P-2: PEDF Regulation of Adipogenesis and Leptin in Prostate CA

肥胖已成为美国的一个主要健康流行病，影响近30%的人口， 并且它显著增加了患包括癌症在内的多种疾病的风险。虽然 大量研究表明，体重指数（BMI）>30 kg/m2的男性之间存在一致的联系 和前列腺癌（PCa）死亡风险增加，评估肥胖男性PCa风险的研究 并不确定脂肪组织作为一种内分泌器官，是可溶性蛋白质的丰富来源 包括瘦素和色素上皮衍生因子（PEDF）。肥胖者瘦素水平升高 由于小鼠缺乏瘦素或瘦素受体， Oecome肥胖.瘦素还可以诱导血管生成，刺激雄激素不敏感的 PCa细胞，并且其水平在具有更侵袭性疾病的PCa患者的血清中升高。对比 关于瘦素的促肿瘤活性，我们的数据显示PEDF是一种有效的血管生成抑制剂， 可以通过诱导支持脉管系统的凋亡来抑制体内PCa癌细胞生长。此外，委员会认为， PEDF敲除小鼠发展具有高基质血管分布的进行性前列腺PIN， 腹部和盆腔脂肪组织沉积，瘦素和瘦素受体增加 在靶组织中的表达，包括前列腺基质。在PCa患者中，血清PEDF水平为 在Gleason评分较高的患者中显著降低。根据这些数据，我们假设PEDF是一种 前列腺生长和脂肪形成的重要负调节剂，部分通过负调节 瘦素因此，肥胖可以促进局部和循环瘦素和PEDF水平的失衡，导致 一个促肿瘤发生的环境。本研究旨在（a）阐明PEDF和瘦素在肿瘤中的作用 （B）确定Gleason评分 与PCa患者中游离瘦素和PEDF的循环水平相关，以及（c）评估前列腺组织是否 瘦素、PEDF及其受体的表达水平或脂肪细胞密度具有预后价值。 在美国，肥胖是一个日益严重的公共健康问题，某些癌症的风险也更高 在肥胖个体中。这两种疾病之间联系的生物学基础尚不清楚。我们 初步研究表明，脂肪细胞、瘦素和色素上皮细胞之间存在信号网络 衍生因子和这些因子中任一种的失调可促进促肿瘤发生环境。 这里提出的研究有可能提供机制的见解，提高癌症的风险， 肥胖患者，并可以确定新的前列腺癌预后标志物。

Obesity has become a major health epidemic in the United States, affecting nearly 30% of the population, and it significantly increases the risk of developing a wide spectrum of diseases including cancer. Although arge studies have demonstrated a consistent link between men with a body mass index (BMI) >30 kg/m and an increased risk of death from prostate cancer (PCa), studies evaluating the risk of PCa in obese men are not conclusive. Adipose tissue functions as an endocrine organ and is a rich source of soluble proteins ncluding leptin and pigment epithelium-derived factor (PEDF). Leptin levels are elevated inobese ndividuals, and it functions to maintain normal body weight since mice null for leptin or the leptin receptor oecome obese. Leptin can also induce angiogenesis and stimulate the proliferation of androgen-insensitive PCa cells, and its levels are elevated in the serum of PCa patients with more aggressive disease. Incontrast :o leptin's tumor promoting activities, our data revealed that PEDF is a potent inhibitor of angiogenesis that can suppress PCa cancer cell growth in vivo by inducing apoptosis of the supporting vasculature. Moreover, PEDF null mice develop progressive prostatic PIN with high stromal vascularity and have increased deposition of adipose tissue in the abdominal and pelvic regions with increased leptin and leptin receptor expression in target tissues, including the prostate stroma. In PCa patients, PEDF levels in serum were significantly lower in patients with higher Gleason scores. From these data, we hypothesized that PEDF is an important negative regulator of prostate growth and of adipogenesis, in part, through negative regulation of leptin. Therefore, obesity can promote an imbalance in local and circulating leptin and PEDF levels leading to a pro-tumorigenic environment. This study intends to (a) elucidate the roles of PEDF and leptin in tumor progression and identify the signaling pathways between these molecules, (b) determine if Gleason score correlates with circulating levels of free leptin and PEDF in PCa patients, and (c) to assess if prostate tissue expression levels of leptin, PEDF and their receptors, or adipocyte density, have prognostic value. Obesity is an increasing public health problem in the United States and the risk of certain cancers are higher in obese individuals. The biology underlying the link between these two diseases remains unclear. Our preliminary studies suggest that a signaling network exists between fat cells, leptin and pigment epithelium derived factor and dysregulation of any one of these factors can promote a pro-tumorigenic environment. The studies proposed here have the potential to provide mechanistic insight into the enhanced cancer risk in obese patients and could identify new prognostic markers for prostate cancer.