Macrophage Inhibitory Cytokine-1 Induced by a High-Fat Diet Promotes Prostate Cancer Progression by Stimulating Tumor Promoting Cytokine Production from Tumor Stromal Cells

Background: Recent studies have indicated that a high-fat diet (HFD) and/or HFD-induced obesity may influence prostate cancer (PCa) progression, but the role of HFD in PCa microenvironment is unclear. Methods: : In this study, we investigated the role of HFD on PCa stromal microenvironment using the PC-3M-luc-C6 PCa model mice fed with HFD or control diet, especially focusing on macrophage inhibitory cytokine-1 (MIC-1) and its effect on the tumor microenvironment. In addition, the synergistic effect of periprostatic adipocytes (PPAC), derived from primary PCa patients, on activation and cytokine secretion of prostate stromal fibroblasts were investigated. The expression pattern and role of MIC-1 signaling on human PCa stroma activation and PCa progression were investigated. Results: : The HFD consumption stimulated PCa cell growth and invasion as a result of upregulated MIC-1 signaling and subsequent increased secretion of interleukin (IL)-8 and IL-6 from prostate stromal fibroblasts in the PC-3M-luc-C6 PCa model mice. In addition, PPAC directly stimulated MIC-1 production from PC-3 cells and IL-8 secretion in prostate stromal fibroblasts through upregulation of the adipolysis and free fatty acid (FFA) release. The increased serum MIC-1 was significantly correlated with human PCa stroma activation, high serum IL-8, IL-6 and lipase activity, advanced PCa progression, and high body mass index of the patients. Glial-derived neurotrophic factor receptor alpha-like (GFRAL), a specific receptor of MIC-1, was highly expressed in both the cytoplasm and membrane of the PCa cells and the surrounding stromal fibroblasts, and the expression level was decreased by androgen deprivation therapy and chemotherapy. Conclusion: HFD-mediated activation of the PCa stromal microenvironment through metabolically upregulated MIC-1 signaling by increased available free fatty acids may be a critical mechanism of HFD and/or obesity induced PCa progression.