Effect of omega-3 fatty acid diet on prostate cancer progression and cholesterol efflux in tumor-associated macrophages-dependence on GPR120

BackgroundPreclinical and clinical translational research supports the role of an omega-3 fatty acid diet for prostate cancer prevention and treatment. The anti-prostate cancer effects of an omega-3 diet require a functional host g-protein coupled receptor 120 (GPR120) but the underlying effects on the tumor microenvironment and host immune system are yet to be elucidated.MethodsFriend leukemia virus B (FVB) mice received bone marrow from green fluorescent protein (GFP) labeled GPR120 wild-type (WT) or knockout (KO) mice followed by implanting Myc-driven mouse prostate cancer (MycCap) allografts and feeding an omega-3 or omega-6 diet. Tumor associated immune cells were characterized by flow cytometry, and CD206+ tumor infiltrating M2-like macrophages were isolated for gene expression studies. MycCap prostate cancer cell conditioned medium (CM) was used to stimulate murine macrophage cells (RAW264.7) and bone marrow-derived (BMD) macrophages to study the effects of docosahexanoic acid (DHA, fish-derived omega-3 fatty acid) on M2 macrophage function and cholesterol metabolism.ResultsThe bone marrow transplantation study showed that an omega-3 as compared to an omega-6 diet inhibited MycCaP allograft tumor growth only in mice receiving GPR120 WT but not GPR120 KO bone marrow. In the omega-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. RAW264.7 murine macrophages and BMDMs exposed to MycCaP cell CM had increased gene expression of cholesterol transporters, depleted cholesterol levels, and were converted to the M2 phenotype. These effects were inhibited by DHA through the GPR120 receptor.ConclusionHost bone marrow cells with functional GPR120 are essential for the anticancer effects of dietary omega-3 fatty acids, and a key target of the omega-3 diet are the M2-like CD206+ macrophages. Our preclinical findings provide rationale for clinical trials evaluating omega-3 fatty acids as a potential therapy for prostate cancer through inhibition of GPR120 functional M2-like macrophages.

Automated summary

Preclinical and clinical translational research supports the role of an omega-3 fatty acid diet for prostate cancer prevention and treatment, but the underlying mechanisms are not fully understood. This study found that the anticancer effects of an omega-3 diet are mediated through GPR120 functional M2-like macrophages.