Glioma-derived small extracellular vesicles induce pericyte-phenotype transition of glioma stem cells under hypoxic conditions.

BACKGROUND: Glioblastoma (GBM) is the most common and lethal primary brain tumor characterized by extensive vascularization. Anti-angiogenic therapy for this cancer offers the possibility of universal efficacy. However, preclinical and clinical studies suggest that anti-VEGF drug such as Bevacizumab actively promotes tumor invasion, which ultimately leads to a therapy-resistant and recurrent phenotype of GBMs. Whether Bevacizumab can improve survival over chemotherapy alone remains debated. Herein, we emphasized the importance of small extracellular vesicles (sEVs) internalization by glioma stem cells (GSCs) in giving rise to the failure of anti-angiogenic therapy in the treatment of GBMs and discovered a specific therapeutic target for this damaging disease.

METHODS: To experimentally prove that hypoxia condition promotes the release of GBM cells-derived sEVs, which could be taken up by the surrounding GSCs, we used an ultracentrifugation strategy to isolate GBM-derived sEVs under hypoxic or normoxic conditions, performed bioinformatics analysis and multidimensional molecular biology experiments, and established a xenograft mouse model.

RESULTS: The internalization of sEVs by GSCs was proved to promote tumor growth and angiogenesis through the pericyte-phenotype transition. Hypoxia-derived sEVs could efficiently deliver TGF-β1 to GSCs, thus resulting in the activation of the TGF-β signaling pathway and the consequent pericyte-phenotype transition. Specifically targeting GSC-derived pericyte using Ibrutinib can reverse the effects of GBM-derived sEVs and enhance the tumor-eradicating effects when combined with Bevacizumab.

CONCLUSION: This present study provides a new interpretation of the failure of anti-angiogenic therapy in the non-operative treatment of GBMs and discovers a promising therapeutic target for this intractable disease.