Carcinogen

Translated literally, the term “carcinogen” means giving rise to carcinomas, or epithelial malignancies. In practice, “carcinogen” is used to describe any physical or chemical agent that increases the incidence of tumors in animal models or in human populations. Chemical carcinogens are a diverse group of agents with a range of properties. Much of the early work on carcinogenesis in animal models identified two stages: tumor initiation, thought to involve a mutational event, and tumor promotion, which probably did not. Although this classification of events is still useful in animal studies, it is now recognized as an oversimplification. Cancer develops through a series of stages, which have been exceptionally well-characterized in certain cancers such as those of the colon (1). (An historic perspective on the development of understanding the nature of carcinogenesis is given by Harris (2)). Many of the steps in carcinogenesis involve either mutations or epigenetic changes, with cells gaining a selective advantage and undergoing clonal expansion as a result of activation of protooncogenes and/or inactivation of tumor suppressor genes. “Epigenetic” is defined as “all processes relating to the expression (transcription and translation) and the interaction of the genetic material. Epigenetic mechanisms may act at three levels of cell organization: (1) Turn genes off or modulate protein biosynthesis, (2) regulate the translation of messenger RNA into proteins, and (3) regulate the topographic distribution and function of proteins.” (3). Metastatic spread of the cancer involves the activation of further oncogenes controlling various aspects of cell adhesion and movement. A scheme showing some of the events involved in various stages of cancer development is shown in Figure 1.

Figure 1. Factors involved in the various stages of carcinogenesis.

Mutagenicity is the major mechanism for the activation of proto-oncogenes, and most carcinogens are also mutagens. Miller and Miller (4) claimed that the property in common to all the diverse carcinogens is that they either interact directly with DNA or can be metabolically activated to nucleophilic intermediates that are reactive with DNA. While this is certainly true for most carcinogens, there is increasing recognition that not all carcinogens are DNA reactive. For example, inhibitors of topoisomerase II enzymes have been shown to induce human cancers (5), and these act to cause DNA breaks indirectly by poisoning the enzyme. A number of carcinogens may act through epigenetic mechanisms. There is also a class of carcinogens that have no action at all on the genetic material (eg, peroxisome proliferators, which are thought to work through receptor binding and modification of fatty acid metabolism (6)).

While there is no doubt that mutagenic mechanisms are involved in carcinogenesis, there is considerable doubt as to the relative roles of exogenous and endogenous mutagens in the development of human cancers. Exogenous mutagens include alkylating chemicals such as nitrogen mustards and nitrosamines, usually encountered in cancer therapy, and industrial chemicals such as vinyl chloride, dimethyl sulfate, and bis(chloromethyl) ether. Prominent endogenous mutagenic processes include oxy-radical DNA damage, DNA depurination, DNA polymerase infidelity, and deamination of 5-methylcytosine.

References

1. B. Vogelstein, E. R. Fearon, S. R. Hamilton, S. E. Kern et al. (1988) N. Engl. J. Med. 319, 525–532.

2. C. C. Harris (1991) Cancer Res. 51 (Suppl.), 5023s–5044s. 

3. R. Reiger, A. Michaelis, and M. M. Green (1991) Glossary of Genetics: Classical and Molecular. Springer-Verlag, New York. 

4. E. C. Miller and J. A. Miller (1966) Pharmacol. Rev. 18, 805. 

5. L. R. Ferguson and B. C. Baguley (1994) Environ. Mol. Mutagen. 24, 245–261. 

6. S. Green (1995) Mutat. Res. 333, 101–109.