Department of Neurosurgery, Brain Tumor Center, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.
Precision Medicine Research Center, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Yonsei Med J. 2023 Mar;64(3):157-166. doi: 10.3349/ymj.2022.0430.
Glioblastoma (GBM) is one of the most lethal human tumors with a highly infiltrative phenotype. Our previous studies showed that GBM originates in the subventricular zone, and that tumor-derived mesenchymal stem-like cells (tMSLCs) promote the invasiveness of GBM tumorspheres (TSs). Here, we extend these studies in terms of ventricles using several types of GBM patient-derived cells.
The invasiveness of GBM TSs and ventricle spheres (VSs) were quantified via collagen-based 3D invasion assays. Gene expression profiles were obtained from microarray data. A mouse orthotopic xenograft model was used for in vivo experiments.
After molecular and functional characterization of ventricle-derived mesenchymal stem-like cells (vMSLCs), we investigated the effects of these cells on the invasiveness of GBM TSs. We found that vMSLC-conditioned media (CM) significantly accelerated the invasiveness of GBM TSs and VSs, compared to the control and even tMSLC-CM. Transcriptome analyses revealed that vMSLC secreted significantly higher levels of several invasiveness-associated cytokines. Moreover, differentially expressed genes between vMSLCs and tMSLCs were enriched for migration, adhesion, and chemotaxis-related gene sets, providing a mechanistic basis for vMSLC-induced invasion of GBM TSs. In vivo experiments using a mouse orthotopic xenograft model confirmed vMSLC-induced increases in the invasiveness of GBM TSs.
Although vMSLCs are non-tumorigenic, this study adds to our understanding of how GBM cells acquire infiltrative features by vMSLCs, which are present in the region where GBM genesis originates.
胶质母细胞瘤（GBM）是最致命的人类肿瘤之一，具有高度浸润性表型。我们之前的研究表明，GBM 起源于侧脑室下区，肿瘤衍生的间充质干细胞样细胞（tMSLCs）促进 GBM 肿瘤球（TSs）的侵袭性。在这里，我们使用几种类型的 GBM 患者来源细胞扩展了这些在脑室中的研究。
通过基于胶原蛋白的 3D 侵袭测定法定量测量 GBM TSs 和脑室球体（VSs）的侵袭性。从微阵列数据获得基因表达谱。使用小鼠原位异种移植模型进行体内实验。
在对脑室衍生的间充质干细胞样细胞（vMSLCs）进行分子和功能表征后，我们研究了这些细胞对 GBM TSs 侵袭性的影响。我们发现，与对照甚至 tMSLC-CM 相比，vMSLC 条件培养基（CM）显著加速了 GBM TSs 和 VSs 的侵袭性。转录组分析显示，vMSLC 分泌的几种侵袭相关细胞因子水平显著升高。此外，vMSLCs 和 tMSLCs 之间差异表达的基因富集了迁移、粘附和趋化相关基因集，为 vMSLC 诱导的 GBM TSs 侵袭提供了机制基础。使用小鼠原位异种移植模型的体内实验证实了 vMSLC 诱导的 GBM TSs 侵袭性增加。
尽管 vMSLCs 是非致瘤性的，但这项研究增加了我们对 GBM 细胞如何通过存在于 GBM 起源区域的 vMSLCs 获得浸润性特征的理解。
