Although it has been long recognized that increased cell proliferation and neoplasia are related, it is only within the last decade that substantial emphasis has been placed on a potential role of cell proliferation itself in increasing the risk of neoplastic development (Croy, 1993). The present debate centers around whether cell proliferation itself is carcinogenic or whether it func- tions only as implied in our original definition of neoplasia (Chapter 2). Ames and colleagues (Ames and Gold, 1990a; Ames et al., 1993) have argued that mitogenesis is itself mutagenic and, in the presence of numerous real and potential opportunities for endogenous mutation, en- hances the risk for mutation far more than seen in a quiescent cell. Furthermore, during cell
Table 9.7 Enhancement of the Risk of Spontaneous Initiation and
Progression by Cell Proliferation
Increased risk of mutation during cell division
Enhanced chance for aneuploidy during mitosis
Enhancement of gene amplification at time of cell division (S phase) Alteration of cytosine methylation during S phase
division, single-stranded DNA does not have the protection of base-pairing or histones and thus is more sensitive to damage than double-stranded DNA. Finally, these authors argue that cell division triggers mitotic recombination, gene conversion, and nondisjunction while allowing gene duplication and loss of 5-methylcytosine in DNA. A summary of these factors is seen in Table 9.7. All of these processes can be directly related to karyotypic abnormalities seen in the stage of progression. Similarly, cytotoxicity occurring at extremely high doses of agents being tested for carcinogenicity (Chapter 13) causes lysosomal breakdown, chromosome aberrations, and DNA double-strand breaks, all of which are again related to the characteristics of progressor agents (Bradley et al., 1987). Biological modeling of specific experimental systems has also led to the conclusion that rates of cell proliferation are integral if not the key factor in carcinogenesis of the rodent bladder induced by chemical carcinogens (Cohen and Ellwein, 1991a). Further- more, a critical role for cell proliferation in carcinogenesis may be evidenced by the fact that a number of carcinogenic agents exhibit their carcinogenicity only when target cells are stimu- lated to divide and proliferate, usually as a result of toxicity induced by excessive doses of the test agent—e.g., exceeding the maximally tolerated dose (MTD) (Chapter 13). Furthermore, several studies (Table 9.8) have demonstrated a distinct correlation between the induction of cell proliferation as reflected in the labeling index (LI) and the development of neoplasia. Cunning- ham (1996) has similarly reported a positive association between increased cell proliferation and carcinogenesis.
On the other hand, several authors have argued that cell proliferation is not a major risk for neoplastic development (Weinstein, 1992; Farber, 1996; Melnick, 1992; Ward et al., 1993). In addition, arguments have been raised that chemical toxicity may not be a factor in the risk of
Table 9.8 Cell Proliferation Correlated with the Carcinogenic Effects of Chemicals
chemical carcinogenesis (Huff, 1993; Tennant et al., 1991; Hoel et al., 1988). Despite these res- ervations, however, it is difficult to argue that cell replication is not an inherent factor in carcino- genesis, although it is clear that a variety of other factors are also critical in the carcinogenic process. Furthermore, cell replication, as noted in the points made by Ames and colleagues (see above), enhances the risk of spontaneous initiation and progression as well as that induced by specific chemical, physical, or biological carcinogens. The enhanced cellular replication induced by promoting agents clearly suggests that a mutationally altered cell within an initiated clone has a greater risk of spontaneously entering the stage of progression than do normal cells derived from noninitiated cells. As seen above, cellular replication itself occurring during the stage of progression causes the continued evolution of karyotypic instability characteristic of and leading to greater degrees of malignancy.