Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Stem Cell Res Ther. 2023 Apr 1;14(1):56. doi: 10.1186/s13287-023-03285-9.
Recent studies have demonstrated that glioma-associated mesenchymal stem cells (GA-MSCs) are implicated in the regulation of glioma malignant progression. However, the prognostic value of GA-MSCs has not been comprehensively explored in glioma.
We extracted GA-MSCs from glioma tissues, established intracranial xenograft models in nude mice, and obtained GA-MSC-related genes (GA-MSCRGs) by using microarrays. The transcriptome data and clinical information of glioma patients were obtained from the CGGA and TCGA databases. We screened 8 prognostic GA-MSCRGs to construct a prognostic index by using the multivariate Cox regression method. The validity of the GA-MSCRGPI was verified in the training (CGGA693) and validation (TCGA and CGGA325) cohorts. The expression patterns of these 8 GA-MSCRGs were validated in 78 glioma tissue specimens by using a qRT‒PCR assay.
GA-MSCs were successfully isolated from glioma tissues. Based on intracranial xenograft models and transcriptome microarray screening, 8 genes (MCM7, CDK6, ORC1, CCL20, TNFRSF12A, POLA1, TRAF1 and TIAM1) were selected for the construction of a GA-MSC-related gene prognostic index (GA-MSCRGPI). In both the training and validation cohorts, high GA-MSCRGPI patients showed an inferior survival outcome compared with low GA-MSCRGPI patients. A nomogram was established based on independent prognostic indicators (age, WHO grade and GA-MSCRGPI) and exhibited a strong forecasting ability for overall survival (OS). Moreover, we found that the GA-MSCRGPI could evaluate the prognosis of glioma patients undergoing chemoradiotherapy. The high GA-MSCRGPI group exhibited higher immune, stromal and ESTIMATE scores; lower tumor purity; higher infiltration of Tregs and M2-type macrophages; fewer activated NK cells; and higher expression of immune checkpoints. Tumor Immune Dysfunction and Exclusion (TIDE) showed that the high GA-MSCRGPI group had more responders to ICI therapy. The results of the genetic mutation profile and tumor mutation burden (TMB) in different GA-MSCRGPI subgroups further supplement GA-MSCRGPI-related mechanisms. Finally, the expression patterns of 8 selected GA-MSCRGs in GA-MSCRGPI were correlated with glioma WHO grades to a certain extent.
The constructed GA-MSCRGPI could predict prognosis and guide individualized therapy in glioma patients.
最近的研究表明，神经胶质瘤相关间充质干细胞（GA-MSCs）参与调控神经胶质瘤的恶性进展。然而，GA-MSCs 在神经胶质瘤中的预后价值尚未得到全面探讨。
我们从神经胶质瘤组织中提取 GA-MSCs，建立裸鼠颅内异种移植模型，并通过微阵列获得 GA-MSC 相关基因（GA-MSCRGs）。从 CGGA 和 TCGA 数据库中获取神经胶质瘤患者的转录组数据和临床信息。我们使用多变量 Cox 回归方法筛选出 8 个预后 GA-MSCRGs，构建预后指数（GA-MSCRGPI）。在训练集（CGGA693）和验证集（TCGA 和 CGGA325）中验证 GA-MSCRGPI 的有效性。使用 qRT-PCR 检测 78 例神经胶质瘤组织标本中这 8 个 GA-MSCRGs 的表达模式。
成功从神经胶质瘤组织中分离出 GA-MSCs。基于颅内异种移植模型和转录组微阵列筛选，选择 8 个基因（MCM7、CDK6、ORC1、CCL20、TNFRSF12A、POLA1、TRAF1 和 TIAM1）构建 GA-MSC 相关基因预后指数（GA-MSCRGPI）。在训练集和验证集中，GA-MSCRGPI 高的患者总生存期（OS）明显差于 GA-MSCRGPI 低的患者。根据独立预后指标（年龄、WHO 分级和 GA-MSCRGPI）建立了一个列线图，对 OS 具有很强的预测能力。此外，我们发现 GA-MSCRGPI 可以评估接受放化疗的神经胶质瘤患者的预后。GA-MSCRGPI 高的患者表现出更高的免疫、基质和 ESTIMATE 评分；更低的肿瘤纯度；更高的 Treg 和 M2 型巨噬细胞浸润；更少的活化 NK 细胞；以及更高的免疫检查点表达。肿瘤免疫功能障碍和排斥（TIDE）显示，GA-MSCRGPI 高的患者对 ICI 治疗的反应更多。不同 GA-MSCRGPI 亚组的遗传突变谱和肿瘤突变负荷（TMB）结果进一步补充了 GA-MSCRGPI 相关机制。最后，GA-MSCRGPI 中 8 个选定的 GA-MSCRGs 的表达模式与神经胶质瘤 WHO 分级有一定的相关性。
构建的 GA-MSCRGPI 可预测神经胶质瘤患者的预后，并指导个体化治疗。
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