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

作者全名："Cheng, Yue; Li, Shijie; Hou, Yongying; Wan, Weijun; Wang, Ke; Fu, Shihui; Yuan, Ye; Yang, Kaidi; Ye, Xiufeng"

作者地址："[Cheng, Yue; Li, Shijie; Hou, Yongying; Wan, Weijun; Wang, Ke; Ye, Xiufeng] Chongqing Med Univ, Inst Pathol Dept, Basic Med Coll, Chongqing 400038, Peoples R China; [Yuan, Ye] Chongqing Univ Canc Hosp, Dept Med Oncol, Chongqing, Peoples R China; [Yang, Kaidi] Chinese Peoples Liberat Army Gen Hosp, Dept Oncol, Hainan Hosp, Sanya, Hainan Province, Peoples R China; [Fu, Shihui] Chinese Peoples Liberat Army Gen Hosp, Dept Cardiol, Hainan Hosp, Sanya, Hainan Province, Peoples R China"

通信作者："Ye, XF (通讯作者)，Chongqing Med Univ, Inst Pathol Dept, Basic Med Coll, Chongqing 400038, Peoples R China.; Yuan, Y (通讯作者)，Chongqing Univ Canc Hosp, Dept Med Oncol, Chongqing, Peoples R China.; Yang, KD (通讯作者)，Chinese Peoples Liberat Army Gen Hosp, Dept Oncol, Hainan Hosp, Sanya, Hainan Province, Peoples R China."

来源：CELLULAR SIGNALLING

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:001023032200001

JCR分区：Q2

影响因子：4.4

年份：2023

卷号：109

期号：　

开始页：　

结束页：　

文献类型：Article

关键词：Glioblastoma; Small extracellular vesicles; Glioma stem cell; Anti-angiogenesis; Pericyte-phenotype transition

摘要："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 drugs, such as Bevacizumab, actively promote 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 emphasize 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 discover a specific therapeutic target for this damaging disease. Methods: To experimentally prove that hypoxia conditions promote 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 proven to promote tumor growth and angiogenesis through the pericyte-phenotype transition. Hypoxia-derived sEVs could efficiently deliver TGF-81 to GSCs, thus resulting in the activation of the TGF-8 signaling pathway and the consequent pericyte-phenotype transition. Specifically targeting GSC-derived pericytes 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."

基金机构：Open Project of Key Laboratory of Tumor Immunopathology of Ministry of Education [2020jsz603]

基金资助正文：Funding We would like to thank the supported grants from Open Project of Key Laboratory of Tumor Immunopathology of Ministry of Education (2020jsz603 to YY) .