Delivery of MGMT mRNA to glioma cells by reactive astrocyte-derived exosomes confers a temozolomide resistance phenotype

• Published in: Cancer letters Vol. 433; pp. 210 - 220
• Main Authors: Yu, Tianfu, Wang, XieFeng, Zhi, Tongle, Zhang, Junxia, Wang, Yingyi, Nie, Er, Zhou, Fengqi, You, Yongping, Liu, Ning
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.10.2018; Elsevier Limited
• Subjects: Antineoplastic Agents, Alkylating - pharmacology; Apoptosis; Apoptosis - genetics; Astrocyte; Astrocytes - metabolism; Brain Neoplasms - pathology; Cancer therapies; Cell Line, Tumor; Deoxyribonucleic acid; DNA; DNA alkyltransferase; DNA methylation; DNA Modification Methylases - genetics; DNA Modification Methylases - metabolism; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; Drug Resistance, Neoplasm - genetics; Exosomes; Exosomes - metabolism; Genotype & phenotype; Glioma; Glioma - pathology; Glioma cells; Humans; Metastasis; Microenvironment; MicroRNAs; Microscopy; mRNA; Phenotypes; Proteins; R&D; Research & development; RNA, Messenger - genetics; Temozolomide; Temozolomide - pharmacology; Tumor Microenvironment; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; United States > US; China; Temozolomide; Astrocyte; Microenvironment; Glioma; Exosomes
• ISSN: 0304-3835; 1872-7980; 1872-7980
• DOI: 10.1016/j.canlet.2018.06.041

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. •Glioma cells stimulate normal astrocytes into reactive astrocytes via a non-contact way.•Co-culture with astrocytes enhances the chemoresistance of glioma cells.•Astrocyte-derived exosomal MGMT mRNA can be functionally translated into MGMT protein by recipient glioma cells.