Cytokines Stimulate Prostate Epithelial Proliferation

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DESCRIPTION (provided by applicant): The long-standing association of chronic inflammation with cancer has led to the discovery that inflammatory mediators such as interleukins can promote tumor growth. These inflammatory mediators are generally conceived as having a primary role inflammation and their effects on tumor cell growth has generally been considered a non-specific growth effect. However, we present evidence that inflammatory mediators actually exert a previously unrecognized role in promoting epithelial growth during normal prostate development. Our preliminary data show robust expression of inflammatory mediators in the developing prostate in the absence of cellular inflammation and demonstrate that these inflammatory mediators promote epithelial growth and a selective expansion of p63+ epithelial cells. We will also show that mice deficient in interleukin-1 receptor exhibit significantly disrupted prostate development and hyperplastic response to inflammation. These observations lead us to propose the provocative thesis that the effects of inflammatory mediators on epithelial proliferation in chronic inflammation and cancer are a re-iteration of their actions during normal development. We propose two specific aims to address the specific hypothesis that IL-1R mediated signaling stimulates proliferation of epithelial progenitor cells and mesenchyme in the developing prostate. Aim 1: Characterize the expression and actions of IL-1 ligands during prostate development. Studies will be performed both in vivo and in vitro using pharmacologic manipulation to determine the role of these inflammatory mediators in promoting epithelial proliferation and expansion of progenitor cells during prostate development. Aim 2: Characterize the effect of IL-1R LOF on prostate development. We will test the biologic relevance IL-1R in prostate growth by examining the effect of genetic disruption of IL1-R1 on prostate development, epithelial and mesenchymal proliferation, and progenitor cell expansion. We expect these studies to show that so-called inflammatory mediators actually play a central role in regulating progenitor cell proliferation. If correct, this would suggest that expression of inflammatory mediators by leukocytes recruited to a site of injury promotes epithelial progenitor cell proliferation as part of the regenerative repair process. These studies have the potential to revolutionize the understanding of cytokine action in the prostate, provide insights into the mechanisms by which chronic inflammation produces hyperplasia and dysplasia, and provide the scientific basis for therapeutic interventions to forestall progression to neoplasia. PUBLIC HEALTH RELEVANCE We expect these studies to show that so-called inflammatory mediators actually play a central role in regulating progenitor cell proliferation. If correct, this would suggest that expression of inflammatory mediators by leukocytes recruited to a site of injury promotes epithelial progenitor cell proliferation as part of the regenerative repair process. These studies have the potential to revolutionize the understanding of cytokine action in the prostate, provide insights into the mechanisms by which chronic inflammation produces hyperplasia and dysplasia, and provide the scientific basis for therapeutic interventions to forestall progression to neoplasia.