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: 8444310
• 负责人: Susan Crawford
• 金额: $ 20.54万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444310
• 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 Patient; Cell Communication; Cessation of life; Clinical; Data; Deposition; Disease; Endocrine Glands; Environment; Enzyme-Linked Immunosorbent Assay; Epidemic; Epithelial; Epithelial Cells; 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; P-2; 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 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; prostate cancer cell; prostate cancer model; 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.

肥胖已经成为美国主要的健康流行病，影响了近30%的人口，