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

 描述(申请人提供)：许多研究表明，饮食能量平衡在前列腺癌(PCa)和许多其他癌症中起着重要作用。我们最近的研究表明，饮食诱导肥胖(DIO)促进了HiMyc转基因小鼠前列腺癌的进展，而限制卡路里(CR)则抑制了这种PCa小鼠模型的进展。此外，我们还发现，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小鼠的PCA进展。这些细胞变化与局部大量细胞因子、趋化因子和生长因子表达的变化有关。总体而言，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，特别是与肥胖相关的PCa进展的关键靶点。在这个项目中，我们建议使用描述良好的HiMyc小鼠前列腺癌模型以及我们最近开发的来自HiMyc小鼠的新的肿瘤细胞系(称为HMVP2)来继续研究与饮食能量平衡效应相关的机制，特别是肥胖对前列腺癌进展的影响。我们将利用HiMyc小鼠模型重点研究肿瘤微环境，特别是白色脂肪组织(WAT)在推动PCa进展中的作用。我们还将重点关注初步发现，趋化因子CXCL12(SDF-1)在肥胖HiMyc小鼠WAT的间质血管部分(SVF)高度上调，并将在该小鼠模型中研究其在肥胖驱动的PCa进展中的作用。需要检验的假设是，在肥胖中，脂肪基质细胞(ASC)的招募部分通过其G蛋白偶联受体CXCR4和CXCR7通过CXCL12信号促进了PCA的进展。通过使用一种特异性地去除ASC的多肽(D-Wat)，我们将测试这种细胞群在癌症进展中的重要性，并确定其在肿瘤微环境中对CXCL12信号的贡献。通过使用基因敲除、基因敲除和过度表达的小鼠模型，我们将检验靶向CXCL12、CXCR4和CXCR7是否可以抵消肥胖对前列腺癌进展的影响。最后，我们将测试针对CXCL12/受体相互作用的小分子抑制剂的有效性，或者与生姜中发现的自然产生的抗炎植物化学物质[6-shogaol(6-SHO)]联合使用，以抵消肥胖对前列腺癌进展的影响。其具体目的是：i)确定前列腺癌相关WAT中产生CXCL12的细胞；ii)确定ASC来源的CXCL12在肥胖驱动的PCa进展中的重要性；iii)研究CXCR4和CXCR7信号在肥胖驱动的PCa进展中的具体作用；以及iv)测试通过CXCR4抑制CXCL12信号在肥胖驱动的PCa进展中的药理学方法。该项目的完成将为未来针对特定信号通路和/或细胞群体的转译研究提供基础，以降低PCa死亡率并防止肥胖对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.