High-Fat Diet-Induced Inflammation Accelerates Prostate Cancer Growth via IL6 Signaling

Abstract

High-fat diet (HFD) could induce prostate cancer progression. The aim of this study is to identify mechanisms of HFD-induced prostate cancer progression, focusing on inflammation. We administered HFD and celecoxib to autochthonous immunocompetent Pb-Cre;(fl/fl) model mice for prostate cancer. Tumor growth was evaluated by tumor weight and Ki67 stain, and local immune cells were assessed by flow cytometry at 22 weeks of age. Cytokines which correlated with tumor growth were identified, and the changes of tumor growth and local immune cells after inhibition of the cytokine signals were evaluated in the mice. IHC analyses using prostatectomy specimens of obese patients were performed. HFD accelerated tumor growth and increased the myeloid-derived suppressor cells (MDSCs) fraction and M2/M1 macrophage ratio in the model mice. Celecoxib-suppressed tumor growth, and decreased both local MDSCs and M2/M1 macrophage ratio in HFD-fed mice. HFD-induced tumor growth was associated with IL6 secreted by prostatic macrophages, as were phosphorylated STAT3 (pSTAT3)-positive tumor cells. Anti-IL6 receptor antibody administration suppressed tumor growth, and decreased local MDSCs and pSTAT3-positive cell fractions in HFD-fed mice. The tumor-infiltrating CD11b-positive cell count was significantly higher in prostatectomy specimens of obese than those of nonobese patients with prostate cancer. HFD increased MDSCs and accelerated prostate cancer tumor growth via IL6/pSTAT3 signaling in the mice. This mechanism could exist in obese patients with prostate cancer. IL6-mediated inflammation could be a therapeutic target for prostate cancer. .

Metformin inhibits prostate cancer growth induced by a high‐fat diet in Pten‐deficient model mice

“…From these reports, metformin is suggested to suppress the accumulation of MDSCs reflecting inflammation in the prostate, which decreased prostate weights. HFD resulted in obesity in our previous report using Pten ‐deficient model mice . The present results suggest that metformin could have potential clinical benefits for obese prostate cancer patients.…”

“…Metformin was reported to reduce prostate cancer growth prominently under HFD, acting through the modulation of several tumoral‐associated processes in a xenograft model of human cell lines using immunodeficient mice . We have reported that HFD increased local MDSCs and accelerated prostate cancer growth through interleukin‐6/pSTAT3 signaling in genetically‐engineered ( Pten ‐deficient) model mice, and that these phenomena could also exist in humans . The aim of the present study was to ascertain how metformin inhibits prostate cancer growth, using immunocompetent Pten ‐deficient model mice and HFD.…”

“…All mice were killed at 22 weeks‐of‐age for evaluation of tumor weight and local MDSCs. Tumor weight was correlated with prostate cancer growth in the model mice, and local MDSCs were evaluated by flow cytometry . CD45 FITC (clone: 30‐F11; BD Pharmingen, Franklin Lakes, NJ, USA), CD11b APC (clone: M1/70; BD Pharmingen), Ly‐6G and Ly‐6C PE (clone: RB6‐8C5; BD Pharmingen) were used as antibodies for flow cytometry.…”

Influence of Diet and Nutrition on Prostate Cancer

“…Previous studies have focused on the relationship between fat-induced inflammation and PCa [29][30][31][32][33]. In a study using prostate-specific phosphatase and tensin homolog (Pten) −/− mice, we found that an HFD doubled the tumor weight in the model mice but did not increase tumor weight in mice administrated celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, or an anti-interleukin (IL)-6 antibody [29].…”

Myeloid‐derived suppressor cells: Roles in the tumor microenvironment and tumor radiotherapy

“…High‐fat diet could induce prostate cancer progression through increasing MDSCs via IL‐6/pSTAT3 signaling in the mice. This mechanism could exist in obese prostate cancer patients . Besides STAT3, the other STAT family members including STAT1, STAT5 and STAT6 also have significant effects on the activity and function of MDSCs .…”