Abstract 971: Obesity initiates a self-perpetuating inflammatory response in LNCaP prostate cancer cells

Abstract

Abstract Background: Obesity increases prostate cancer (PCa) mortality but the mechanism remains unclear. Obesity induced chronic inflammation may be an important factor in advanced PCa. Studies have shown a local inflammatory microenvironment can promote prostate tumorigenesis. Obese men with advanced PCa have high levels of cytokines in their prostate and plasma. Clinical studies promoting weight loss in obese PCa patients have not demonstrated significant benefit in reducing disease progression, suggesting that once initiated, progression is self-sustaining. The role of obesity in stimulating the release of inflammatory autocrine factors in PCa cells and its effect on metastasis remains unclear. Previously, we have shown PCa cells exposed to obese sera increased migration, invasion, proliferation, MMP -9 activity and changes in EMT markers. Our aim was to determine whether PCa cells sustain an inflammatory response initiated by obesity and autocrine factors secreted by PCa cells sustain the metastatic phenotype shown in our previous studies. We hypothesize obesity initiates a self-perpetuating inflammatory response in PCa cells increasing metastatic potential. 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, mice were sacrificed, sera was collected and used for in vitro studies. To determine if the initial effects of obesity on PCa invasion are sustained by soluble factors secreted by PCa cells, we treated LNCaP cells with obese or control sera for 30 minutes. Treatments were replaced with serum free media for 18 hours. After 18 hours, conditioned media (CM) was harvested and used for in vitro studies. Cytokine protein array was used to detect a cytokines in conditioned media. Biological assays were used to investigate the effect of conditioned media on invasion, changes in EMT markers, proliferation and cell migration. Results: After stimulation with obese sera, PCa cells secreted high levels of cytokines that mediate inflammatory processes including CCL2, IL-6, IL-8, Rantes and SDF-1. PCa cells treated with obese-stimulated CM resulted in a 2-fold increase in invasive capacity. Obese-stimulated CM resulted in a dispersion of e-cadherin from the cell membrane and nuclear translocation of β-catenin. CM from cells treated with obese sera modulated migration and proliferation promoting an aggressive prostate cancer phenotype. Conclusion: PCa cells treated with obese sera sustain an inflammatory response in the absence of sera. Autocrine factors secreted by obesity treated cells sustain the metastatic phenotype similar to that of PCa cells treated directly with obese sera. The preliminary results from these in vitro studies warrant further in vivo research into the role of weight loss either through diet or exercise on PCa progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 971. doi:10.1158/1538-7445.AM2011-971