The FASEB Journal, Vol 5, 2280-2286, Copyright © 1991 by The Federation of American Societies for Experimental Biology

REVIEWS

Facts and theories concerning the mechanisms of carcinogenesis

HC Pitot and YP Dragan
Department of Oncology, McArdle Laboratory for Cancer Research, University of Wisconsin, Madison 53706.

Carcinogenesis can be induced experimentally by exposure to exogenous agents or it can occur spontaneously without intentional or active intervention. Carcinogenesis can be actively induced by chemicals, radiation, infectious biological agents, transgenesis, or selective breeding. In the human and occasionally when testing potential carcinogens in animals, cancer may result from passive exposure to carcinogens encountered in the ambient environment or from changes in the internal milieu of the animal. Many carcinogens alter the structure of DNA resulting in carcinogenesis, but a significant number of carcinogens do not appear to act through this mechanism. When the action of specific carcinogenic agents is considered in relation to the stages of cancer development, initiation, promotion, and progression, the mechanism of the induction of carcinogenesis by DNA-reactive agents that alter genomic structure can be reconciled with those agents that do not act in this manner. As some cells are fortuitously initiated by uncontrolled variables such as irradiation and through changes in normal processes, the stimulation of growth and altered genetic expression by nongenotoxic agents may result indirectly in cancer development. The final stage of carcinogenesis, progression, can occur spontaneously, enhanced by formation and propagation of genetic errors due to increased cellular proliferation associated with the promotion stage. In addition, chemical and viral agents that lack the capacity for initiation and promotion may actively convert cells in the stage of promotion to the stage of progression. Therefore, the diverse mechanisms of action of carcinogenic agents in relation to their effects on specific stages in the natural history of cancer development allow for greater congruence of many of the theories of carcinogenesis. The influence of the roles of nongenotoxic carcinogenic agents and the potential role of progressor agents on the carcinogenesis process allow a more accurate identification of the potential risk that specific carcinogenic agents pose for increasing human cancer.

This article has been cited by other articles:

				N. Omidvar, S. Kogan, S. Beurlet, C. le Pogam, A. Janin, R. West, M.-E. Noguera, M. Reboul, A. Soulie, C. Leboeuf, et al. BCL-2 and Mutant NRAS Interact Physically and Functionally in a Mouse Model of Progressive Myelodysplasia Cancer Res., December 15, 2007; 67(24): 11657 - 11667. [Abstract] [Full Text] [PDF]

				M.-H. Tai, C.-C. Chang, L.K. Olson, and J. E. Trosko Oct4 expression in adult human stem cells: evidence in support of the stem cell theory of carcinogenesis Carcinogenesis, February 1, 2005; 26(2): 495 - 502. [Abstract] [Full Text] [PDF]

				T. Imai, J.-I. Onose, M. Hasumura, M. Ueda, T. Takizawa, and M. Hirose Sequential Analysis of Development of Invasive Thyroid Follicular Cell Carcinomas in Inflamed Capsular Regions of Rats Treated with Sulfadimethoxine after N-bis(2-hydroxypropyl)nitrosamine-initiation Toxicol Pathol, February 1, 2004; 32(2): 229 - 236. [Abstract] [PDF]

				R. E. Watson, G. M. Curtin, D. J. Doolittle, and J. I. Goodman Progressive Alterations in Global and GC-Rich DNA Methylation during Tumorigenesis Toxicol. Sci., October 1, 2003; 75(2): 289 - 299. [Abstract] [Full Text] [PDF]

				P. J Villeneuve, D. A Agnew, K. C Johnson, and Y. Mao Brain cancer and occupational exposure to magnetic fields among men: results from a Canadian population-based case-control study Int. J. Epidemiol., February 1, 2002; 31(1): 210 - 217. [Abstract] [Full Text] [PDF]

				J. I. Goodman Operational Reversibility is a Key Aspect of Carcinogenesis Toxicol. Sci., December 1, 2001; 64(2): 147 - 148. [Abstract] [Full Text] [PDF]

				B. Grasl-Kraupp, G. Luebeck, A. Wagner, A. Low-Baselli, M. de Gunst, T. Waldhor, S. Moolgavkar, and R. Schulte-Hermann Quantitative analysis of tumor initiation in rat liver: role of cell replication and cell death (apoptosis) Carcinogenesis, July 1, 2000; 21(7): 1411 - 1421. [Abstract] [Full Text] [PDF]

				P. J Villeneuve, D. A Agnew, A. B Miller, and P. N Corey Non-Hodgkin's lymphoma among electric utility workers in Ontario: the evaluation of alternate indices of exposure to 60 Hz electric and magnetic fields Occup. Environ. Med., April 1, 2000; 57(4): 249 - 257. [Abstract] [Full Text]

				A. Low-Baselli, K. Hufnagl, W. Parzefall, R. Schulte-Hermann, and B. Grasl-Kraupp Initiated rat hepatocytes in primary culture: a novel tool to study alterations in growth control during the first stage of carcinogenesis Carcinogenesis, January 1, 2000; 21(1): 79 - 86. [Abstract] [Full Text] [PDF]