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

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.

Metformin therapy associated with survival benefit in lung cancer patients with diabetes

“…The nude mice study also provided further evidence indicating that the combined treatment of metformin with the mostly common agent cisplatin for lung cancer was capable of enhancing the anti-tumor efficacy [12]. Proposed potential molecular mechanisms have been suggested for the anti-neoplastic action of metformin by some experimental data [29–32]. There was a extensively accepted mechanism of metformin action that metformin could activate the LKB1/AMPK signal axis in lung cancer cell, subsequently resulting in reduced cancer cell growth and proliferation via the suppression of mTOR activity [15].…”

Chlorogenic acid inhibits glioblastoma growth through repolarizating macrophage from M2 to M1 phenotype

“…These compounds include the natural products zoledronic acid19 and emodin20, therapeutic monoclonal antibodies including anti-CD471321 and the phosphatidylserine-targeting antibody 2aG414, and chemotherapy agents, doxycycline and metformin2223. Chlorogenic acid (5-caffeoylquinic acid, CHA), the ester formed between caffeic acid and quinic acid24, is a phenolic compound found in the human diet, in coffee, apples, pears and in green tea.…”

The Next Frontier: Head and Neck Cancer Immunoprevention

“…Besides its impact on OPL cells, metformin suppresses the polarization of pro-tumorigenic M2-like tumor associated macrophages and protects CD8+ tumor-infiltrating lymphocytes from functional exhaustion in the tumor microenvironment (8,9). Classical COX inhibitors, including aspirin, have been recently shown to override the tumor suppressive effect of the inflammatory mediator, PGE2, thereby synergizing with anti-PD1 blockade in inducing the eradication of tumors (10).…”