Senescent Cells Promote Cancer
Ana Krtolica , Simona Parrinello , Stephen Lockett
[1,3] , Pierre-Yves Desprez  , and Judith Campisi [1, 4],
"Senescent Fibroblasts Promote Epithelial Cell Growth and TumorigenesisA Link Between Cancer and Aging,"
Proc. Natl. Acad. Sci. USA, Vol. 98, Issue 21, pp. 12072-7 (October 9, 2001).
Edited by Robert A. Weinberg, Whitehead Institute for Biomedical Research, Cambridge, MA, and approved August 14, 2001 (Received for review February 1, 2001)
Mammalian cells can respond to damage or stress by entering a state of arrested 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 mechanism is not well understood. We show that senescent human fibroblasts stimulate premalignant and malignant, but not normal, epithelial cells to proliferate in culture and form tumors in mice. In culture, the growth stimulation was evident when senescent cells comprised only ten percent of the fibroblast population and was equally robust whether senescence was induced by replicative exhaustion, oncogenic RAS, p14ARF, or hydrogen peroxide. Moreover, it was due at least in part to soluble and insoluble factors secreted by senescent cells. In mice, senescent, much more than presenescent, fibroblasts caused premalignant and malignant epithelial cells to form tumors. Our findings suggest that, although cellular senescence suppresses tumorigenesis early in life, it may promote cancer in aged organisms, suggesting it is an example of evolutionary antagonistic pleiotropy.
 Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720;
 Geraldine Brush Cancer Research Institute, California Pacific Medical Center, San Francisco, CA 94115
 Present address: National Cancer Institute, Science Applications International Corporation-Frederick, Frederick, MD 21702.
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