB) and possibly other tumor promoting agents is a process of natural selection for cells resistant to the growth inhibitory environment produced by the tumor promoter. Moreover, experimental results with PB suggest that relative increases in the expression of the M6P/IGF2r, the TGFβ receptors, and TGFβ1 in normal versus initiated hepatocytes establish the growth inhibitory pressure in the liver required for promoting agents to selectively enhance the formation of liver tumors. The concept of liver tumor promotion being a process of natural selection for a resistant phenotype has now given rise to a new risk assessment model based on negative selection, which may better predict the carcinogenic risk that chemical agents pose to humans.