Yang Zhao, Xie Hongjun, He Dalin, Li Lei
Sex Hormone Research Center, Department of Urology, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
Oncotarget. 2016 Jul 12;7(28):44478-44491. doi: 10.18632/oncotarget.9873.
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.
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，尤其是在RCC恶性进展阶段，仍不清楚。在此，我们发现巨噬细胞比周围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细胞通过CXCL8信号募集巨噬细胞的能力比正常肾上皮细胞更强。募集更多巨噬细胞的结果可能会增强RCC细胞的侵袭能力。机制剖析显示，浸润性巨噬细胞可通过诱导上皮-间质转化并通过激活AKT/mTOR信号增加癌症干细胞样群体，进而导致RCC细胞侵袭增加。RCC细胞与巨噬细胞的原位异种移植小鼠模型也证实，浸润性巨噬细胞可通过AKT/mTOR信号促进RCC细胞进展。总之，我们的结果揭示了一种新机制，即RCC肿瘤微环境中的巨噬细胞可通过激活AKT/mTOR信号增加RCC转移。靶向这一新发现的信号通路可能有助于我们更好地抑制RCC转移。
