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

Ling Ding,Guikai Liang,Zhangting Yao,Qiaojun He,Huihui Chen,Bo Yang,Yulu Zhou,Honghai Wu,Jieqiong Zhang,Ruiyang Liu

doi:10.18632/oncotarget.5541

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.

Highlights

Macrophages are a major cellular component of murine and human tumors, where they are commonly termed tumor-associated macrophages (TAMs)
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
It is reported that metformin could block the invasion and metastasis in several types of cancers, including endometrial carcinoma, ovarian cancer, melanoma and breast cancer

Summary

Introduction

Macrophages are a major cellular component of murine and human tumors, where they are commonly termed tumor-associated macrophages (TAMs). Analysis of the transcriptome of TAMs derived from mouse models of breast cancer has provided evidence that enrichment in macrophage transcripts is predictive of poor prognosis and reduced survival in human breast cancer [10, 11]. TAMs in malignant tumors tend to resemble alternatively activated macrophages (M2-like), which enhance tumor-associated angiogenesis, promote the ability of tumor migration and invasion, as well as suppress the antitumor immune responses. Inhibition of CSF-1 receptor, which is essential for macrophage differentiation, significantly increased survival and suppressed established tumors, accompanied by decreased M2-like TAM [18]. By skewing TAM polarization away from the M2- to M1-like phenotype, HRG promotes antitumor immune responses and vessel normalization, decreases tumor growth and metastasis and enhances chemotherapy [4]

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