Abstract 1526: Obesity modulates the microenvironment promoting NF-κB activity in prostate cancer cells
Authors: Price Ramona Salcedo , Cavazos David , deGraffenried Linda A. 
Published: August 2012

Background: Obese men have an increased risk in dying from prostate cancer (PCa) but the mechanism(s) remain unclear. Obesity results in chronic inflammation and the local inflammatory microenvironment may promote prostate tumorigenesis. Specifically, Inflammatory mediators such as IL-6 and NF-κB are associated with advanced PCa. NF-κB is a family of transcription factors that control survival, proliferation, angiogenesis and invasion. Studies have shown that tumor-associated fibroblasts and inflammatory cells may adversely effect tumor progression and promote therapeutic resistance. The role of obesity in modulating the microenvironment and its effect on prostate tumor progression is unknown. We have shown sera from obese mice increases migration, invasion and proliferation in PCa cells. Similar to cancer cells exposed to sera from obese mice; the microenvironment may induce NF-κB activation and promote migration, invasion, and proliferation in PCa cells. Because NF-κB is important in advanced PCa, our aim was to determine whether obesity initiates fibroblast and monocyte-induced NF-κB activity in PCa cells. We hypothesize obesity-modulates the microenvironment increasing NF-κB activity in prostate cancer cells. Methods: We developed an in vitro model, which mimics the systemic effect of obesity. 6 week old C57bl/6 male mice were fed a diet induced obesity chow (60% calories from fat) or control chow (10% calories from fat). After 12 weeks, sera were collected. LNCaP (PCa), WPMY (myofibroblasts) and U937 (macrophage-like) cells were used for in vitro studies. Conditioned media (CM) was obtained by exposing WPMY or U937 to mice sera, the media was removed, cells were washed with PBS and serum free media was added. After 18 hours, CM was harvested. Luciferase assay was used to measure NF-κB transcriptional activity. MTT was employed to measure proliferation. Invasion chambers were used to measure invasive capacity. Western blot will be used to measure BCL-2, Survivin, VEGF, IL-1α and C-Myc. Results: LNCaP cells exposed to WPMY obese-CM and U937 obese-CM significantly increased NF-κB activity compared to control-CM (p value&lt;0,05). LNCaP cells co-cultured with WPMY or U937 and obese sera increased NF-κB activity 2 fold compared to control. There was no difference in NF-κB transcriptional activity in LNCaP cells exposed to obese or control sera. Obese-CM from U937 promotes proliferation while fibroblasts had no significant difference between obese-CM or control-CM. Obesity results in increased invasive capacity of WPMY and U937 cells. LNCaP cells exposed WPMY or U937 obese-CM resulted in increased invasion. Conclusion: Obesity modulates the microenvironment; myofibroblasts and macrophage-like cells, promoting invasion, proliferation and NF-κB activity in PCa cells. Understanding the link between obesity and the tumor microenvironment may provide therapeutic targets.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1526. doi:1538-7445.AM2012-1526