Cell proliferation not associated with carcinogenesis in rodents and humans.

Cell proliferation has often been found to be associated with carcinogenesis in rodents and humans at different stages of the multistage carcinogenesis process. The multistage process includes initiation, promotion, and progression phases. At each phase, increasing the normal level of cell turnover of target cells may enhance carcinogenesis. However, we present evidence that normal levels of cell turnover, or increasing the rate of cell turnover at these different stages, do not necessarily lead to enhanced carcinogenesis. In normal tissues, the length of the cell cycle depends on the age of the host and varies from tissue to tissue. Tissues with normal short cell cycles, such as intestine and bone marrow, do not show a high rate of spontaneous tumors in most species. Cells with higher turnover should be more susceptible to carcinogens at the initiation stage of carcinogenesis if cell proliferation per se causes cancer and if these cells or their progeny survive. Cancer in humans is more often associated with specific etiological factors rather than with the natural proliferative rate of specific tissues. For many tissues of humans and rodents, age-related diseases develop in a progressive, irreversible manner. Often, naturally occurring chronic degenerative and inflammatory changes in a tissue (e.g., kidney, liver, heart, reproductive tract) lead to chronic regeneration of the damaged tissue. Yet, cancer is rarely found in these tissues. In rodent carcinogenesis experiments, chronic toxic lesions, accompanied by increases in normal levels of cell turnover, have sometimes been observed in target organs of nongenotoxic carcinogens. More often, however, organ-specific nongenotoxic toxins are not carcinogens. These toxins include compounds toxic for the liver, kidney, and nasal cavity. In 19 inhalation bioassays conducted by the National Toxicology Program, 5/5 nasal carcinogens and 12/14 nasal noncarcinogens caused nasal lesions usually associated with chronic cell proliferation. Although cell proliferation may contribute to multistage carcinogenesis, cell proliferation is not necessarily a tumor promoter or cocarcinogen.