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。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。趋化因子是趋化性的小分子，最初发现与白细胞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，可促进肿瘤细胞存活，生长和迁移。 前列腺癌肿瘤发生和转移取决于血管生成。 CXCL5是CXC趋化因子家族的成员，其三个氨基酸基序是谷氨酸 - 达素 - 精氨酸（ELR+），并且是有效的血管生成启动子。 CXCL5与其推定的受体CXCR2结合，启动了信号传导，并与肺（非小型），结肠癌和前列腺癌有关。尽管CXCL5由前列腺癌细胞表达，但尚未确定其在血管生成和前列腺癌进展中的作用。前列腺的慢性炎症可能导致增生性炎症性萎缩（PIA），这可能是前列腺上皮内肿瘤（PIN）的早期组织学前体，随后是前列腺癌。因此，鉴定PIA和PIN中涉及的因素和信号通路可能不仅有助于制定策略以防止其发展，还可以防止其发展为前列腺癌。在疾病的侵入性阶段，我们对CXCL5及其受体CXCR2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起重要作用。这可能很重要，因为饮食中的抗血管生成产物（例如染料木黄酮）可以通过调节这种趋化因子信号通路来起作用。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）确定是否由前列腺癌细胞分泌的CxCl5是否会调节血管内皮生长因子的表达，这是对生长群的生长因子，并且可以确定属于象征性的生长因子，如果构成了疾病的生长因子，则可以构成疾病的生长因子。通过CXCL5。分子研究将包括实时RT-PCR，ELISA，细胞迁移和入侵测定，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传导途径的机制和抑制这些途径的方法将有助于开发治疗策略以抑制或预防前列腺癌的进展。 公共卫生相关性：趋化因子及其受体在癌症血管生成，侵入性和转移中起多余的作用。 CXCL5是促血管生成趋化因子亚科的成员，与几种癌症类型的进展有关。我们打算研究CXCL5在前列腺癌细胞的血管生成中的作用，并抑制该信号传导途径。