Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
Department of Neurosurgery, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, 221000, China.
Cancer Lett. 2018 Oct 1;433:210-220. doi: 10.1016/j.canlet.2018.06.041. Epub 2018 Jul 6.
The glioma-astrocyte interaction plays an important role in tumor microenvironment remodeling; however, the underlying mechanism has not been completely clarified. In this study, we show that glioma cells stimulate normal human astrocyte (NHA) into reactive astrocyte (RAS) in a non-contact manner. Additionally, the amount of O6-alkylguanine DNA alkyltransferase (MGMT) mRNA in exosomes (EXOs) released by RAS was significantly increased compared with that in non-reactive NHA. Importantly, MGMT-negative glioma cells can take up RAS-EXOs and acquire a temozolomide (TMZ)-resistant phenotype via the translation of exogenous exosomal MGMT mRNA both in vitro and in vivo. Our findings illuminate a novel phenomenon that may be a potent mechanism underlying glioma recurrence in which glioma-associated NHAs protect MGMT-negative glioma cells from TMZ-induced apoptosis by the functional intercellular transfer of exosomal MGMT mRNA.
胶质瘤-星形胶质细胞相互作用在肿瘤微环境重塑中发挥着重要作用；然而，其潜在机制尚未完全阐明。在本研究中，我们表明，胶质瘤细胞以非接触的方式刺激正常人星形胶质细胞（NHA）转化为反应性星形胶质细胞（RAS）。此外，与非反应性 NHA 相比，RAS 释放的外泌体（EXOs）中的 O6-烷基鸟嘌呤 DNA 烷基转移酶（MGMT）mRNA 量显著增加。重要的是，MGMT 阴性的胶质瘤细胞可以摄取 RAS-EXOs，并通过体外和体内翻译外源性外泌体 MGMT mRNA 获得替莫唑胺（TMZ）耐药表型。我们的研究结果阐明了一种新现象，这可能是胶质瘤复发的一种潜在机制，其中胶质瘤相关的 NHAs 通过功能细胞间转移外泌体 MGMT mRNA 来保护 MGMT 阴性的胶质瘤细胞免受 TMZ 诱导的细胞凋亡。
