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 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 mechani...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2001-10, Vol.98 (21), p.12072-12077
Main Authors: Krtolica, Ana, Parrinello, Simona, Lockett, Stephen, Desprez, Pierre-Yves, Campisi, Judith
Format: Article
Language:English
Subjects:
Aging
Aging - physiology
Animals
Biological Sciences
Cancer
Cell Division
Cell growth
Cell Line
Cell lines
Cells
Cellular biology
Cellular senescence
Cellular Senescence - physiology
Cultured cells
Epithelial cells
Epithelial Cells - cytology
Epithelial Cells - physiology
Fibroblasts
Fibroblasts - cytology
Fibroblasts - physiology
Fluorescence
Genetics
Kinetics
Lawns
Mice
Mice, Nude
Neoplasms - etiology
Neoplasms, Experimental - etiology
Neoplasms, Experimental - physiopathology
Precancerous Conditions
Tumors
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Summary: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 10% 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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.211053698