Metformin Inhibits Prostate Cancer Progression by Targeting Tumor-Associated Inflammatory Infiltration

Qiuli Liu, Dali Tong, Gaolei Liu, Jie Gao, Lin-ang Wang, Jing Xu, Xingxia Yang, Qiubo Xie, Yiqiang Huang, Jian Pang, Luofu Wang, Yong He, Dianzheng Zhang, Qiang Ma, Weihua Lan, Jun Jiang

Inflammatory infiltration plays important roles in both carcinogenesis and metastasis. We are interested in understanding the inhibitory mechanism of metformin on tumor-associated inflammation in prostate cancer. By using TRAMP mouse model, in vitro macrophage migration assays, and patient samples, we examined the effect of metformin on tumor-associated inflammation during the initiation and after androgen deprivation therapy of prostate cancer. Treating TRAMP mice with metformin delays prostate cancer progression from LGPIN to HGPIN, WD to UD, and PIN to adenocarcinoma with concurrent inhibition of inflammatory infiltration evidenced by reduced recruitment of macrophages. Furthermore, metformin is capable of inhibiting the following processes: inflammatory infiltration after ADT induced by surgically castration in mice, bicalutamide treatment in patients and hormone deprivation in LNCaP cells. Mechanistically, metformin represses inflammatory infiltration by downregulating both COX2 and PGE2 in tumor cells. Metformin is capable of repressing prostate cancer progression by inhibiting infiltration of tumor-associated macrophages, especially those induced by ADT, by inhibiting COX2/PGE2 axis, suggesting that a combination of ADT with metformin could be a more efficient therapeutic strategy for prostate cancer treatment.