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

ABSTRACT: 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.

SUBMITTER: Yang Z

PROVIDER: S-EPMC5190112 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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

Yang Zhao Z Xie Hongjun H He Dalin D Li Lei L

Oncotarget 20160701 28

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 ...[more]

PMID: 27283897

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Project description:BackgroundTumor microenvironments (TMEs) activate various axes/pathways, predominantly inflammatory and hypoxic responses, impact tumorigenesis, metastasis and therapeutic resistance significantly. Although molecular pathways of individual TME are extensively studied, evidence showing interaction and crosstalk between hypoxia and inflammation remain unclear. Thus, we examined whether interferon (IFN) could modulate both inflammatory and hypoxic responses under normoxia and its relation with cancer development.MethodsIFN was used to induce inflammation response and HIF-1? expression in various cancer cell lines. Corresponding signaling pathways were then analyzed by a combination of pharmacological inhibitors, immunoblotting, GST-Raf pull-down assays, dominant-negative and short-hairpin RNA-mediated knockdown approaches. Specifically, roles of functional HIF-1? in the IFN-induced epithelial-mesenchymal transition (EMT) and other tumorigenic propensities were examined by knockdown, pharmacological inhibition, luciferase reporter, clonogenic, anchorage-independent growth, wound-healing, vasculogenic mimicry, invasion and sphere-formation assays as well as cellular morphology observation.ResultsWe showed for the first time that IFN induced functional HIF-1? expression in a time- and dose- dependent manner in various cancer cell lines under both hypoxic and normoxic conditions, and then leading to an activated HIF-1? pathway in an IFN-mediated pro-inflammatory TME. IFN regulates anti-apoptosis activity, cellular metastasis, EMT and vasculogenic mimicry by a novel mechanism through mainly the activation of PI3K/AKT/mTOR axis. Subsequently, pharmacological and genetic modulations of HIF-1?, JAK, PI3K/AKT/mTOR or p38 pathways efficiently abrogate above IFN-induced tumorigenic propensities. Moreover, HIF-1? is required for the IFN-induced invasiveness, tumorigenesis and vasculogenic mimicry. Further supports for the HIF-1?-dependent tumorigenesis were obtained from results of xenograft mouse model and sphere-formation assay.ConclusionsOur mechanistic study showed an induction of HIF-1? and EMT ability in an IFN-mediated inflammatory TME and thus demonstrating a novel interaction between inflammatory and hypoxic TMEs. Moreover, targeting HIF-1? may be a potential target for inhibiting tumor tumorigenesis and EMT by decreasing cancer cells wound healing and anchorage-independent colony growth. Our results also lead to rationale guidance for developing new therapeutic strategies to prevent relapse via targeting TME-providing IFN signaling and HIF-1? programming.

Dataset Information

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

Publications

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

Similar Datasets

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