期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 22, 期 8, 页码 3825-3836出版社
WILEY
DOI: 10.1111/jcmm.13655
关键词
anti-angiogenesis; antitumour; macrophage polarization; metformin; tumour-associated macrophages
资金
- National Natural Science Foundation of China [81272342, 81472747, 81602638, 81602502]
- Keypoint Research and Invention Program of Shaanxi Province [2017SF-017, 2016SF196]
- Natural Science Foundation of Shaanxi Province [2016JM8125]
- College Scientific Research Foundation of Xi'an Jiaotong University [xjj2016104]
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 invitro 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.
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