Effect of Omega-3 Fatty Acid Diet on Prostate Cancer Progression and Cholesterol Efflux in Tumor Associated Macrophages – Dependence on GPR120

Abstract

Abstract Background Preclinical and clinical translational research supports the role of an ω-3 fatty acid diet for prostate cancer prevention and treatment. The anti-prostate cancer effects of an ω-3 diet require a functional host g-protein coupled receptor (GPR120) but the underlying effects on the immune system in the tumor microenvironment are yet to be elucidated. Methods FVB mice received bone marrow from green fluorescent protein (GFP) labeled GPR120 wild-type (WT) or knockout (KO) mice followed by MycCap allograft implantation. Mice were fed an ω-3 diet compared to an ω-6 diet. Tumor associated immune cells were characterized by flow cytometry. Transgenic FVB hi-Myc mice were fed an ω-3 compared to an ω-6 diet for 6 months followed by pathology analysis of prostate lobes. Results Through the use of a bone marrow transplantation model, we found that an ω-3 as compared to an ω-6 diet inhibited MycCaP allograft tumor growth in mice receiving GPR120 WT but not GPR120 KO bone marrow. In the ω-3 group, GPR120 WT BMD M2-like macrophages infiltrating the tumor were significantly reduced in number and gene expression of cholesterol transporters Abca1, Abca6, and Abcg1. In addition, feeding an ω-3 as compared to an ω-6 diet slowed the progression to adenocarcinoma in a transgenic hi-Myc prostate cancer mouse model with functional GPR120. M2 macrophages play a critically important role in prostate cancer progression. Herein we report that RAW264.7 cells and BMD macrophages exposed to MycCaP cell conditioned media had increased gene expression of cholesterol transporters, depleted cholesterol levels, and were converted to the M2 phenotype. These effects were inhibited by ω-3 fatty acids through the GPR120 receptor. Conclusion Our preclinical findings provide rationale for clinical trials evaluating ω-3 fatty acids as a potential therapy for prostate cancer through inhibition of GPR120 functional M2 macrophages.