Roles of phenotypic heterogeneity and microenvironment feedback in early tumor development.

The local microenvironment of a tumor plays an important and commonly observed role in cancer development and progression. Dynamic changes in the tissue microenvironment are thought to epigenetically disrupt healthy cellular phenotypes and drive cancer incidence. Despite the experimental work in this area there are no conceptual models to understand the interplay between the epigenetic dysregulation in the microenvironment of early tumors and the appearance of cancer driver mutations. Here, we develop a minimal model of the tissue microenvironment which considers three interacting subpopulations: healthy, phenotypically dysregulated, and mutated cancer cells. Healthy cells can epigenetically (reversibly) transition to the dysregulated phenotype, and from there to the cancer state. The epigenetic transition rates of noncancer cells can be influenced by the number of cancer cells in the microenvironment (termed microenvironment feedback). Our model delineates the regime in which microenvironment feedback accelerates the rate of cancer initiation. In addition, the model shows when and how microenvironment feedback may inhibit cancer progression. We discuss how our framework may provide resolution to some of the puzzling experimental observations of slow cancer progression.