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Departments of Preventive Medicine [S. P-M., M. C. P., R. K. R., B. E. H.], and Biochemistry [P. A. J.], University of Southern California School of Medicine, Los Angeles, California 90033
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.
1 This work was supported in part by Awards FRA-329 and SIG-2 from the American Cancer Society and Grant 5-P30Ca14089 from the National Cancer Institute. We wish to acknowledge the role of the Cancer Surveillance Program in identifying cases for several of the studies cited; this program is supported by Grants 050E-8709 from the State of California and CA17054 from the NIH.
2 To whom requests for reprints should be addressed.
Received 6/ 7/90. Accepted 8/30/90.
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