Open AccessMetformin's antitumour and anti‐angiogenic activities are mediated by skewing macrophage polarization
Author(s) -
Wang JiChang,
Sun Xin,
Ma Qiang,
Fu GuiFeng,
Cong LongLong,
Zhang Hong,
Fan DeFu,
Feng Jun,
Lu ShaoYing,
Liu JianLin,
Li GuangYue,
Liu PeiJun
Publication year - 2018
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.13655
Subject(s) - metformin , macrophage polarization , macrophage , angiogenesis , cancer research , medicine , pharmacology , chemistry , endocrinology , in vitro , diabetes mellitus , biochemistry
Beneficial effects of metformin on cancer risk and mortality have been proved by epidemiological and clinical studies, thus attracting research interest in elucidating the underlying mechanisms. Recently, tumour‐associated macrophages ( TAM s) appeared to be implicated in metformin‐induced antitumour activities. However, how metformin inhibits TAM s‐induced tumour progression remains ill‐defined. Here, we report that metformin‐induced antitumour and anti‐angiogenic activities were not or only partially contributed by its direct inhibition of functions of tumour and endothelial cells. By skewing TAM polarization from M2‐ to M1‐like phenotype, metformin inhibited both tumour growth and angiogenesis. Depletion of TAM s by clodronate liposomes eliminated M2‐ TAM s‐induced angiogenic promotion, while also abrogating M1‐ TAM s‐mediated anti‐angiogenesis, thus promoting angiogenesis in tumours from metformin treatment mice. Further in vitro experiments using TAM s‐conditioned medium and a coculture system were performed, which demonstrated an inhibitory effect of metformin on endothelial sprouting and tumour cell proliferation promoted by M2‐polarized RAW 264.7 macrophages. Based on these results, metformin‐induced inhibition of tumour growth and angiogenesis is greatly contributed by skewing of TAM s polarization in microenvironment, thus offering therapeutic opportunities for metformin in cancer treatment.