Most adult cancers increase with age. Cellular senescence, a potent tumor suppressive mechanism, is now believed to contribute to age-related pathologies. In aging tissues, the protective properties of cellular senescence are derailed: as senescent cells accumulate, they secrete pro-inflammatory cytokines, chemokines and proteases creating a pro-carcinogenic microenvironment. The senescence associated secretory phenotype (SASP) drives this deleterious characteristic of cellular senescence. A direct role for senescent cells in cancer development and progression in vivo during normal aging remains unexplored. Thus, the first goal of this proposal is to determine the effect of senescent cells on age related carcinogenesis. The second goal is to determine the effect of the polyphenol epigallocatechingallate (EGCG), a potent anti-cancer agent found in green tea on the SASP. To accomplish these goals, a novel transgenic mouse model, p16-3MR, designed to selectively eliminate senescent cells expressing the established cellular senescence marker, p16INK4a (p16) coupled with the two-stage skin carcinogenesis model will be employed. To test this project's hypothesis that the accumulation of senescent cells in aged animals facilitates skin carcinogenesis and EGCG abrogates the negative aspects of cellular senescence, I plan to: (1) Determine whether senescent cells initiate skin cancer in aged mice. (2) Evaluate whether senescent cells promote skin cancer in old mice. (3) Examine the effect of EGCG on the SASP using both the skin carcinogenesis mouse model and embryonic fibroblasts (MEFs) derived from wild type mice. (4) Delineate the molecular mechanisms by which EGCG affects SASPs. The proposed experiments will delineate a novel role for aging in carcinogenesis and pave the way for the development of natural dietary compounds as therapeutic agents against cancer.
This proposal explores the novel hypothesis that normal aging contributes to carcinogenesis in vivo due to an accumulation of senescent cells and their pro- inflammatory senescence-associated secretory phenotype (SASP), and that EGCG reduces the harmful effects of senescent cells. The proposed experiments will determine the stage at which cellular senescence fuels carcinogenesis and provide a rationale for developing natural chemotherapeutic compounds against the SASP.