(Verbatim) - One manifestation of the enhanced longevity of Americans is the increased number of various types of skin cancers, and the accumulation of cell types in the skin that may be approaching the end of their replicative potential. While both epidermal keratinocytes and dermal fibroblasts have been identified in elderly individuals that express markers associated with senescence, the biological significance of senescent cells in skin is unknown, either with respect to aging or tumorigenesis. While considerable knowledge has emerged regarding senescent fibroblasts, much less progress has been made using senescent epidermal keratinocyte Senescence can be regarded as a dynamic process and not a static condition for these skin-derived cell types. Our hypothesis is that senescent keratinocytes play important roles both in an autocrine and paracrine fashion to suppress tumorigenesis in the skin. We propose to perform a systematic series of experiments to define the molecular attributes of senescent keratinocytes, and move beyond this phenotypic perspective to include functional studies. Preliminary data indicate distinctive molecular changes such as induction of the cell cycle inhibitor protein p16 in senescent keratinocytes, as well as the ability of senescent keratinocytes to inhibit proliferation of malignant cell types. Now that we have uncovered several different methods for triggering the senescent phenotype in keratinocytes that can be reproducibly switched to simulate replicative senescence, rapid progress in this field will be possible. Both in-vitro and in-vivo assays will be utilized to characterize the phenotype and function of senescent keratinocytes. By successfully completing the proposed objectives, new therapeutic strategies will emerge to target pre-malignant keratinocytes, as well as pre-existing cutaneous malignancies. Since many tumor cells bypass the senescent pathway, knowledge gained about the molecular basis by which senescence is triggered in normal keratinocytes, could be applied to the malignant cells by re-instating the senescent pathway leading to irreversible growth arrest.
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