Role of the Angiogenic Chemokine, CXCL5, in Prostate Cancer

描述（由申请人提供）：血管生成趋化因子CXCL 5在前列腺癌中的作用。本研究的主要目的是确定血管生成趋化因子CXCL 5在前列腺癌进展中的作用。趋化因子是一种具有化学吸引力的小分子，最初发现其参与白细胞的募集和运输至炎症部位。然而，已经证明肿瘤细胞表达促进肿瘤细胞存活、生长和迁移的趋化因子受体和/或其配体。 前列腺癌的发生和转移依赖于血管生成。CXCL 5是具有三个氨基酸基序谷氨酸-亮氨酸-精氨酸（ELR+）的趋化因子CXC家族的成员，并且是有效的血管生成促进剂。CXCL 5与其假定受体CXCR 2结合，启动信号传导，并与肺癌（非小细胞肺癌）、结肠直肠癌和前列腺癌有关。虽然CXCL 5由前列腺癌细胞表达，但其在血管生成和前列腺癌进展中的作用尚未确定。前列腺慢性炎症可导致增生性炎性萎缩（PIA），这可能是前列腺上皮内瘤变（PIN）和随后前列腺癌的早期组织学前兆。因此，识别PIA和PIN中涉及的因子和信号通路可能有助于制定策略，不仅可以预防它，还可以预防其进展为前列腺癌。我们特别感兴趣的是CXCL 5及其受体CXCR 2在疾病的侵袭前阶段的表达模式。中心假设是CXCL 5可能通过增加血管生成在前列腺癌的进展中起重要作用。这可能很重要，因为膳食抗血管生成产品（如染料木黄酮）可能通过调节这种趋化因子信号通路发挥作用。本研究的目的是a）确定CXCL 5及其受体CXCR 2在具有和不具有肿瘤病变的前列腺组织中的表达，B）确定前列腺癌细胞分泌的CXCL 5是否调节血管内皮生长因子（血管生成所必需的生长因子）的表达，c）确定染料木黄酮，可以抑制前列腺癌细胞的血管生成和侵袭力，并且如果它是通过CXCL 5介导的。分子研究将包括实时RT-PCR、ELISA、细胞迁移和侵袭测定、蛋白质印迹和免疫组织化学以及RNA干扰。了解血管生成趋化因子信号通路的机制和抑制这些通路的方法将有助于开发抑制或预防前列腺癌进展的治疗策略。 公共卫生相关性：趋化因子及其受体在癌症血管生成、侵袭和转移中发挥许多非冗余作用。CXCL 5是促血管生成趋化因子亚家族的成员，与几种癌症类型的进展有关。我们打算研究CXCL 5在前列腺癌细胞血管生成中的作用以及抑制该信号通路的方法。

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.