BACKGROUND Glioblastomas are the most common and lethal primary brain tumors. Microglia, the resident immune cells of the brain, survey their environment and respond to pathogens, toxins, and tumors. Glioblastoma cells communicate with microglia, in part by releasing extracellular vesicles (EVs). Despite the presence of large numbers of microglia in glioblastoma, the tumors continue to grow, and these neuroimmune cells appear incapable of keeping the tumor in check. To understand this process, we analyzed gene expression in microglia interacting with glioblastoma cells. METHODS We used RNASeq of isolated microglia to analyze the expression patterns of genes involved in key microglial functions in mice with glioblastoma. We focused on microglia that had taken up tumor-derived EVs and therefore were within and immediately adjacent to the tumor. RESULTS We show that these microglia have downregulated expression of genes involved in sensing tumor cells and tumor-derived danger signals, as well as genes used for tumor killing. In contrast, expression of genes involved in facilitating tumor spread was upregulated. These changes appear to be in part EV-mediated, since intracranial injection of EVs in normal mice led to similar transcriptional changes in microglia. We observed a similar microglial transcriptomic signature when we analyzed datasets from human patients with glioblastoma. CONCLUSION Our data define a microgliaGlioblastoma specific phenotype, whereby glioblastomas have hijacked gene expression in the neuroimmune system to favor avoiding tumor sensing, suppressing the immune response, clearing a path for invasion, and enhancing tumor propagation. For further exploration, we developed an interactive online tool at http://www.glioma-microglia.com with all expression data and additional functional and pathway information for each gene.

中文翻译：

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胶质母细胞瘤劫持小胶质细胞基因表达以支持肿瘤生长。

背景技术胶质母细胞瘤是最常见和致命的原发性脑肿瘤。小胶质细胞是大脑的常驻免疫细胞，它调查它们的环境并对病原体、毒素和肿瘤作出反应。胶质母细胞瘤细胞与小胶质细胞通讯，部分通过释放细胞外囊泡 (EV)。尽管胶质母细胞瘤中存在大量小胶质细胞，但肿瘤仍在继续生长，这些神经免疫细胞似乎无法控制肿瘤。为了理解这个过程，我们分析了与胶质母细胞瘤细胞相互作用的小胶质细胞中的基因表达。方法 我们使用分离的小胶质细胞的 RNASeq 来分析与胶质母细胞瘤小鼠关键小胶质细胞功能相关的基因的表达模式。我们专注于吸收肿瘤衍生 EV 的小胶质细胞，因此位于肿瘤内并紧邻肿瘤。结果 我们表明，这些小胶质细胞下调了参与感知肿瘤细胞和肿瘤衍生危险信号的基因的表达，以及用于肿瘤杀伤的基因的表达。相反，参与促进肿瘤扩散的基因表达上调。这些变化似乎部分是 EV 介导的，因为在正常小鼠中颅内注射 EV 会导致小胶质细胞发生类似的转录变化。当我们分析来自人类胶质母细胞瘤患者的数据集时，我们观察到了类似的小胶质细胞转录组特征。结论 我们的数据定义了一种小胶质细胞胶质母细胞瘤特异性表型，其中胶质母细胞瘤劫持了神经免疫系统中的基因表达，以有利于避免肿瘤感知、抑制免疫反应、清除入侵路径和增强肿瘤传播。为了进一步探索，