Omega-3 eicosapentaenoic acid reduces prostate tumor vascularity

Abstract

The impact of omega (ω)-3 fatty acids on prostate cancer is controversial in epidemiological studies but experimental studies suggest a protective effect. However, little is known about the mechanism of action. Here, we studied the effects of purified fatty acid molecules on prostate tumor progression using the TRAMPC2 syngeneic immunocompetent mouse model. Compared with ω-6 or ω-9-supplemented animals, we observed that late-stage prostate tumor growth was reduced with a monoacylglyceride (MAG)-conjugated form of eicosapentaenoic acid (EPA) supplementation, whereas docosahexanenoic acid (DHA) caused an early reduction. MAG-EPA significantly decreased tumor blood vessel diameter (P < 0.001). RNA sequencing analysis revealed that MAG-EPA downregulated angiogenesis- and vascular-related pathways in tumors. We also observed this tissue vascular phenotype in a clinical trial testing MAG-EPA versus a high oleic sunflower oil placebo. Using anti-CD31 IHC, we observed that MAG-EPA reduced blood vessel diameter in prostate tumor tissue (P = 0.03) but not in normal adjacent tissue. Finally, testing autocrine and paracrine effects in an avascular tumor spheroid growth assay, both exogenous MAG-EPA and endogenous w3 reduced VEGF secretion and in vitro endothelial cell tube formation and blocked tumor spheroid growth, suggesting that ω3 molecules can directly hinder prostate cancer cell growth. Altogether, our results suggest that fatty acids regulate prostate cancer growth and that a tumor-specific microenvironment is required for the anti-vascular effect of MAG-EPA in patients with prostate cancer.