Infiltrating macrophages increase RCC epithelial mesenchymal transition (EMT) and stem cell-like populations via AKT and mTOR signaling.
Infiltrating macrophages increase RCC epithelial mesenchymal transition (EMT) and stem cell-like populations via AKT and mTOR signaling.
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DOI：
10.18632/oncotarget.9873
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发表时间：
2016-07-12
期刊：
影响因子：
--
通讯作者：
Li L
中科院分区：
文献类型：
--
作者：
Yang Z;Xie H;He D;Li L
浸润性巨噬细胞是肿瘤发生和发展过程中炎症的关键组成部分。然而，巨噬细胞在肾细胞癌（RCC）中的作用，特别是在RCC恶性进展阶段的作用尚不清楚。在这里，我们发现巨噬细胞比周围的非肿瘤组织更容易被募集到RCC组织中。体外共培养系统也证实RCC细胞比正常肾上皮细胞具有更好的通过CXCL8信号募集巨噬细胞的能力。招募更多巨噬细胞的结果可能会增加RCC细胞的侵袭能力。机制解剖表明，浸润性巨噬细胞可通过激活AKT/mTOR信号，诱导上皮-间质转化，增加肿瘤干细胞样细胞群，进而导致RCC细胞侵袭增加。同种异种移植RCC细胞和巨噬细胞小鼠模型也证实了浸润巨噬细胞可通过AKT/mTOR信号促进RCC细胞的进展。总之，我们的研究结果揭示了一种新的机制，即RCC肿瘤微环境中的巨噬细胞通过激活AKT/mTOR信号来增加RCC转移。靶向这种新发现的信号可能有助于我们更好地抑制RCC转移。
Infiltrating macrophages are a key component of inflammation during tumorigenesis and progression. However, the role of macrophages in renal cell carcinoma (RCC), especially in the stage of RCC malignant progression, is still unclear. Here, we found the macrophages could be recruited more easily into RCC tissues than the surrounding non-tumor tissues. In vitro co-culture system also confirmed RCC cells had a better capacity to recruit macrophages via CXCL8 signaling than normal renal epithelial cells. The consequences of recruiting more macrophages may then increase RCC cells invasion abilities. Mechanism dissection revealed that infiltrating macrophages could function through induction of epithelial-mesenchymal transition and increased cancer stem cell-like populations via activation of AKT/mTOR signal, and then led to increasing RCC cells invasion. The orthotopically xenografted mouse model with RCC cells and macrophages also confirmed that infiltrating macrophages could increase RCC cells progression via AKT/mTOR signal. Together, our results reveal a new mechanism that macrophages in the RCC tumor microenvironment could increase RCC metastasis via activation of the AKT/mTOR signals. Targeting this newly identified signaling may help us to better inhibit RCC metastasis.
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各种各样的癌症相关MTOR突变是过度激活的，可以预测雷帕霉素的敏感性。
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