Metformin prevents cancer metastasis by inhibiting M2-1ike polarization of tumor associated macrophages

摘要

Aim Accumulated evidence suggests that M2-1ike polarized tumor associated macrophages （TAMs） plays an important role in cancer progression and metastasis, establishing TAMs, especially M2-1ike 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 M2-1ike macrophages promoted migration of cancer cells and endothelial cells. Metformin triggered AMPKαl activation in macrophage and silencing of AMPKotl partially abrogated the inhibitory effect of metformin in IL-13 induced M2-1ike polarization. Administration of AICAR, another activator of AMPK, also blocked the M2-1ike polarization of macrophages. Metformin greatly reduced the number of metastases of Lewis lung cancer without affecting tumor growth. In tumor tissues, the percentage of M2-1ike macrophage was decreased and the anti-metastatic effect of metformin was abolished the area of pericyte-coated vessels was increased. Further, when the animals were treated with macrophages eliminating agent clodronate liposome. These findings suggest that metformin is able to block the M2-1ike polarization of macrophages partially through AMPKαl, which plays an im- portant role in metformin inhibited metastasis of Lewis lung cancer.