Single tumor-initiating cells evade immune clearance by recruiting type II macrophages.
Single tumor-initiating cells evade immune clearance by recruiting type II macrophages.
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DOI：
10.1101/gad.294348.116
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发表时间：
2017-02-01
影响因子：
10.5
通讯作者：
Zhao B
中科院分区：
文献类型：
--
作者：
Guo X;Zhao Y;Yan H;Yang Y;Shen S;Dai X;Ji X;Ji F;Gong XG;Li L;Bai X;Feng XH;Liang T;Ji J;Chen L;Wang H;Zhao B
郭某等人。显示肝脏肿瘤启动细胞(TICS)早在单细胞阶段就主动招募M2巨噬细胞。消除TIC相关的巨噬细胞以依赖于免疫系统的方式消除肿瘤形成。肿瘤浸润型(M2)巨噬细胞通过抑制免疫清除、促进增殖和刺激血管生成来促进肿瘤的发生。有趣的是，巨噬细胞也被发现在含有肝脏肿瘤启动细胞(TICs)的改变的肝细胞的小灶中丰富。然而，由于技术上的困难，TICS是否以及如何特异性地招募巨噬细胞以及这些巨噬细胞在肿瘤启动中的功能仍然是未知的。在这项研究中，通过产生基因定义的肝脏TIC，我们证明了TIC从单细胞阶段就积极地招募M2巨噬细胞。消除TIC相关巨噬细胞(TICAM)以依赖于免疫系统的方式消除肿瘤形成。从机制上讲，河马通路效应器是相关蛋白(YAP)的激活是抽搐引起巨噬细胞募集的基础。这些结果首次证明巨噬细胞在体内对单个TIC的存活起决定性作用，并为靶向YAP或M2巨噬细胞消除TIC提供了原理依据。
Guo et al. show that liver tumor-initiating cells (TICs) actively recruit M2 macrophages from as early as the single-cell stage. Elimination of TIC-associated macrophages abolishes tumorigenesis in a manner dependent on the immune system. Tumor infiltrated type II (M2) macrophages promote tumorigenesis by suppressing immune clearance, promoting proliferation, and stimulating angiogenesis. Interestingly, macrophages were also found to enrich in small foci of altered hepatocytes containing liver tumor-initiating cells (TICs). However, whether and how TICs specifically recruit macrophages and the function of these macrophages in tumor initiation remain unknown due to technical difficulties. In this study, by generating genetically defined liver TICs, we demonstrate that TICs actively recruit M2 macrophages from as early as the single-cell stage. Elimination of TIC-associated macrophages (TICAMs) abolishes tumorigenesis in a manner dependent on the immune system. Mechanistically, activation of the Hippo pathway effector Yes-associated protein (YAP) underlies macrophage recruitment by TICs. These results demonstrate for the first time that macrophages play a decisive role in the survival of single TICs in vivo and provide a proof of principle for TIC elimination by targeting YAP or M2 macrophages.