Stem Cell Self-Renewal and Cancer Cell Proliferation Are Regulated by Common Networks That Balance the Activation of Proto-oncogenes and Tumor Suppressors

Abstract

Networks of proto-oncogenes and tumor suppressors that control cancer cell proliferation also regulate stem cell self-renewaland possibly stem cell aging. Proto-oncogenes promote regenerative capacity by promoting stem cell function but must bebalanced with tumor suppressor activity to avoid neoplastic proliferation. Conversely, tumor suppressors inhibit regenerativecapacity by promoting cell death or senescence in stem cells. For example, the polycomb family proto-oncogene, Bmi-1, isconsistently required for the self-renewal of diverse adult stem cells, as well as for the proliferation of cancer cells in the sametissues. Bmi-1 promotes stem cell self-renewal partly by repressing the expression of Ink4a and Arf, tumor suppressor genesthat are commonly deleted in cancer. Despite ongoing Bmi-1 expression, Ink4a expression increases with age, potentiallyreducing stem cell frequency and function. Increased tumor suppressor activity during aging therefore may partly account forage-related declines in stem cell function. Thus, networks of proto-oncogenes and tumor suppressors have evolved to coordinatelyregulate stem cell function throughout life. Imbalances within such networks cause cancer or premature declines instem cell activity that resemble accelerated aging.