Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.

Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells i...

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Autores principales:	Jean-Philippe Coppé, Christopher K Patil, Francis Rodier, Yu Sun, Denise P Muñoz, Joshua Goldstein, Peter S Nelson, Pierre-Yves Desprez, Judith Campisi
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2008
Materias:	Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/45144fb904334b6d83ac21f7112cd481
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spelling	oai:doaj.org-article:45144fb904334b6d83ac21f7112cd4812021-11-25T05:33:54ZSenescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.1544-91731545-788510.1371/journal.pbio.0060301https://doaj.org/article/45144fb904334b6d83ac21f7112cd4812008-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/19053174/?tool=EBIhttps://doaj.org/toc/1544-9173https://doaj.org/toc/1545-7885Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.Jean-Philippe CoppéChristopher K PatilFrancis RodierYu SunDenise P MuñozJoshua GoldsteinPeter S NelsonPierre-Yves DesprezJudith CampisiPublic Library of Science (PLoS)articleBiology (General)QH301-705.5ENPLoS Biology, Vol 6, Iss 12, Pp 2853-2868 (2008)
institution	DOAJ
collection	DOAJ
language	EN
topic	Biology (General) QH301-705.5
spellingShingle	Biology (General) QH301-705.5 Jean-Philippe Coppé Christopher K Patil Francis Rodier Yu Sun Denise P Muñoz Joshua Goldstein Peter S Nelson Pierre-Yves Desprez Judith Campisi Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
description	Cellular senescence suppresses cancer by arresting cell proliferation, essentially permanently, in response to oncogenic stimuli, including genotoxic stress. We modified the use of antibody arrays to provide a quantitative assessment of factors secreted by senescent cells. We show that human cells induced to senesce by genotoxic stress secrete myriad factors associated with inflammation and malignancy. This senescence-associated secretory phenotype (SASP) developed slowly over several days and only after DNA damage of sufficient magnitude to induce senescence. Remarkably similar SASPs developed in normal fibroblasts, normal epithelial cells, and epithelial tumor cells after genotoxic stress in culture, and in epithelial tumor cells in vivo after treatment of prostate cancer patients with DNA-damaging chemotherapy. In cultured premalignant epithelial cells, SASPs induced an epithelial-mesenchyme transition and invasiveness, hallmarks of malignancy, by a paracrine mechanism that depended largely on the SASP factors interleukin (IL)-6 and IL-8. Strikingly, two manipulations markedly amplified, and accelerated development of, the SASPs: oncogenic RAS expression, which causes genotoxic stress and senescence in normal cells, and functional loss of the p53 tumor suppressor protein. Both loss of p53 and gain of oncogenic RAS also exacerbated the promalignant paracrine activities of the SASPs. Our findings define a central feature of genotoxic stress-induced senescence. Moreover, they suggest a cell-nonautonomous mechanism by which p53 can restrain, and oncogenic RAS can promote, the development of age-related cancer by altering the tissue microenvironment.
format	article
author	Jean-Philippe Coppé Christopher K Patil Francis Rodier Yu Sun Denise P Muñoz Joshua Goldstein Peter S Nelson Pierre-Yves Desprez Judith Campisi
author_facet	Jean-Philippe Coppé Christopher K Patil Francis Rodier Yu Sun Denise P Muñoz Joshua Goldstein Peter S Nelson Pierre-Yves Desprez Judith Campisi
author_sort	Jean-Philippe Coppé
title	Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
title_short	Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
title_full	Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
title_fullStr	Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
title_full_unstemmed	Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.
title_sort	senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic ras and the p53 tumor suppressor.
publisher	Public Library of Science (PLoS)
publishDate	2008
url	https://doaj.org/article/45144fb904334b6d83ac21f7112cd481
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Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor.

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