Preneoplastic lesions in kidney and carcinogenesis by non-genotoxic compounds.

Abstract

Carcinogenesis is known to be a multistep process which involves two or more genetic events and requires cell proliferation (Pitot 1986; Barrett and Wiseman 1987; Farber and Sarma 1987; Knudson 1987; Cerutti 1988; Lutz 1990). The genetic events can result from point mutations, chromosomal rearrangements (Croce and Klein 1990), insertions or deletions of genes, and gene amplification. Cell replication is required to convert DNA damage to mutations, irrespective of whether this damage is occurring spontaneously or induced by DNA damaging (genotoxic) compounds. Spontaneous mutations are assumed to stem from spontaneous genetic events such as depurination and deamination of DNA, formation of covalent DNA adducts by physiological reactive cellular constituents, DNA damage by oxygen free radicals produced in cellular metabolism, errors in DNA replication (Loeb 1989). Normally the cell has the possibility to either repair the damaged DNA, or, if the damage is irrepairable, to destroy itself via tumor suppressor gene product (e.g. p53) mediated apoptosis (Lane 1993). Abrogated DNA repair or apoptosis of damaged cells in conjunction with a cell proliferative stimulus can lead to the formation of clusters of mutated cells and clonal expansion. Continued enhanced proliferation and expansion of such clones increases the probability of additional genetic events within these populations (Knudson 1987) thus providing a basis for the formation of preneoplastic lesions and progression to veritable tumors (Swenberg et al. 1987; Dietrich and Swenberg 1991b). Although the sequence of events described above appears reasonable, little direct evidence has been put forward so far. However, some corroboration is provided by the observation that control animals from strains of laboratory rodents present with an appreciable incidence of spontaneous preneoplastic lesions and tumors (Dietrich and Swenberg 1991b). The incidence of spontaneous tumors varies greatly from tissue to tissue, strain to strain, sex to sex, and species to species (Swenberg and Short 1987).