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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Northwestern University at Chicago
United States
Zip Code
Hung, Michelle E; Lenzini, Stephen B; Stranford, Devin M et al. (2018) Enrichment of Extracellular Vesicle Subpopulations Via Affinity Chromatography. Methods Mol Biol 1740:109-124
Weiner, Adam B; Tsai, Kyle P; Keeter, Mary-Kate et al. (2018) The Influence of Decision Aids on Prostate Cancer Screening Preferences: A Randomized Survey Study. J Urol 200:1048-1055
Nettey, Oluwarotimi S; Walker, Austin J; Keeter, Mary Kate et al. (2018) Self-reported Black race predicts significant prostate cancer independent of clinical setting and clinical and socioeconomic risk factors. Urol Oncol 36:501.e1-501.e8
Xu, Li; Gordon, Ryan; Farmer, Rebecca et al. (2018) Precision therapeutic targeting of human cancer cell motility. Nat Commun 9:2454
Zhang, Qiang; Helfand, Brian T; Carneiro, Benedito A et al. (2018) Efficacy Against Human Prostate Cancer by Prostate-specific Membrane Antigen-specific, Transforming Growth Factor-? Insensitive Genetically Targeted CD8+ T-cells Derived from Patients with Metastatic Castrate-resistant Disease. Eur Urol 73:648-652
Pascal, Laura E; Masoodi, Khalid Z; Liu, June et al. (2017) Conditional deletion of ELL2 induces murine prostate intraepithelial neoplasia. J Endocrinol 235:123-136
Dominguez, Donye; Ye, Cong; Geng, Zhe et al. (2017) Exogenous IL-33 Restores Dendritic Cell Activation and Maturation in Established Cancer. J Immunol 198:1365-1375
Murphy, A B; Nyame, Y A; Batai, K et al. (2017) Does prostate volume correlate with vitamin D deficiency among men undergoing prostate biopsy? Prostate Cancer Prostatic Dis 20:55-60
Loeb, Stacy; Shin, Sanghyuk S; Broyles, Dennis L et al. (2017) Prostate Health Index improves multivariable risk prediction of aggressive prostate cancer. BJU Int 120:61-68
Zhang, Minghui; Dominguez, Donye; Chen, Siqi et al. (2017) WEE1 inhibition by MK1775 as a single-agent therapy inhibits ovarian cancer viability. Oncol Lett 14:3580-3586

Showing the most recent 10 out of 209 publications