Yang Yi-Ping, Nguyen Phan Nguyen Nhi, Ma Hsin-I, Ho Wen-Jin, Chen Yi-Wei, Chien Yueh, Yarmishyn Aliaksandr A, Huang Pin-I, Lo Wen-Liang, Wang Chien-Ying, Liu Yung-Yang, Lee Yi-Yen, Lin Chien-Min, Chen Ming-Teh, Wang Mong-Lien
Department of Medical Research, Taipei Veterans General Hospital, Taipei 112, Taiwan.
School of Pharmaceutical Science, National Yang Ming University, Taipei 112, Taiwan.
Cancers (Basel). 2019 May 24;11(5):720. doi: 10.3390/cancers11050720.
Atypical teratoid/rhabdoid tumor (ATRT) is a rare pediatric brain tumor with extremely high aggressiveness and poor prognosis. The tumor microenvironment is regulated by a complex interaction among distinct cell types, yet the crosstalk between tumor-associated mesenchymal stem cells (tMSCs) and naïve ATRT cells are unclear. In this study, we sought to identify the secretory factor(s) that is responsible for the tMSC-mediated regulation of ATRT migration. Comparing with ATRT cell alone, co-culture of tMSCs or addition of its conditioned medium (tMSC-CM) promoted the migration of ATRT, and this effect could be abrogated by exosome release inhibitor GW4869. The exosomes in tMSC-CM were detected by transmission electron microscope and flow cytometry. ATRT naïve cell-derived conditioned media (ATRT-CM) also enhanced the exosome secretion from tMSCs, indicating the interplay between ATRT cells and tMSCs. Microarray analysis revealed that, compared with that in bone marrow-derived MSCs, microRNA155 is the most upregulated microRNA in the tMSC-CM. Tracing the PK67-labeled exosomes secreted from tMSCs confirmed their incorporation into naïve ATRT cells. After entering ATRT cells, miR155 promoted ATRT cell migration by directly targeting . Knockdown of mimicked the miR155-driven ATRT cell migration, whereas overexpression or the delivery of exosomes with miR155 knockdown suppressed the migration. Furthermore, abrogation of exosome release with GW4869 reduced the tumorigenesis of the xenograft containing naïve ATRT cells and tMSCs in immunocompromised recipients. In conclusion, our data have demonstrated that tMSCs secreted miR155-enriched exosomes, and the exosome incorporation and miR155 delivery further promoted migration in ATRT cells via a -dependent mechanism.
非典型畸胎样/横纹肌样瘤（ATRT）是一种罕见的儿童脑肿瘤，具有极高的侵袭性和较差的预后。肿瘤微环境由不同细胞类型之间的复杂相互作用调节，但肿瘤相关间充质干细胞（tMSC）与原始ATRT细胞之间的相互作用尚不清楚。在本研究中，我们试图确定负责tMSC介导的ATRT迁移调节的分泌因子。与单独的ATRT细胞相比，tMSC的共培养或添加其条件培养基（tMSC-CM）促进了ATRT的迁移，并且这种作用可被外泌体释放抑制剂GW4869消除。通过透射电子显微镜和流式细胞术检测tMSC-CM中的外泌体。原始ATRT细胞来源的条件培养基（ATRT-CM）也增强了tMSC的外泌体分泌，表明ATRT细胞与tMSC之间存在相互作用。微阵列分析显示，与骨髓来源的间充质干细胞相比，microRNA155是tMSC-CM中上调最明显的microRNA。追踪tMSC分泌的PK67标记外泌体证实它们被原始ATRT细胞摄取。进入ATRT细胞后，miR155通过直接靶向促进ATRT细胞迁移。敲低模拟了miR155驱动的ATRT细胞迁移，而的过表达或用miR155敲低的外泌体递送抑制了迁移。此外,用GW4869消除外泌体释放减少了免疫受损受体中含有原始ATRT细胞和tMSC的异种移植瘤的肿瘤发生。总之，我们的数据表明tMSC分泌富含miR155的外泌体，外泌体摄取和miR155递送通过依赖的机制进一步促进ATRT细胞的迁移。 （注：原文中部分内容缺失，如“miR155 promoted ATRT cell migration by directly targeting.”后面缺失具体靶向内容，“Knockdown of mimicked the miR155-driven ATRT cell migration”和“whereas overexpression or the delivery of exosomes with miR155 knockdown suppressed the migration.”中也缺失相关内容，但按照要求进行了完整翻译。）
