Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages.
Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages.
复制标题
二甲双胍通过抑制肿瘤相关巨噬细胞的 M2 样极化来预防癌症转移
DOI：
10.18632/oncotarget.5541
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发表时间：
2015-11-03
期刊：
影响因子：
--
通讯作者：
He Q
中科院分区：
文献类型：
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作者：
Ding L;Liang G;Yao Z;Zhang J;Liu R;Chen H;Zhou Y;Wu H;Yang B;He Q
累积的证据表明，M2样极化的肿瘤相关巨噬细胞（TAM）在癌症进展和转移中起重要作用，确立了TAM，特别是M2样TAM作为治疗干预的有吸引力的靶标。我们发现二甲双胍显著抑制了IL-13诱导的巨噬细胞M2样极化，如CD 206表达降低、M2标记物mRNA下调和M2样巨噬细胞抑制促进癌细胞和内皮细胞迁移所示。二甲双胍可激活巨噬细胞中AMPKα1，AMPKα1沉默可部分消除二甲双胍对IL-13诱导的M2样极化的抑制作用。给予AMPK的另一种激活剂AICAR也阻断了巨噬细胞的M2样极化。二甲双胍大大减少了刘易斯肺癌的转移数量，而不影响肿瘤生长。在肿瘤组织中，M2样巨噬细胞的百分比减少，周细胞包被的血管面积增加。此外，当用巨噬细胞消除剂氯膦酸盐脂质体处理动物时，二甲双胍的抗转移作用消失。提示二甲双胍可部分通过AMPKα1阻断巨噬细胞M2样极化，AMPKα1在二甲双胍抑制刘易斯肺癌转移中起重要作用。
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.