Department of Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.
Cancer Res. 2012 Mar 15;72(6):1363-72. doi: 10.1158/0008-5472.CAN-11-2684. Epub 2012 Jan 27.
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.
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，但单核细胞分化为 TAM 的机制尚不清楚。在这里，我们报告 mTOR 通路是调节单核细胞分化为 TAM 的关键因素。在脂多糖刺激的人外周单核细胞中，mTOR 被雷帕霉素抑制或通过 RNAi 介导的 mTOR 抑制剂结节性硬化复合物 2（TSC2）的敲低而被激活。雷帕霉素导致单核细胞分化为释放更多白细胞介素（IL）-12 和更少 IL-10 的 M1 巨噬细胞，而 TSC2 敲低导致单核细胞分化为释放更少 IL-12 和更多 IL-10 的 M2 巨噬细胞。以类似的方式，与 TSC2 缺陷单核细胞或雷帕霉素处理的单核细胞共培养的人脐静脉内皮细胞的血管生成特性分别得到促进或减少。此外，分别输注 TSC2 缺陷或 TSC2 过表达单核细胞促进或减少了小鼠异种移植中的肿瘤血管生成和生长。最后，体内巨噬细胞耗竭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 通路定义为决定单核细胞分化为促进血管生成的 M2 表型 TAM 的关键因素。
