Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages

// Ling Ding 1 , Guikai Liang 1 , Zhangting Yao 1 , Jieqiong Zhang 1 , Ruiyang Liu 1 , Huihui Chen 1 , Yulu Zhou 1 , Honghai Wu 1 , Bo Yang 1 , Qiaojun He 1 1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China Correspondence to: Qiaojun He, e-mail: qiaojunhe@zju.edu.cn Keywords: metformin, macrophage polarization, cancer metastasis, AMPKα1 Received: July 05, 2015      Accepted: October 09, 2015      Published: October 19, 2015 ABSTRACT Accumulated evidence suggests that M2-like polarized tumor associated macrophages (TAMs) plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-like TAMs as an appealing target for therapy intervention. Here we found that metformin significantly suppressed IL-13 induced M2-like polarization of macrophages, as illustrated by reduced expression of CD206, down-regulation of M2 marker mRNAs, and inhibition of M2-like macrophages promoted migration of cancer cells and endothelial cells. Metformin triggered AMPKα1 activation in macrophage and silencing of AMPKα1 partially abrogated the inhibitory effect of metformin in IL-13 induced M2-like polarization. Administration of AICAR, another activator of AMPK, also blocked the M2-like polarization of macrophages. Metformin greatly reduced the number of metastases of Lewis lung cancer without affecting tumor growth. In tumor tissues, the percentage of M2-like macrophage was decreased and the area of pericyte-coated vessels was increased. Further, the anti-metastatic effect of metformin was abolished when the animals were treated with macrophages eliminating agent clodronate liposome. These findings suggest that metformin is able to block the M2-like polarization of macrophages partially through AMPKα1, which plays an important role in metformin inhibited metastasis of Lewis lung cancer.