Infiltrating macrophages increase RCC epithelial mesenchymal transition (EMT) and stem cell-like populations via AKT and mTOR signaling

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.