ABSTRACT
Tumorigenicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 605 15.8 Role of Secondary Genotoxicity during
Tobacco-Smoke-Induced Adaptation . . . . . . . . . . . . . . . . . . . . 608 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 612
A considerable amount of experimental data supports the concept that the pathogenesis of human lung cancer is dependent upon the sequential alteration of oncogenes and tumor suppressor genes, which, in turn, impact signaling pathways responsible for the regulation of cellular proliferation, differentiation, and apoptosis. Within this conceptual framework,
a number of specific gene and chromosomal changes have been associated with lung tumor formation, although the exact sequence and timing of these changes are yet to be elucidated. During the course of the last several years, our laboratory has engaged in a series of studies intended to expand current understanding of the molecular events contributing to toxicant-induced tumorigenicity. These efforts have benefited significantly through the application of experimental findings from mouse skin studies examining the multistage process of tobacco-smoke-induced tumor formation; specifically, the contribution of specific toxicants to the seemingly discrete yet complementary stages of initiation, promotion (including conversion and propagation), and progression. This chapter summarizes the current understanding of the molecular changes associated with lung tumorigenesis and proposes a model for the specific events contributing to this multistage process. This model is discussed in terms of an emerging theory that secondary (indirect) genotoxicity and eventual adaptation to toxicant-induced damage contribute significantly to lung tumor formation.
