Nongenotoxic Carcinogenesis

Abstract

A number of compounds can increase the incidence of neoplasms relative to that observed in appropriate controls. These agents are labeled as carcinogens, although this effect is context-dependent. Certain agents increase the incidence of cancer by directly interacting with the genetic material or through its regulation. A number of compounds do not directly interact with the genetic material, yet they can increase the incidence of neoplasms under selected exposure conditions in appropriate animal models. Agents that are carcinogenic through nongenotoxic mechanisms display a threshold, are reversible in the early stages, and perturb gene expression. Some of these agents act by altering the processes involved in cell proliferation, apoptosis, and differentiation. The liver has been extensively used as a model system to assess the mechanisms and processes involved in chemically induced carcinogenesis. The logical target of direct-acting carcinogens is the diploid population of hepatocytes. Many agents are able to alter cell proliferation or apoptosis and lead to a selective increase in the putatively preneoplastic population in the liver. Many of these nongenotoxic compounds may alter the growth of the preneoplastic cells in the liver resulting in their outgrowth. Perturbation of the ploidization process through modulation of hormonal control of this cell population provides an important mechanism in the development of preneoplastic and ultimately neoplastic lesions through a nongenotoxic mechanism. These promoting agents tend to act in a tissue-specific and sometimes in a species-specific manner. Understanding the relevance of the mechanism of perturbation of the outgrowth of preneoplastic cells in response to nongenotoxic agents is necessary to understand under what conditions of exposure they provide a risk of enhanced cancer development.