We reported previously that microglia decreased the growth of human brain tumor-initiating cells (BTICs). Through microarray analyses of BTICs exposed in vitro to microglia, we found the induction of several genes ascribed to have roles in cell cycle arrest, reduced cell proliferation and differentiation. Herein, we tested the hypothesis that one of these genes, growth arrest specific 1 (Gas1), is a novel growth reduction factor that is induced in BTICs by microglia. We found that microglia increased the expression of Gas1 transcript and protein in glioblastoma patient-derived BTIC lines. Using neurosphere assay we show that RNAi-induced reduction of Gas1 expression in BTICs blunted the microglia-mediated BTIC growth reduction. The role of Gas1 in mediating BTIC growth arrest was further validated using orthotopic brain xenografts in mice. When microglia-induced Gas1-expressing BTIC cells (mGas1-BTICs) were implanted intra-cranially in mice, tumor growth was markedly decreased; this was mirrored in the remarkable increase in survival of mGas1-BT025 and mGas1-BT048 implanted mice, compared to mice implanted with non-microglia-exposed BTIC cells. In conclusion, this study has identified Gas1 as a novel factor and mechanism through which microglia arrest the growth of BTICs for anti-tumor property.

中文翻译：

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小胶质细胞在人脑肿瘤启动细胞中诱导Gas1表达，从而降低肿瘤发生能力。

我们先前曾报道小胶质细胞减少了人脑肿瘤启动细胞（BTIC）的生长。通过对体外暴露于小胶质细胞的BTIC进行的微阵列分析，我们发现了诱导归因于在细胞周期停滞，减少细胞增殖和分化中起作用的几种基因。在本文中，我们测试了以下假设：这些基因之一是生长停滞特异性1（Gas1），是一种由小胶质细胞在BTICs中诱导的新型生长减少因子。我们发现小胶质细胞增加了胶质母细胞瘤患者来源的BTIC系中Gas1转录本和蛋白质的表达。使用神经球测定，我们表明RNAi诱导的BTIC中Gas1表达的减少钝化了小胶质细胞介导的BTIC生长减少。使用原位脑异种移植物在小鼠中进一步验证了Gas1在介导BTIC生长停滞中的作用。当在小鼠颅内植入小胶质细胞诱导的表达Gas1的BTIC细胞（mGas1-BTICs）时，肿瘤的生长明显减少。与植入未暴露小胶质细胞的BTIC细胞相比，植入mGas1-BT025和mGas1-BT048的小鼠的存活率显着提高，这反映了这一点。总之，这项研究已将Gas1鉴定为小胶质细胞阻止BTICs生长的新因子和机制，从而具有抗肿瘤特性。