Role of the Angiogenic Chemokine, CXCL5, in Prostate Cancer

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DESCRIPTION (provided by applicant): Role of the angiogenic chemokine, CXCL5, in prostate cancer. The main goal of this study is to determine the role of the angiogenic chemokine, CXCL5, in prostate cancer progression. Chemokines are chemoattractive small molecules that were initially discovered to be involved in recruitment and trafficking of leucocytes to inflammatory sites. However, it has been demonstrated that tumor cells express chemokine receptors and/or their ligands that facilitate tumor cell survival, growth and migration. Prostate cancer tumorigenesis and metastasis is dependent on angiogenesis. CXCL5 is a member of CXC family of chemokines with the three amino acid motif, glutamic acid-leucine-arginine (ELR+) and is a potent angiogenic promoter. CXCL5 binds to its putative receptor, CXCR2, initiates signaling and has been implicated in cancers of lung (non-small), colorectum and prostate. Although CXCL5 is expressed by prostate cancer cells, its role in angiogenesis and prostate cancer progression has not been established. Chronic inflammation of the prostate could lead to proliferative inflammatory atrophy (PIA) which may be an early histological precursor to prostate intraepithelial neoplasia (PIN) and subsequently to prostate cancer. Therefore, identification of factors and signaling pathways involved in PIA and PIN may aid in devising strategies not only to prevent it but also to prevent its progression to prostate cancer. We are particularly interested in the expression pattern of CXCL5 and its receptor, CXCR2, in the preinvasive stages of the disease. The central hypothesis is that CXCL5 plays a significant role in the progression of prostate cancer possibly via increased angiogenesis. This may be important in that dietary antiangiogenic products such as genistein may act by regulation of this chemokine signaling pathway. The aims of the present study are to a) determine the expression of CXCL5 and its receptor, CXCR2, in prostatic tissues with and without neoplastic lesions b) determine if CXCL5 secreted by prostate cancer cells regulates the expression of vascular endothelial growth factor, a growth factor essential for angiogenesis c) determine if genistein, can inhibit angiogenesis and invasiveness of prostate cancer cells and if it is mediated through CXCL5. Molecular studies will include real-time RT-PCR, ELISA, cell migration and invasion assays, western blotting and immunohistochemistry and RNA interference. Understanding the mechanisms of angiogenic chemokine signaling pathways and approaches to inhibit these pathways will help to develop therapeutic strategies to inhibit or prevent prostate cancer progression. PUBLIC HEALTH RELEVANCE: Chemokines and their receptors play a number of non-redundant roles in cancer angiogenesis, invasiveness, and metastasis. CXCL5, a member of the subfamily of proangiogenic chemokines, is implicated in the progression of several cancer types. We intend to investigate the role of CXCL5 in angiogenesis of prostate cancer cells and approaches to inhibit this signaling pathway.