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

肥胖已成为美国主要的健康流行病，影响到近30%的人口， 而且它显著增加了罹患包括癌症在内的多种疾病的风险。虽然 ARGE研究表明，男性与体重指数(BMI)和30公斤/米体重之间存在一致的联系 以及前列腺癌(PCA)死亡风险的增加，评估肥胖男性患前列腺癌风险的研究 都不是决定性的。脂肪组织具有内分泌器官的功能，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)。肥胖者的瘦素水平升高 由于小鼠不表达瘦素或瘦素受体，因此瘦素可维持正常体重。 真是太胖了。瘦素还可以诱导血管生成，刺激雄激素不敏感的细胞增殖 在侵袭性疾病较多的前列腺癌患者血清中，其水平升高。对比 ：o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因子， 可通过诱导支持血管系统的凋亡抑制体内PCa癌细胞的生长。此外， PEDF基因缺失的小鼠发生进行性前列腺PIN，间质血管密度高，并增加 腹部和盆腔脂肪组织沉积，瘦素和瘦素受体增加 在靶组织中表达，包括前列腺间质。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控因子，部分是通过负调控 瘦素。因此，肥胖可以促进局部和循环中瘦素和PEDF水平的失衡 一个有利于肿瘤形成的环境。本研究旨在(A)阐明PEDF和瘦素在肿瘤中的作用 并确定这些分子之间的信号通路，(B)确定格里森评分 与前列腺癌患者循环中游离瘦素和PEDF水平的相关性，以及(C)评估前列腺组织 瘦素、PEDF及其受体的表达水平或脂肪细胞密度对预后有价值。 在美国，肥胖是一个日益严重的公共健康问题，患某些癌症的风险更高 在肥胖者身上。这两种疾病之间联系的生物学基础尚不清楚。我们的 初步研究表明，脂肪细胞、瘦素和色素上皮之间存在一个信号网络。 衍生因子和这些因子中任何一种的失调都可以促进促进肿瘤形成的环境。 这里提出的研究有可能提供对癌症风险增加的机械洞察力。 肥胖患者，并可以确定前列腺癌的新预后标记物。

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.