Cellular senescence is a tumor-suppressive mechanism that permanently arrests cells at risk for malignant transformation. However, accumulating evidence shows that senescent cells can have deleterious effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescence-associated secretory phenotype (SASP) that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.

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.

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, p14 ARF , 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.

Chronic inflammation is associated with aging and plays a causative role in several age-related diseases such as cancer, atherosclerosis and osteoarthritis. The source of this chronic inflammation is often attributed to the progressive activation of immune cells over time. However, recent studies have shown that the process of cellular senescence, a tumor suppressive stress response that is also associated with aging, entails a striking increase in the secretion of pro-inflammatory proteins and might be an important additional contributor to chronic inflammation. Here, we list the secreted factors that make up the pro-inflammatory phenotype of senescent cells and describe the impact of these factors on tissue homeostasis. We also summarize the cellular pathways/processes that are known to regulate this phenotype -namely, the DNA damage response, microRNAs, key transcription factors and kinases and chromatin remodeling. Keywordsaging; cancer; inflammation; cytokines; interleukins; tumor suppression Acute InflammationExternal signs of inflammation -pain, redness, heat and swelling -were known long before biologists began to investigate their molecular and cellular mechanisms. We now know that the external signs of inflammation are caused by the dilation of blood vessels and action of phagocytes at the site of injury. Phagocytes, in turn, produce pro-inflammatory factors such as cytokines and chemokines, which attract leukocytes to deal with the presence of foreign organisms or particles. Normally, the inflammatory response ceases within hours or days, once the foreign objects have been removed, and damaged tissue then begins to heal. This type of inflammation is known as acute inflammation.Corresponding author: Campisi, J. (jcampisi@buckinstitute.org). * These authors contributed equally Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Chronic inflammation in aging and age-related diseasesChronic inflammation, by contrast, is the continued presence (sometimes over many years) of pro-inflammatory factors at levels higher than baseline, but many fold lower than those found in acute inflammation. Chronically inflamed tissues are characterized by the presence of infiltrating lymphocytes and macrophages, abundant blood vessels, fibrosis, and often, tissue necrosis [1,2]. Chronic inflammation, as measured by the serum levels of pro-inflammatory mediators near sites of pathology, is associated with many age-related pathophysiologic processes and diseases, including Alzheimer's disease, diabetes, atherosclerosis, osteoarthritis and cancer, among others [3,...

Cellular senescence, which is associated with aging, is a process by which cells enter a state of permanent cell cycle arrest, therefore constituting a potent tumor suppressive mechanism. Recent studies show that, despite the beneficial effects of cellular senescence, senescent cells can also exert harmful effects on the tissue microenvironment. The most significant of these effects is the acquisition of a senescent-associated secretory phenotype (SASP), which entails a striking increase in the secretion of pro-inflammatory cytokines. Here, we summarize our knowledge of the SASP and the impact it has on tissue microenvironments and ability to stimulate tumor progression.

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Invasion and metastasis of aggressive breast cancer cells is the final and fatal step during cancer progression, and is the least understood genetically. Clinically, there are still limited therapeutic interventions for aggressive and metastatic breast cancers available. Clearly, effective and nontoxic therapies are urgently required. Id-1, an inhibitor of basic helix-loop-helix transcription factors, has recently been shown to be a key regulator of the metastatic potential of breast and additional cancers. Using a mouse model, we previously determined that metastatic breast cancer cells became significantly less invasive in vitro and less metastatic in vivo when Id-1 was down-regulated by stable transduction with antisense Id-1. It is not possible at this point, however, to use antisense technology to reduce Id-1 expression in patients with metastatic breast cancer. Here, we report that cannabidiol (CBD), a cannabinoid with a low-toxicity profile, could down-regulate Id-1 expression in aggressive human breast cancer cells. The CBD concentrations effective at inhibiting Id-1 expression correlated with those used to inhibit the proliferative and invasive phenotype of breast cancer cells. CBD was able to inhibit Id-1 expression at the mRNA and protein level in a concentration-dependent fashion. These effects seemed to occur as the result of an inhibition of the Id-1 gene at the promoter level. Importantly, CBD did not inhibit invasiveness in cells that ectopically expressed Id-1. In conclusion, CBD represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness. [Mol Cancer Ther 2007;6(11):2921 -7]

Cell proliferation and differentiation are precisely coordinated during the development and maturation of the mammary gland, and this balance invariably is disrupted during carcinogenesis. Little is known about the cell-specific transcription factors that regulate these processes in the mammary gland. The mouse mammary epithelial cell line SCp2 grows well under standard culture conditions but arrests growth, forms alveolus-like structures, and expresses ␤-casein, a differentiation marker, 4 to 5 days after exposure to basement membrane and lactogenic hormones (differentiation signals). We show that this differentiation entails a marked decline in the expression of Id-1, a helix-loop-helix (HLH) protein that inactivates basic HLH transcription factors in other cell types. SCp2 cells stably transfected with an Id-1 expression vector grew more rapidly than control cells under standard conditions, but in response to differentiation signals, they arrested growth and formed three-dimensional structures similar to those of control cells. Id-1-expressing cells did not, however, express ␤-casein. Moreover, 8 to 10 days after receiving differentiation signals, they lost three-dimensional organization, invaded the basement membrane, and then resumed growth. SCp2 cells expressing an Id-1 antisense vector grew more slowly than controls; in response to differentiation signals, they remained stably growth arrested and fully differentiated, as did control cells. We suggest that Id-1 renders cells refractory to differentiation signals and receptive to growth signals by inactivating one or more basic HLH proteins that coordinate growth and differentiation in the mammary epithelium.