Huang Shilu, Zhang Peng, Yin Nanheng, Xu Zhipeng, Liu Xinglei, Wu Anyi, Zhang Xiaopei, Li Zengyang, Zhang Zhicheng, Zhong Tao, Liu Liang, Shi Yan, Dong Jun
Department of Neurosurgery, The Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Department of Neurosurgery, Rugao People's Hospital, RuGao 226500, China.
iScience. 2024 Feb 22;27(3):109270. doi: 10.1016/j.isci.2024.109270. eCollection 2024 Mar 15.
Glioblastoma stem cells (GSCs) reside in hypoxic periarteriolar niches of glioblastoma micro-environment, however, the crosstalk of GSCs with macrophages on regulating tumor angiogenesis and progression are not fully elucidated. GSCs-derived exosomes (GSCs-exos) are essential mediators during tumor immune-microenvironment remodeling initiated by GSCs, resulting in M2 polarization of tumor-associated macrophages (TAMs) as we reported previously. Our data disclosed aberrant upregulation of miR-374b-3p in both clinical glioblastoma specimens and human cell lines of GSCs. MiR-374b-3p level was high in GSCs-exos and can be internalized by macrophages. Mechanistically, GSCs exosomal miR-374b-3p induced M2 polarization of macrophages by downregulating phosphatase and tensin expression, thereby promoting migration and tube formation of vascular endothelial cells after coculture with M2 macrophages. Cumulatively, these data indicated that GSCs exosomal miR-374b-3p can enhance tumor angiogenesis by inducing M2 polarization of macrophages, as well as promote malignant progression of glioblastoma. Targeting exosomal miR-374b-3p may serve as a potential target against glioblastoma.
胶质母细胞瘤干细胞（GSCs）存在于胶质母细胞瘤微环境的缺氧小动脉周围龛中，然而，GSCs与巨噬细胞在调节肿瘤血管生成和进展方面的相互作用尚未完全阐明。GSCs衍生的外泌体（GSCs-exos）是GSCs启动的肿瘤免疫微环境重塑过程中的重要介质，如我们之前报道的那样，会导致肿瘤相关巨噬细胞（TAMs）发生M2极化。我们的数据显示，在临床胶质母细胞瘤标本和GSCs的人类细胞系中，miR-374b-3p均异常上调。miR-374b-3p在GSCs-exos中水平较高，且可被巨噬细胞内化。从机制上讲，GSCs外泌体miR-374b-3p通过下调磷酸酶和张力蛋白表达诱导巨噬细胞发生M2极化，从而在与M2巨噬细胞共培养后促进血管内皮细胞的迁移和管腔形成。总体而言，这些数据表明，GSCs外泌体miR-374b-3p可通过诱导巨噬细胞发生M2极化增强肿瘤血管生成，并促进胶质母细胞瘤的恶性进展。靶向作用于外泌体miR-374b-3p可能成为对抗胶质母细胞瘤的潜在靶点。
