Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1.
Glioma-associated microglia/macrophages display an expression profile different from M1 and M2 polarization and highly express Gpnmb and Spp1.
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神经胶质瘤相关的小胶质细胞/巨噬细胞表现出与 M1 和 M2 极化不同的表达谱，并高度表达 Gpnmb 和 Spp1。
DOI：
10.1371/journal.pone.0116644
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Kettenmann H
中科院分区：
文献类型：
--
作者：
Szulzewsky F;Pelz A;Feng X;Synowitz M;Markovic D;Langmann T;Holtman IR;Wang X;Eggen BJ;Boddeke HW;Hambardzumyan D;Wolf SA;Kettenmann H
恶性胶质瘤是人类最具侵袭性的肿瘤，目前尚无成功的治疗方法。多形性胶质母细胞瘤（GBM）是最高级别的胶质瘤，其患者在确诊后的平均生存时间仅为一年左右。小胶质细胞和外周巨噬细胞/单核细胞都在胶质瘤内部和周围聚集，但不能发挥有效的抗肿瘤活性，甚至不能支持肿瘤生长。在这里，我们使用微阵列分析来比较胶质瘤相关的小胶质细胞/巨噬细胞和初始对照细胞的表达谱。样品由naïve和gl261植入的C57BL/6小鼠脑中的CD11b+ macs分离细胞产生。与对照细胞相比，胶质瘤相关的小胶质细胞/巨噬细胞中约有1000个基因上调或下调2倍以上。通过与已发表的M1、M2a、b、c极化巨噬细胞数据集的比较，我们发现了一种与M1或M2基因表达模式只有部分重叠的基因表达模式。从两种不同的胶质瘤小鼠模型中生成用于qRT-PCR验证所选M1和M2a，b，c特异性基因的样本，并通过流式细胞术分离以区分常驻小胶质细胞和入侵巨噬细胞。我们在两种模型中证实了独特的胶质瘤相关小胶质细胞/巨噬细胞表型，包括M1和M2a，b，c特异性基因的混合物。验证这些基因在GBM、低级别脑肿瘤和对照标本中分离的CD11b+小胶质细胞/巨噬细胞中的表达。除了M1/M2基因分析外，我们还证明Gpnmb和Spp1的表达在小鼠和人类胶质瘤相关的小胶质细胞/巨噬细胞中都高度上调。与基因表达数据相关的患者生存数据表明，这些基因的高表达与人类GBM的不良预后相关。我们还发现，在小鼠和人GBM中，小胶质细胞/巨噬细胞是这些转录本的主要来源。我们的发现为未来的抗胶质瘤治疗提供了新的潜在靶点。
Malignant glioma belong to the most aggressive neoplasms in humans with no successful treatment available. Patients suffering from glioblastoma multiforme (GBM), the highest-grade glioma, have an average survival time of only around one year after diagnosis. Both microglia and peripheral macrophages/monocytes accumulate within and around glioma, but fail to exert effective anti-tumor activity and even support tumor growth. Here we use microarray analysis to compare the expression profiles of glioma-associated microglia/macrophages and naive control cells. Samples were generated from CD11b+ MACS-isolated cells from naïve and GL261-implanted C57BL/6 mouse brains. Around 1000 genes were more than 2-fold up- or downregulated in glioma-associated microglia/macrophages when compared to control cells. A comparison with published data sets of M1, M2a,b,c-polarized macrophages revealed a gene expression pattern that has only partial overlap with any of the M1 or M2 gene expression patterns. Samples for the qRT-PCR validation of selected M1 and M2a,b,c-specific genes were generated from two different glioma mouse models and isolated by flow cytometry to distinguish between resident microglia and invading macrophages. We confirmed in both models the unique glioma-associated microglia/macrophage phenotype including a mixture of M1 and M2a,b,c-specific genes. To validate the expression of these genes in human we MACS-isolated CD11b+ microglia/macrophages from GBM, lower grade brain tumors and control specimens. Apart from the M1/M2 gene analysis, we demonstrate that the expression of Gpnmb and Spp1 is highly upregulated in both murine and human glioma-associated microglia/macrophages. High expression of these genes has been associated with poor prognosis in human GBM, as indicated by patient survival data linked to gene expression data. We also show that microglia/macrophages are the predominant source of these transcripts in murine and human GBM. Our findings provide new potential targets for future anti-glioma therapy.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
3.7
作者：
Brennan C;Momota H;Hambardzumyan D;Ozawa T;Tandon A;Pedraza A;Holland E
通讯作者：
Holland E
影响因子：
5.4
作者：
Chung, Jin-Sung;Bonkobara, Makoto;Tomihari, Mizuki;Cruz, Ponciano A., Jr.;Ariizumi, Kiyoshi
通讯作者：
Ariizumi, Kiyoshi
影响因子：
5.8
作者：
Eichler, GS;Huang, S;Ingber, DE
通讯作者：
Ingber, DE
影响因子：
3.7
作者：
Engler JR;Robinson AE;Smirnov I;Hodgson JG;Berger MS;Gupta N;James CD;Molinaro A;Phillips JJ
通讯作者：
Phillips JJ