| Cells continually experience stress and damage from exogenous and endogenous sources. While their responses can range from complete recovery to cell death, proliferating cells are also capable of triggering a permanent cell-cycle arrest termed cellular senescence. Cellular senescence depends on the tumor suppressor genes p53 and pRB and suppresses cancer by preventing proliferation of cells at risk for neoplastic progression. However, senescent cells persist, secrete molecules that alter local tissue microenvironment and can promote tumor cell growth. This suggests the senescence response is antagonistically pleiotropic, and thus contribute to aging phenotypes including late life cancer.; We show here, using antibody arrays, zymograms, western blots, and enzyme linked immunosorbent assay (ELISA), that senescent fibroblasts secrete numerous growth factors, interleukins (ILs), cytokines, chemokines and matrix metalloproteinases (MMPs), including those implicated in tumorigenesis and inflammation. This complex senescence-associated secretory phenotype (SASP) is conserved among different human and mouse fibroblasts strains, and is sensitive to oxidative stress.; Senescent cells alter their microenvironment and affect the behavior of neighboring cells. Specifically, the secretion of MMP-3 by senescent fibroblasts can disrupt mammary epithelial alveolar morphogenesis, functional differentiation and branching morphogenesis. The secretion of GROalpha by senescent fibroblasts is responsible for promoting epithelial cell proliferation in culture. Secretion of IL-6 and IL-8 by senescent fibroblasts enhances the invasive ability of breast cancer cells. Finally, senescent fibroblasts stimulate tumor vascularization in mice, and stimulates endothelial cell migration and invasiveness in culture, through VEGF secretion. These findings support the idea that senescent cells contribute to age-related pathology, including cancer, and may also explain the loss of tissue function and organization that is a hallmark of aging.; We find that the SASP is induced by senescence-inducing conditions that can activate p53, such as DNA damage, telomere shortening or activated oncogene (Ras). Strikingly, loss of p53 function greatly enhances the SASP and, in the absence of the p16INK4a component of the pRB pathway, uncouples it from the senescence growth arrest. These findings indicate that the SASP is a genotoxic stress response that is restrained by p53, and identify a novel cell non-autonomous mechanism by which p53 can suppress. |
