Role of the Angiogenic Chemokine, CXCL5, in Prostate Cancer

描述(申请人提供)：血管生成趋化因子CXCL5在前列腺癌中的作用。这项研究的主要目的是确定血管生成趋化因子CXCL5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，最初被发现参与白细胞的募集和运输到炎症部位。然而，已经证明肿瘤细胞表达趋化因子受体和/或其配体，促进肿瘤细胞的生存、生长和迁移。 前列腺癌的发生和转移依赖于血管生成。CXCL5是CXC家族趋化因子家族的成员，具有谷氨酸-亮氨酸-精氨酸(ELR)三个氨基酸基序，是一种强有力的血管生成促进剂。CXCL5与其假定的受体CXCR2结合，启动信号转导，并与肺癌(非小细胞肺癌)、结直肠癌和前列腺癌有关。尽管CXCL5在前列腺癌细胞中表达，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)，这可能是前列腺癌(PIN)的早期组织学先兆。因此，识别PIA和PIN中涉及的因素和信号通路可能有助于制定策略，不仅可以预防它，还可以防止其发展为前列腺癌。我们对CXCL5及其受体CXCR2在疾病侵袭前期的表达模式特别感兴趣。中心假说是CXCL5可能通过增加血管生成在前列腺癌的进展中发挥重要作用。这一点可能很重要，因为饮食中的抗血管生成产品，如染料木素，可能通过调节这一趋化因子信号途径发挥作用。本研究的目的是：a)检测CXCL5及其受体CXCR2在前列腺癌和非前列腺癌组织中的表达；b)确定前列腺癌细胞分泌的CXCL5是否调节血管内皮生长因子的表达；c)确定金雀异黄素是否能抑制前列腺癌的血管生成和侵袭力，以及是否通过CXCL5介导。分子研究将包括实时RT-PCR、ELISA、细胞迁移和侵袭分析、Western blotting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途径将有助于制定抑制或防止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、侵袭和转移中扮演着许多非多余的角色。CXCL5是促血管生成趋化因子亚家族的成员，与多种癌症的发生发展密切相关。我们打算研究CXCL5在前列腺癌细胞血管生成中的作用以及抑制这一信号通路的方法。

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.