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

P-2：PEDF 对前列腺 CA 中脂肪生成和瘦素的调节

• 批准号: 8055505
• 负责人: Susan Crawford
• 金额: $ 19.73万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-31 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055505
• 关键词: Abdomen; Accounting; Adipocytes; Adipose tissue; Affect; Angiogenesis Inhibitors; Animals; Antibodies; Apoptosis; Biological Markers; Biology; Body Weight; Body mass index; Cancer Cell Growth; Cancer Model; Cancer Patient; Cell Communication; Cessation of life; Clinical; Data; Deposition; Disease; Endocrine Glands; Environment; Enzyme-Linked Immunosorbent Assay; Epidemic; Epithelial; Epithelial Cells; Fibrinogen; Gleason Grade for Prostate Cancer; Growth; Harvest; Health; Hyperplasia; Individual; Knockout Mice; Leptin; Link; Lipase; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Mediator of activation protein; Messenger RNA; Mus; Obesity; PTEN gene; Patients; Pelvis; Phenotype; Physiological Processes; Population; Postmenopause; Prognostic Marker; Prostate; Prostatic; Proteins; Public Health; Records; Regulation; Relative (related person); Research Personnel; Retrospective Studies; Risk; Risk Factors; Role; Serum; Signal Pathway; Signal Transduction; Source; Specimen; Staining method; Stains; Testing; Tissue Microarray; Tissues; United States; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; Weight Gain; Woman; adipokines; adipophilin; advanced disease; androgen independent prostate cancer; angiogenesis; cancer cell; cancer risk; cell growth; cohort; density; high risk; in vivo; indexing; insight; leptin receptor; lipid biosynthesis; malignant breast neoplasm; men; neutralizing antibody; novel; obesity risk; pigment epithelium-derived factor; pigment epithelium-derived factor receptor; prognostic; promoter; receptor; receptor expression; tumor; tumor progression; tumorigenic

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.

肥胖已成为美国的主要健康流行，影响了近30％的人口， 它大大增加了发展包括癌症在内的广泛疾病的风险。虽然 ARGE研究表明，具有体重指数（BMI）> 30 kg/m的男性之间的联系一致 以及前列腺癌（PCA）死亡的风险增加，研究评估肥胖男性PCA风险的研究 不是结论性的。脂肪组织充当内分泌器官，是可溶性蛋白质的丰富来源 NCLUD瘦素和色素上皮衍生因子（PEDF）。瘦素水平升高 ndividuals及其功能可以保持正常体重，因为小鼠无效瘦素或瘦素受体 Oecome肥胖。瘦素还可以诱导血管生成并刺激雄激素不敏感的增殖 PCA细胞及其水平在患有更具侵略性疾病的PCA患者的血清中升高。相比之下 ：o瘦素的肿瘤促进活动，我们的数据表明，PEDF是一种有效的血管生成抑制剂 可以通过诱导支撑脉管系统的凋亡来抑制体内PCA癌细胞的生长。而且， PEDF NULL小鼠出现高基质血管的进行性前列腺销，并增加了 脂肪组织在腹部和盆腔中的沉积，瘦素和瘦素受体增加 靶组织中的表达，包括前列腺基质。在PCA患者中，血清中的PEDF水平为 Gleason评分较高的患者明显降低。从这些数据中，我们假设PEDF是 前列腺生长和脂肪形成的重要负调节剂，部分是通过负调节 瘦素。因此，肥胖可以促进局部和循环的瘦素和PEDF水平的失衡 到亲肿瘤的环境。这项研究打算（a）阐明PEDF和瘦素在肿瘤中的作用 进展并确定这些分子之间的信号传导途径，（b）确定格里森评分是否是 与PCA患者的游离瘦素和PEDF的循环水平相关，以及（c）评估前列腺组织是否 瘦素，PEDF及其受体或脂肪细胞密度的表达水平具有预后价值。 肥胖是美国越来越多的公共卫生问题，某些癌症的风险更高 在肥胖的个体中。这两种疾病之间联系的生物学尚不清楚。我们的 初步研究表明，脂肪细胞，瘦素和色素上皮之间存在信号网络 这些因素中任何一个因素的衍生因子和失调都可以促进促肿瘤的环境。 这里提出的研究有可能提供机械洞察力，以了解增强的癌症风险 肥胖患者，可以鉴定前列腺癌的新预后标记。