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Plos Biology : Senescence-associated Secretory Phenotypes Reveal Cell-nonautonomous Functions of Oncogenic Ras and the P53 Tumor Suppressor, Volume 6

By Coppe, Jean-philippe

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Book Id: WPLBN0003928973
Format Type: PDF eBook :
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Reproduction Date: 2015

Title: Plos Biology : Senescence-associated Secretory Phenotypes Reveal Cell-nonautonomous Functions of Oncogenic Ras and the P53 Tumor Suppressor, Volume 6  
Author: Coppe, Jean-philippe
Volume: Volume 6
Language: English
Subject: Journals, Science, Biology
Collections: Periodicals: Journal and Magazine Collection (Contemporary), PLoS Biology
Historic
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Publisher: Plos

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Coppe, J. (n.d.). Plos Biology : Senescence-associated Secretory Phenotypes Reveal Cell-nonautonomous Functions of Oncogenic Ras and the P53 Tumor Suppressor, Volume 6. Retrieved from http://netlibrary.net/


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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 DNAdamaging 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.

 

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