Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor

By Jean-Philippe Coppé, C. Patil, F. Rodier, Yu Sun, Denise P. Muñoz, J. Goldstein, P. Nelson, P. Desprez, J. Campisi. PLoS Biology, 2008

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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.

Subfields: Immunology, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/07a0ca4b23a139be2cda988184b3e3dd199e5d12

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Citations in the corpus

Senescence-messaging secretome: SMS-ing cellular stress (2009, background): “Also in the setting of replicative senescence, p53 is not necessary for the concomitant induction of IL-6 and other secreted factor”
Wound repair and regeneration: Mechanisms, signaling, and translation (2014, positive): “Conversely, senescent cells are also known to express cell surface–bound IL-1 α , IL-6, and IL-8 (59)—all of which play key roles in wound repair.”
Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging (2017, background): “Senescent cells are permanently withdrawn from the cell cycle and generally develop a persistent pro-inflammatory phenotype, called the senescence-associated secretory phenotype (SASP) (Coppé et al., 2008).”
The DNA damage response induces inflammation and senescence by inhibiting autophagy of GATA4 (2015, background): “Among the GATA4-regulated, senescenceassociated genes, we found several SASP genes, including those encoding IL6, IL8, C-X-C motif ligand 1 (CXCL1), granulocyte-macrophage colonystimulating factor (GM-CSF), and extracellular matrix (ECM) proteases and inhibitors (7).”
The senescence-associated secretory phenotype and its physiological and pathological implications (2024, neutral): “In 2008, different laboratories independently described the SASP (or the senescence-messaging secretome) 14–17 , primarily as a collection of pro-inflammatory and growth-stimulating proteins.”
Inflammatory Networks during Cellular Senescence: Causes and Consequences (2010, background): “Proteins that are known to stimulate inflammation, including IL-6, IL-8, IL-1, granulocyte macrophage colonystimulating factor (GM-CSF), growth regulated oncogene (GRO)α, monocyte chemotactic protein (MCP)-2, MCP-3, MMP-1, MMP-3, and many of the Insulin-like growth factor (IGF)binding proteins [23,2”
The Senescence-Associated Secretory Phenotype: The Dark Side of Tumor Suppression (2010, background): “Paumelle R, Tulasne D, Kherrouche Z, Plaza S, Leroy C, et al. Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway.”
p38MAPK is a novel DNA damage response‐independent regulator of the senescence‐associated secretory phenotype (2011, methodology): “…potent regulator of SASP MMPs, but a strong positive regulator of many SASP chemokines, cytokines, and growth factors. p38MAPK inhibition mitigates a paracrine effect of senescent cells CM from senescent cells stimulate the ability of cancer cells to invade a basement membrane (Coppe et al, 2008).”
Lamin B1 loss is a senescence-associated biomarker (2012, methodology): “MATERIALS AND METHODS Cell culture Primary human fibroblasts (HCA2, WI-38, IMR-90, BJ strains) were obtained and cultured as described (Coppe et al., 2008).”