The impact of obesity on prostate cancer progression

The link between obesity and the risk of prostate cancer (PCa) is inconclusive. However, studies demonstrate a correlation between obesity, advanced PCa and mortality. Investigating the underlying biological mechanisms by which obesity promotes advanced PCa is necessary to develop potential therapeutic targets that may aid in the efficacy of treating obese men. Obesity-associated changes in tumor biology may modulate key aspects of the hallmarks of cancer; acquisition of characteristics essential for the development and progression of cancer. We hypothesized obesity-induced inflammation promotes PCa progression. Our studies incorporated cell culture and murine models to investigate the role of obesity-related systemic factors on AR signaling, inflammation-stimulated invasive PCa, and the paracrine interaction of the tumor-microenvironment (TME). We sought to recapitulate the systemic effects of obesity to investigate characteristics of the metastatic cascade. Briefly, sera from mice fed 60% or 10% kcal from fat diet for 12 weeks were used for in vitro studies. PCa cells exposed to sera from obese mice increased AR transcriptional activity, proliferation, invasion, migration, MMP-9 activity and EMT: e-cadherin, vimentin and β-catenin. PCa cells exposed to sera from 1 hour maintained the invasive phenotypes similar to PCa cells directly exposed to sera from obese mice. IL-6 is associated with advanced PCa cancer. Depleting sera of IL-6 or IL-6 shRNA suppressed obesity-induced proliferation, invasion, migration and MMP-9 activity in LNCaP cells. Furthermore, in a PTEN spontaneous model of PCa, IL-6 protein and mRNA levels corresponded with progression of PCa in mice fed a high-fat diet. These results suggest IL-6 mediates obesity-induced PCa progression.
Stromal cells that comprise the TME vary in their contribution to the growth of tumors. Our studies show macrophage-like and myofibroblasts increased NF-kB activity in PCa cells exposed to sera from obese mice. An increase in NF-kB activity corresponded with proliferation, prostaglandin E2, and invasion and recruitment of stromal cells by PCa cells. In summary, obesity-related systemic factors promote an invasive PCa phenotype, which may be mediated by Akt, AR, IL-6 and the TME. Obesity-induced changes in tumor biology and the microenvironment provide a niche suitable for invasive prostate cancer.