胶质母细胞瘤相关间充质干细胞相关基因预后指数的建立和验证，用于预测胶质母细胞瘤的预后和指导个体化治疗。
Development and validation of a glioma-associated mesenchymal stem cell-related gene prognostic index for predicting prognosis and guiding individualized therapy in glioma.
机构信息
Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
出版信息
Stem Cell Res Ther. 2023 Apr 1;14(1):56. doi: 10.1186/s13287-023-03285-9.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
The constructed GA-MSCRGPI could predict prognosis and guide individualized therapy in glioma patients.
背景
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。
方法
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。
结果
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。
结论
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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