講座內(nèi)容：Current models of carcinogenesis are dominated by the assumption that oncogenic mutations have defined advantageous fitness effects on recipient stem and progenitor cells, promoting and rate-limiting somatic evolution. However, this assumption is markedly discrepant with evolutionary theory, whereby fitness is a dynamic property of a phenotype imposed upon and widely modulated by environment. We have used been using mouse models of cancer initiation, mathematical models of clonal evolution, and analyses of mutational processes in humans to better understand the evolutionary forces that control somatic cell evolution and thus cancer risk. These studies support a model whereby the primary causes of cancer, such as old age and cigarette smoking, link to increased risk for cancer through their impacts on tissue microenvironments. In particular, our studies support a key role for age or insult mediated increases in inflammation in altering selection for cancer-associated mutations. These studies indicate that strategies to prevent or treat cancers will need to incorporate interventions that alter tissue microenvironments. While we largely cannot prevent mutation accumulation through our lives, we do have the ability to manipulate tissue microenvironments so as to change the evolutionary trajectories of oncogenically-mutated cells.