Macrophage-Induced Tumor Angiogenesis Is Regulated by the TSC2-mTOR Pathway
Macrophage-Induced Tumor Angiogenesis Is Regulated by the TSC2-mTOR Pathway
复制标题
巨噬细胞诱导的肿瘤血管生成受 TSC2-mTOR 通路调节。
DOI：
10.1158/0008-5472.can-11-2684
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发表时间：
2012-03-15
期刊：
影响因子：
11.2
通讯作者：
Liang, Ting-bo
中科院分区：
文献类型：
--
作者：
Chen, Wei;Ma, Tao;Liang, Ting-bo
肿瘤相关巨噬细胞（TAM）在肿瘤发展中具有多方面的作用，但它们与肿瘤血管生成密切相关。然而，尽管TAM （M2表型）的积累促进了肿瘤血管生成，但单核细胞分化产生TAM的机制尚不清楚。在这里，我们报道mTOR通路是调控单核细胞向TAM分化的关键因素。在脂多糖刺激的人外周血单核细胞中，雷帕霉素抑制mTOR或RNA干扰介导的mTOR抑制物结节硬化复合体2 （TSC2）的敲低激活mTOR。雷帕霉素使单核细胞分化为M1巨噬细胞，释放更多的白细胞介素(IL)-12，释放更少的IL-10，而TSC2敲除使单核细胞分化为M2巨噬细胞，释放更少的IL-12和更多的IL-10。同样，在人脐静脉内皮细胞与缺乏tsc2的单核细胞或雷帕霉素处理的单核细胞共培养时，血管生成特性分别得到促进或降低。此外，输注tsc2缺失或tsc2过表达的单核细胞分别促进或抑制小鼠异种移植物的肿瘤血管生成和生长。最后，体内巨噬细胞的消耗足以阻断雷帕霉素对肿瘤的抗血管生成作用。我们的研究结果将TSC2-mTOR通路定义为单核细胞向促进血管生成的M2型TAM分化的关键决定因素。
Tumor-associated macrophages (TAM) have multifaceted roles in tumor development but they have been associated particularly closely with tumor angiogenesis. However, although the accumulation of TAM (M2 phenotype) promotes tumor angiogenesis, the mechanism through which monocytes differentiate to generate TAM is unclear. Here, we report that the mTOR pathway is a critical element in the regulation of monocyte differentiation to TAM. In human peripheral monocytes stimulated by lipopolysaccharide, mTOR was inhibited by rapamycin or activated by RNA interference-mediated knockdown of the mTOR repressor tuberous sclerosis complex 2 (TSC2). Rapamycin caused the monocytes to differentiate into M1 macrophages releasing more interleukin (IL)-12 and less IL-10, whereas TSC2 knockdown caused the monocytes to differentiate into M2 macrophages releasing less IL-12 and more IL-10. In parallel fashion, angiogenic properties were promoted or reduced in human umbilical vein endothelial cells cocultured with TSC2-deficient monocytes or rapamycin-treated monocytes, respectively. Furthermore, tumor angiogenesis and growth in murine xenografts were promoted or reduced by infusion of hosts with TSC2-deficient or TSC2-overexpressing monocytes, respectively. Finally, in vivo depletion of macrophages was sufficient to block the antiangiogenic effects of rapamycin on tumors. Our results define the TSC2-mTOR pathway as a key determinant in the differentiation of monocytes into M2 phenotype TAM that promote angiogenesis.