EVOLUTIONARY DYNAMICS IN CARCINOGENESIS

We have previously demonstrated intra- and extra-cellular factors that govern somatic evolution of the malignant phenotype can be modeled through evolutionary game theory, a mathematical approach that analyzes phenotypic adaptation to in-vivo environmental selection forces. Here we examine the global evolutionary dynamics that control evolutionary dynamics explicitly addressing conflicting data and hypothesis regarding the relative importance of the mutator phenotype and microenvironment controls. We find evolution of invasive cancer follows a biphasic pattern. The first phase occurs within normal tissue, which possesses a remarkable adaptive landscape that permits non-competitive coexistence of multiple cellular populations but renders it vulnerable to invasion. When random genetic mutations produce a fitter phenotype, self-limited clonal expansion is observed — equivalent to a polyp or nevus. This step corresponds to tumor initiation in classical skin carcinogenesis experiments because the mutant population deforms the adaptive landscape resulting in the emergence of unoccupied fitness peaks — a premalignant configuration because, over time, extant cellular populations will tend to evolve toward available fitness maxima forming an invasive cancer. We demonstrate that this phase is governed by intracellular processes, such as the mutation rate, that promote phenotypic diversity and environmental factors that control cellular selection and population growth. These results provide an integrative model of carcinogenesis that incorporates cell-centric approaches such as the mutator phenotype hypothesis with the critical role of the environmental demonstrated by Bissell and others. The biphasic dynamics of carcinogenesis give a quantitative framework of understanding for the empirically observed initiation and promotion/progression stages in skin carcinogenesis experimental models.