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

 描述（由申请人提供）：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（DIO）增强了HiMyc转基因小鼠中PCa的进展，而热量限制（CR）抑制了PCa小鼠模型的进展。此外，我们发现饮食能量平衡至少部分地通过调节组织炎症和血管生成来影响HiMyc小鼠中的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表达的局部变化相关。总的来说，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PCa进展，特别是肥胖相关PCa进展的关键靶点。在这个项目中，我们建议使用充分表征的HiMyc小鼠前列腺肿瘤模型以及我们最近开发的来自HiMyc小鼠的新型肿瘤细胞系（称为HMVP 2），以继续研究与饮食能量平衡效应相关的机制，特别是肥胖，对PCa进展的影响。我们将把这些研究的重点放在肿瘤微环境，特别是白色脂肪组织（WAT）的作用，在驱动PCa的发展使用HiMyc小鼠模型。我们还将关注趋化因子CXCL 12（SDF-1）在肥胖HiMyc小鼠WAT的基质血管部分（SVF）中高度上调的初步发现，并将研究其在该小鼠模型中肥胖驱动的PCa进展中的作用。待检验的假设是，在肥胖症中，脂肪基质细胞（ASC）的募集部分地通过CXCL 12信号传导经由其G蛋白偶联受体CXCR 4和CXCR 7促进PCa进展。通过使用特异性消融ASC的肽（D-WAT），我们将测试该细胞群在癌症进展中的重要性，并确定其对肿瘤微环境中CXCL 12信号传导的贡献。通过使用敲除、敲低和过表达小鼠模型，我们将研究靶向CXCL 12、CXCR 4和CXCR 7是否可以抵消肥胖对PCa进展的影响。最后，我们将测试靶向CXCL 12/受体相互作用的小分子抑制剂单独或与生姜中发现的天然抗炎植物化学物质[6-姜烯酚（6-SHO）]组合的功效，以抵消肥胖对PCa进展的影响。具体目标是：i）鉴定在前列腺相关WAT中产生CXCL 12的细胞; ii）确定ASC衍生的CXCL 12对肥胖驱动的PCa进展的重要性; iii）研究CXCR 4和CXCR 7信号传导在肥胖驱动的PCa进展中的具体作用;以及iv）测试在肥胖驱动的PCa进展中通过CXCR 4抑制CXCL 12信号传导的药理学方法。该项目的完成将为未来针对特定信号通路和/或细胞群的翻译研究提供基础，以降低PCa死亡率并预防肥胖对PCa进展的影响。

 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.