Role of the Angiogenic Chemokine, CXCL5, in Prostate Cancer

血管生成趋化因子 CXCL5 在前列腺癌中的作用

• 批准号: 8337160
• 负责人: Liz Simon
• 金额: $ 14.23万
• 依托单位: TUSKEGEE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8337160
• 关键词: Amino Acid Motifs; Angiogenesis Inhibitors; Angiogenic Proteins; Archives; Arginine; Atrophic; Binding; Biological Assay; CXCL5 gene; Cell Survival; Cells; Chronic; Coculture Techniques; Conditioned Culture Media; Development; Diet; Disease; Disease Progression; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Experimental Designs; Family; Gene Expression; Genetic Transcription; Genistein; Glutamic Acid; Goals; Growth; Growth Factor; IL8RB gene; Immigration; Immune System Part; Immunohistochemistry; In Vitro; Incidence; Incubated; Inflammation; Inflammatory; Interleukin-8B Receptor; Intraepithelial Neoplasia; Lead; Lesion; Leucine; Leukocyte Trafficking; Leukocytes; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mediator of activation protein; Molecular; Neoplasm Metastasis; PC3 cell line; Pathway interactions; Pattern; Play; Prostate; Prostatic Tissue; RNA Interference; Recombinants; Regulation; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Site; Small Interfering RNA; Staging; System; Testing; Therapeutic; Time; Tissue Sample; Tissues; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Western Blotting; angiogenesis; cancer cell; cancer type; cell motility; chemokine; chemokine receptor; design; human tissue; interest; member; migration; neoplastic; neoplastic cell; prevent; promoter; protein expression; receptor; research study; small molecule; tumor; tumor growth; tumor progression; tumorigenesis; vasculogenesis

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.

描述（由申请人提供）：血管生成趋化因子CXCL5在前列腺癌中的作用。本研究的主要目标是确定血管生成趋化因子 CXCL5 在前列腺癌进展中的作用。趋化因子是具有化学吸引力的小分子，最初被发现参与白细胞向炎症部位的募集和运输。然而，已经证明肿瘤细胞表达趋化因子受体和/或其配体，促进肿瘤细胞存活、生长和迁移。 前列腺癌的肿瘤发生和转移依赖于血管生成。 CXCL5 是具有三个氨基酸基序谷氨酸-亮氨酸-精氨酸 (ELR+) 趋化因子 CXC 家族的成员，是一种有效的血管生成启动子。 CXCL5 与其假定受体 CXCR2 结合，启动信号传导，并与肺癌（非小细胞癌）、结直肠癌和前列腺癌有关。尽管CXCL5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。前列腺的慢性炎症可能导致增殖性炎症萎缩（PIA），这可能是前列腺上皮内瘤变（PIN）以及随后的前列腺癌的早期组织学前兆。因此，识别 PIA 和 PIN 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，还可以预防其进展为前列腺癌。我们对 CXCL5 及其受体 CXCR2 在疾病侵袭前阶段的表达模式特别感兴趣。中心假设是 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。这可能很重要，因为膳食抗血管生成产品（例如金雀异黄素）可能通过调节该趋化因子信号通路发挥作用。本研究的目的是 a) 确定有或没有肿瘤病变的前列腺组织中 CXCL5 及其受体 CXCR2 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（一种生长因子）的表达血管生成必需的因子 c) 确定金雀异黄素是否可以抑制前列腺癌细胞的血管生成和侵袭性以及它是否通过 CXCL5 介导。分子研究将包括实时 RT-PCR、ELISA、细胞迁移和侵袭测定、蛋白质印迹、免疫组织化学以及 RNA 干扰。了解血管生成趋化因子信号传导途径的机制和抑制这些途径的方法将有助于制定抑制或预防前列腺癌进展的治疗策略。 公共健康相关性：趋化因子及其受体在癌症血管生成、侵袭和转移中发挥着许多非冗余的作用。 CXCL5 是促血管生成趋化因子亚家族的成员，与多种癌症类型的进展有关。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该信号通路的方法。