Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02129, USA.
Department of Neurosurgery, UMC Utrecht Brain Center, University Medical Center, Utrecht University, 3584 CX, Utrecht, The Netherlands.
J Neuroinflammation. 2020 Apr 16;17(1):120. doi: 10.1186/s12974-020-01797-2.
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.
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.
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.
Our data define a microglia 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.
胶质母细胞瘤是最常见和最致命的原发性脑肿瘤。小胶质细胞是大脑的固有免疫细胞，它们监测周围环境并对病原体、毒素和肿瘤作出反应。胶质母细胞瘤细胞与小胶质细胞相互作用，部分通过释放细胞外囊泡（EVs）进行通讯。尽管胶质母细胞瘤中有大量的小胶质细胞，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。为了了解这一过程，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。
我们使用 RNASeq 对分离的小胶质细胞进行分析，以研究参与具有胶质母细胞瘤的小鼠中关键小胶质细胞功能的基因表达模式。我们重点研究了摄取肿瘤衍生 EV 的小胶质细胞，因此它们处于肿瘤内部和紧邻肿瘤的位置。
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以及用于肿瘤杀伤的基因的表达。相比之下，促进肿瘤扩散的基因表达上调。这些变化似乎部分是由 EV 介导的，因为向正常小鼠颅内注射 EV 会导致小胶质细胞发生类似的转录变化。当我们分析来自胶质母细胞瘤患者的数据集时，我们观察到类似的小胶质细胞转录组特征。
我们的数据定义了一种小胶质细胞特异性表型，即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、为侵袭清除道路，并增强肿瘤传播。为了进一步探索，我们开发了一个交互式在线工具，网址为 http://www.glioma-microglia.com，其中包含所有表达数据以及每个基因的附加功能和途径信息。
