Abstract
Gliomas are the most common primary brain tumor and one of the most lethal solid tumors. Mechanistic studies into identification of novel biomarkers are needed to develop new therapeutic strategies for this deadly disease. The objective for this study was to explore the potential direct impact of IL-17−IL-17R interaction in gliomas. Immunohistochemistry and flow cytometry analysis of 12 tumor samples obtained from patients with high grade gliomas revealed that a considerable population (2–19%) of cells in all malignant gliomas expressed IL-17RA, with remarkable co-expression of the glioma stem cell (GSC) markers CD133, Nestin, and Sox2. IL-17 enhanced the self-renewal of GSCs as determined by proliferation and Matrigel® colony assays. IL-17 also induced cytokine/chemokine (IL-6, IL-8, interferon-γ-inducible protein [IP-10], and monocyte chemoattractant protein-1 [MCP-1]) secretion in GSCs, which were differentially blocked by antibodies against IL-17R and IL-6R. Western blot analysis showed that IL-17 modulated the activity of signal transducer and activator of transcription 3 (STAT3), nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), glycogen synthase kinase-3β (GSK-3β) and β-catenin in GSCs. While IL-17R-mediated secretion of IL-6 and IL-8 were significantly blocked by inhibitors of NF-κB and STAT3; NF-κB inhibitor was more potent than STAT3 inhibitor in blocking IL-17-induced MCP-1 secretion. Overall, our results suggest that IL-17–IL-17R interaction in GSCs induces an autocrine/paracrine cytokine feedback loop, which may provide an important signaling component for maintenance/self-renewal of GSCs via constitutive activation of both NF-κB and STAT3. The results also strongly implicate IL-17R as an important functional biomarker for therapeutic targeting of GSCs.
Highlights
Malignant glioma is the most common type of primary brain tumor with approximately 23,000 newly diagnosed cases per year in the USA [1,2,3]
15% of malignant glioma cells expressed IL-17R and more than 60% of IL17R+ cells co-expressed the glioma stem cell (GSC) markers CD133, Nestin, and Sox2 (Figure 1 and Supplementary Figure S1)
In agreement with the proliferation/colony formation data, these results clearly indicate that the IL-17R in the GSCs are functional and that IL-17R induced cytokine secretion may be differentially regulated by cytokine feedback loops involving nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription 3 (STAT3) signaling
Summary
Malignant glioma is the most common type of primary brain tumor with approximately 23,000 newly diagnosed cases per year in the USA [1,2,3]. In spite of aggressive surgery, radiotherapy and chemotherapy, malignant glioma remains one of the most lethal solid tumors with a median survival of only 15 months, leading to 13000 deaths per year in the USA [4]. More studies are needed to understand the mechanisms of glioma progression, especially focusing on tumorstromal interactions that favor tumor progression, in order to identify new molecular targets for designing more effective therapy for this deadly disease. Several reports have suggested that attenuation of GSC self-renewal or survival could be a promising therapeutic strategy for glioblastoma [9, 10, 17,18,19,20,21]. Elucidating novel mechanisms of GSC self-renewal or expansion could lead to new strategies for the treatment of glioblastoma. Potential significance of inflammatory cytokines on glioma progression via their direct impact on GSCs remains unexplored
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