Increased cell division as a cause of human cancer.

Carcinogenesis research is increasingly focused on chemicals that are not genotoxic and yet, at high doses, can induce cancer, apparently by increasing cell proliferation. We hypothesize that increased cell division per se stimulated by external or internal factors is also associated with the development of many human cancers. Although this hypothesis is well substantiated in the experimental literature, it has not been generalized as an important mechanism for carcinogenesis in human populations. Under this increased cell division model, the pathogenesis of cancer may result from molecular genetic errors induced during the process of cell division and from altered growth control of malignant or premalignant cells. Molecular genetic analysis of human cancers has shown that tumor cells contain multiple genetic defects including mutations, translocations, and amplifications of oncogenes and are reduced to homozygosity for putative tumor suppressor genes; these phenomena all require cell division for their occurrence and fixation. Increased cell division increases the risk of such events occurring. An accumulation of a combination of such genetic errors leads to a neoplastic phenotype. Examples are discussed of human cancers in which increased cell division, which drives the accumulation of genetic errors and can lead to neoplastic transformation, is caused by hormones, drugs, infectious agents, chemicals, physical or mechanical trauma, and other chronic irritation.