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Metformin's antitumour and anti-angiogenic activities are mediated by skewing macrophage polarization.


ABSTRACT: 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 (TAMs) appeared to be implicated in metformin-induced antitumour activities. However, how metformin inhibits TAMs-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 TAMs by clodronate liposomes eliminated M2-TAMs-induced angiogenic promotion, while also abrogating M1-TAMs-mediated anti-angiogenesis, thus promoting angiogenesis in tumours from metformin treatment mice. Further in vitro experiments using TAMs-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 RAW264.7 macrophages. Based on these results, metformin-induced inhibition of tumour growth and angiogenesis is greatly contributed by skewing of TAMs polarization in microenvironment, thus offering therapeutic opportunities for metformin in cancer treatment.

SUBMITTER: Wang JC 

PROVIDER: S-EPMC6050465 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Metformin's antitumour and anti-angiogenic activities are mediated by skewing macrophage polarization.

Wang Ji-Chang JC   Sun Xin X   Ma Qiang Q   Fu Gui-Feng GF   Cong Long-Long LL   Zhang Hong H   Fan De-Fu DF   Feng Jun J   Lu Shao-Ying SY   Liu Jian-Lin JL   Li Guang-Yue GY   Liu Pei-Jun PJ  

Journal of cellular and molecular medicine 20180504 8


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 (TAMs) appeared to be implicated in metformin-induced antitumour activities. However, how metformin inhibits TAMs-induced tumour progression remains ill-defined. Here, we report that metformin-induced antitumour and anti-angiogenic activities were not or only parti  ...[more]

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