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-renewal and possibly stem cell aging. Proto-oncogenes promote regenerative capacity by promoting stem cell function but must be balanced with tumor suppressor activity to avoid neoplastic proliferation. Conversely, tumor suppressors inhibit regenerative capacity by promoting cell death or senescence in stem cells. For example, the polycomb family proto-oncogene, Bmi-1, is consistently required for the self-renewal of diverse adult stem cells, as well as for the proliferation of cancer cells in the same tissues. Bmi-1 promotes stem cell self-renewal partly by repressing the expression of Ink4a and Arf, tumor suppressor genes that are commonly deleted in cancer. Despite ongoing Bmi-1 expression, Ink4a expression increases with age, potentially reducing stem cell frequency and function. Increased tumor suppressor activity during aging therefore may partly account for age-related declines in stem cell function. Thus, networks of proto-oncogenes and tumor suppressors have evolved to coordinately regulate stem cell function throughout life. Imbalances within such networks cause cancer or premature declines in stem cell activity that resemble accelerated aging.