权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.