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：
9751218
负责人：
John DiGiovanni
金额：
$ 38.44万
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 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9751218
关键词：
AMD3100 Adipose tissue Affect 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 Pharmacology Phytochemical Play Population Property Prostate Prostatic Neoplasms Role Signal Pathway Signal Transduction Stromal Cell-Derived Factor 1 Stromal Cells Study Section Testing Thinness Time Tissues Transgenic Mice Tumor Cell Line angiogenesis cell growth chemokine cytokine design efficacy testing energy balance experimental study genetic approach in vivo innovation insight knock-down migration mortality mouse model neoplastic cell novel overexpression prevent prostate cancer model prostate cancer progression protein expression public health relevance receptor recruit shogaol small molecule inhibitor 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（由适用提供）：许多研究表明，饮食能量平衡在前列腺癌（PCA）以及许多其他癌症中起着重要作用。我们最近的研究表明，饮食诱导的肥胖症（DIO）在HIMYC转基因小鼠中PCA的进展增强，而卡路里限制（CR）在这种PCA小鼠模型中抑制了进展。此外，我们发现饮食能量平衡至少部分通过调节组织注射和血管生成会影响HIMYC小鼠的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的局部变化有关。总体而言，我们当前的数据表明，某些生长因子/炎症信号通路可能是预防和控制PCA进展，尤其是与肥胖相关的PCA进展的关键目标。在该项目中，我们建议使用良好的HIMYC小鼠前列腺肿瘤模型以及源自HIMYC小鼠（称为HMVP2）的新型肿瘤细胞系，我们最近开发了这些肿瘤细胞系，以继续研究与饮食能量平衡效应相关的机制，尤其是PCA进展。我们将这些研究将这些研究集中在肿瘤微环境上，尤其是使用HISYC小鼠模型在驱动PCA进展中的作用。我们还将关注初步发现，即趋化因子CXCL12（SDF-1）在肥胖HIMYC小鼠的WAT的基质血管分数（SVF）中高度更新，并将研究其在该小鼠模型中肥胖症驱动的PCA进展中的作用。要检验的假设是，在肥胖症中，脂肪基质细胞（ASC）的募集通过其G蛋白偶联受体CXCR4和CXCR7促进PCA进展，部分通过CXCL12信号传导。通过使用特别消融ASC的肽（D-WAT），我们将测试该细胞种群在癌症进展中的重要性，并确定其对肿瘤微环境中CXCL12信号的贡献。通过使用敲除，敲低和过表达小鼠模型，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，我们将单独或与天然存在的抗炎植物化学[6-Shogaol（6-Sho）]相结合的小分子抑制剂靶向CXCL12/受体相互作用的有效性，以抵消肥胖对PCA进展的影响。具体目的是：i）确定在前列腺相关的WAT中产生CXCL12的细胞； 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信号在肥胖驱动的PCA进程中的特定作用； iv）测试药物方法在肥胖驱动的PCA进展中通过CXCR4抑制CXCL12信号传导。该项目的完成将为未来的转化研究提供针对特定信号通路和/或细胞种群的未来翻译研究，以降低PCA死亡率并防止肥胖对PCA进展的影响。