The Role of CXCL12 Signaling in Obesity-Induced Prostate Cancer Progression

CXCL12 信号在肥胖诱发的前列腺癌进展中的作用

基本信息

批准号：
8989633
负责人：
John DiGiovanni
金额：
$ 40.76万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8989633
关键词：
AMD3100 Adipose tissue Affect Anti-Inflammatory Agents Anti-inflammatory Automobile Driving Blood Vessels CXCL12 gene CXCR4 gene Caloric Restriction Cells Coculture Techniques Data Diet Disease Flow Cytometry Future G-Protein-Coupled Receptors Gene Expression Profile Gene Proteins Ginger Growth Growth Factor Immunofluorescence Immunologic Inflammation Inflammatory Knock-out Malignant Neoplasms Malignant neoplasm of prostate Mus Obese Mice Obesity Overweight Peptides Phytochemical Play Population Property Prostate Prostatic Neoplasms Role Signal Pathway Signal Transduction Stromal Cell-Derived Factor 1 Stromal Cells Study Section Testing Time Tissues Transgenic Mice Tumor Cell Line angiogenesis base cell growth chemokine cytokine design efficacy testing energy balance genetic approach in vivo inhibitor/antagonist innovation insight migration mortality mouse model neoplastic cell novel overexpression prevent prostate cancer model protein expression public health relevance receptor research study shogaol small molecule translational study treatment effect tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): A number of studies indicate that dietary energy balance plays a significant role in prostate cancer (PCa) as well as many other cancers. Our recent studies have shown that diet-induced obesity (DIO) enhanced progression of PCa in HiMyc transgenic mice whereas calorie restriction (CR) inhibited progression in this mouse model of PCa. In addition, we have found that dietary energy balance affects PCa progression in HiMyc mice, at least in part, through modulation of tissue inflammation and angiogenesis. These cellular changes are associated with local changes in expression of a large number of cytokines, chemokines and growth factors. Collectively, our current data suggest that certain growth factor/inflammatory signaling pathways may be key targets for preventing and controlling PCa progression and especially obesity-related PCa progression. In this project, we propose to use the well-characterized HiMyc mouse prostate tumor model as well as a novel tumor cell line derived from HiMyc mice (called HMVP2) that we have recently developed to continue studies of the mechanisms associated with dietary energy balance effects, and in particular obesity, on PCa progression. We will focus these studies on the tumor microenvironment and, in particular, on the role of white adipose tissue (WAT) in driving PCa progression using the HiMyc mouse model. We will also focus on the preliminary finding that the chemokine CXCL12 (SDF-1) is highly upregulated in the stromal vascular fraction (SVF) of WAT from obese HiMyc mice and will study its role in obesity-driven PCa progression in this mouse model. The hypothesis to be tested is that in obesity, the recruitment of adipose stromal cells (ASC) promotes PCa progression in part through CXCL12 signaling via its G-protein coupled receptors, CXCR4 and CXCR7. By using a peptide (D-WAT) that specifically ablates ASC, we will test the importance of this cell population in cancer progression and determine its contribution to CXCL12 signaling in the tumor microenvironment. By using knockout, knockdown, and overexpression mouse models, we will examine whether targeting CXCL12, CXCR4, and CXCR7 can offset the effects of obesity on PCa progression. Finally, we will test the efficacy of a small molecule inhibitor targeting CXCL12/receptor interactions alone or in combination with a naturally occurring anti-inflammatory phytochemical [6-shogaol (6-SHO)] found in ginger to offset the effects of obesity on PCa progression. The Specific Aims are to: i) identify the cells that produce CXCL12 in prostate-associated WAT; ii) determine the importance of ASC-derived CXCL12 on obesity-driven PCa progression; iii) investigate the specific roles of CXCR4 and CXCR7 signaling in obesity-driven PCa progression; and iv) test pharmacologic approaches to inhibition of CXCL12 signaling via CXCR4 in obesity-driven PCa progression. Completion of this project will provide the basis for future translational studies targeting specific signaling pathways and/or cell populations to reduce PCa mortality and prevent the effects of obesity on PCa progression.

描述（由申请人提供）：多项研究表明，膳食能量平衡在前列腺癌（PCa）以及许多其他癌症中发挥着重要作用，我们最近的研究表明，饮食引起的肥胖（DIO）会加速前列腺癌的进展。在 HiMyc 转基因小鼠中，热量限制 (CR) 抑制了该小鼠 PCa 模型的进展。此外，我们发现饮食能量平衡至少部分通过调节组织炎症和炎症来影响 PCa 进展。这些细胞变化与大量细胞因子、趋化因子和生长因子表达的局部变化有关，我们目前的数据表明，某些生长因子/炎症信号通路可能是预防和控制前列腺癌进展的关键靶点。在这个项目中，我们建议使用特征良好的 HiMyc 小鼠前列腺肿瘤模型以及我们最近开发的源自 HiMyc 小鼠的新型肿瘤细胞系（称为 HMVP2）来继续研究其机制。与相关联膳食能量平衡（特别是肥胖）对 PCa 进展的影响我们将这些研究重点放在肿瘤微环境上，特别是使用 HiMyc 小鼠模型研究白色脂肪组织 (WAT) 在驱动 PCa 进展中的作用。初步发现肥胖 HiMyc 小鼠 WAT 的基质血管部分 (SVF) 中趋化因子 CXCL12 (SDF-1) 高度上调，并将研究其在肥胖驱动的 PCa 进展中的作用在该小鼠模型中，要测试的假设是，在肥胖中，脂肪基质细胞 (ASC) 的募集部分通过其 G 蛋白偶联受体 CXCR4 和 CXCR7 的 CXCL12 信号传导促进 PCa 进展。 -WAT），专门消除 ASC，我们将测试该细胞群在癌症进展中的重要性，并通过使用敲除、敲低和确定其对肿瘤微环境中 CXCL12 信号传导的贡献。在过表达小鼠模型中，我们将检查靶向 CXCL12、CXCR4 和 CXCR7 是否可以抵消肥胖对 PCa 进展的影响。最后，我们将测试单独靶向 CXCL12/受体相互作用的小分子抑制剂或与天然存在的药物组合的功效。在生姜中发现的抗炎植物化学物质 [6-姜烯酚 (6-SHO)] 可抵消肥胖对 PCa 进展的影响。具体目标是： i) 识别导致 PCa 进展的细胞。在前列腺相关的 WAT 中产生 CXCL12；ii) 确定 ASC 衍生的 CXCL12 对肥胖驱动的 PCa 进展的重要性；iii) 研究 CXCR4 和 CXCR7 信号传导在肥胖驱动的 PCa 进展中的具体作用；以及 iv) 测试药物治疗方法；通过 CXCR4 抑制肥胖驱动的 PCa 进展中的 CXCL12 信号传导该项目的完成将为未来针对特定信号传导途径和/或细胞群的转化研究奠定基础。降低 PCa 死亡率并防止肥胖对 PCa 进展的影响。