Abstract
Cellular senescence has emerged as a potent tumor suppression mechanism that restrains proliferation of cells at risk for malignant transformation. Although senescent cells have permanently exited the cell cycle, their presence can have detrimental effects on the surrounding tissue, largely due to the development of the senescence-associated secretory phenotype (SASP). Here, we review the tumor-suppressive and tumor-promoting consequences of the senescence response, focusing on the SASP as a key mediator of this dichotomy. Accumulating evidence suggests that the persistence of senescent cells can exacerbate the development of a pro-inflammatory, immunosuppressive microenvironment that can favor tumorigenesis. Given that senescence of tumor and stromal cells is a frequent outcome of anti-cancer therapy, approaches that harness the growth inhibitory effects of senescence while limiting its detrimental effects are likely to have great clinical potential.
Highlights
Limiting the unrestrained proliferation of tumor cells is a primary goal of anti-cancer therapies
While increased mutational load in tumor cells surviving genotoxic chemotherapy may contribute to chemoresistance, accumulating evidence suggests that chemotherapyinduced DNA damage can have unintended tumor-promoting consequences related to DNA damage response (DDR)-induced senescence and stromal effects of chemotherapy
Given that senescence can act as a double-edged sword in tumorigenesis, it is imperative to consider its dual nature in the design and use of senescence-inducing anti-cancer therapies
Summary
Limiting the unrestrained proliferation of tumor cells is a primary goal of anti-cancer therapies. The Pten loss-induced cellular senescence was accompanied by a SASP that included chemoattractant cytokines, the resulting tumors exhibited infiltration by CD11b+Gr1+ myeloid-derived suppressor cells that inhibited proliferation of CD8+ cytotoxic T cells and activation of NK cells, creating an immunosuppressive, pro-tumorigenic microenvironment[59]. While increased mutational load in tumor cells surviving genotoxic chemotherapy may contribute to chemoresistance, accumulating evidence suggests that chemotherapyinduced DNA damage can have unintended tumor-promoting consequences related to DDR-induced senescence and stromal effects of chemotherapy. In β-cancer cells lacking functional pRb and p53 due to expression of SV40 T-antigen under the control of the rat insulin promoter (RIP-Tag), TH1 cytokines interferon gamma (IFN-γ) and tumor necrosis factor (TNF) induce senescent growth arrest in vitro, accompanied by restoration of functional p16INK4A/pRb75. The work of Toso et al provides in vivo proof of principle that the pro-tumorigenic effects of senescence can be manipulated toward a tumorsuppressive phenotype[59]
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