Senescent fibroblasts promote epithelial cell growth and tumorigenesis: A link between cancer and aging

Mammalian cells can respond to damage or stress by entering a state of arre sted growth and altered function termed cellular senescence. Several lines of evidence suggest that the senescence response suppresses tumorigenesis. Cellular senescence is also thought to contribute to aging, but the mechani sm is not well understood. We show that senescent human fibroblasts stimula te premalignant and malignant, but not normal, epithelial cells to prolifer ate in culture and form tumors in mice. in culture, the growth stimulation was evident when senescent cells comprised only 10% of the fibroblast popul ation and was equally robust whether senescence was induced by replicative exhaustion, oncogenic RAS, p14(ARF), or hydrogen peroxide. Moreover, it was due at least in part to soluble and insoluble factors secreted by senescen t cells. In mice, senescent, much more than presenescent, fibroblasts cause d premalignant and malignant epithelial cells to form tumors. our findings suggest that, although cellular senescence suppresses tumorigenesis early i n life, it may promote cancer in aged organisms, suggesting it is an exampl e of evolutionary antagonistic pleiotropy.