Cell Proliferation and Cell Death in Rat Liver Carcinogenesis by Chemicals

Abstract

Cell proliferation has often been implicated to play a critical role in the carcinogenic process. In the liver, for example, it is believed that at least one round of cell division is necessary for the accomplishment of the first step of the carcinogenic process, initiation, probably by allowing fixation of carcinogen-induced critical lesions into the newly made DNA (Cayama et al. 1978; Ishikawa et al. 1980; Columbano et al. 1981). In the promotion stage, enhanced cell division may be a stimulus for a clonal expansion of initiated hepatocyte (Pound and McGuire 1978a; Dragani et al. 1986; Farber and Sarma 1987; Columbano et al. 1990). The finding that several non-genotoxic agents which induce hepatic growth also induce liver tumor formation, has renewed interest about the role of cell proliferation in tumor development (Rao and Reddy 1987; Mirsalis 1987; Marsman et al. 1988;). Thus, in the past few years the manner of conducting and interpreting rodent cancer biossays (based on treatment of the animals with the Maximum Tolerated Dose (MTD), has been criticized because chemically-induced cell proliferation is often seen at the MTD. It has been postulated that this increased proliferation per se plays a major role in tumor formation and that doses that do not induce cell proliferation would not be carcinogenic (Ames and Gold 1990; Cohen and Ellwein 1990).