Molecular profiling of the tumor microenvironment in glioblastoma patients: correlation of microglia/macrophage polarization state with metalloprotease expression profiles and survival
Molecular profiling of the tumor microenvironment in glioblastoma patients: correlation of microglia/macrophage polarization state with metalloprotease expression profiles and survival
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DOI：
10.1042/bsr20182361
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发表时间：
2019-06-20
影响因子：
4
通讯作者：
Nimsky, Christopher
中科院分区：
文献类型：
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作者：
Gjorgjevski, Marko;Hannen, Ricarda;Nimsky, Christopher
由于胶质母细胞瘤（GBM）预后不良，迫切需要开发新的治疗策略。除了消除 GBM 肿瘤细胞和干细胞外，一种新的治疗方法旨在针对神经胶质瘤相关的小胶质细胞/巨噬细胞 (GAM)。我们通过在 20 名 GBM 患者中利用 M1/M2 样极化标记物，研究了与患者预后相关的 GAM 分子谱。使用定量 PCR (qPCR)，标记物 CXCL10 (M1) 和 CCL13 (M2) 在人类巨噬细胞中得到验证，并应用于 GBM 组织的整体分析。此外，还分析了已知与 GBM 进展相关的蛋白酶基因（ADAM8、MMP9、MMP14、ADAM10、ADAM17）与 M1/M2 标记的相关性。值得注意的是，ADAM10 和 ADAM17 的表达水平与 M1 样表型显着相关，并且与患者生存呈正相关。虽然 ADAM8 mRNA 表达与 M1 和 M2 样标记物同等相关，但 MMP9 和 MMP14 基因与 M2 样表型显着相关，并与 GBM 患者队列中预后受损相关。因此，我们提供了强大而可靠的 qPCR 标记组合来表征 GBM 患者的整体小胶质细胞/巨噬细胞状态和相关蛋白酶谱，可用于分析肿瘤微环境、患者预后并预选那些通过复极化靶向小胶质细胞/巨噬细胞群可能有益的 GBM 患者。
Due to poor prognosis of glioblastoma (GBM), there is an urgent need to develop new therapeutic strategies. Besides eliminating GBM tumor cells and stem cells, a novel therapeutic approach aims to target Glioma-associated microglia/macrophages (GAMs). We investigated the molecular profile of GAMs correlated with patient prognosis by exploiting M1/M2-like polarization markers in a cohort of 20 GBM patients. Using quantitative PCR (qPCR), the markers CXCL10 (M1) and CCL13 (M2) were validated in human macrophages and applied to a global analysis of GBM tissue. Furthermore, proteinase genes, known to be associated with GBM progression (ADAM8, MMP9, MMP14, ADAM10, ADAM17), were analyzed in correlation to M1/M2 markers. Notably, expression levels of ADAM10 and ADAM17 are significantly correlated with an M1-like phenotype and are positively associated to patient survival. Whilst ADAM8 mRNA expression was equally correlated with M1and M2-like markers, genes for MMP9 and MMP14 are significantly associated with an M2-like phenotype and association to impaired prognosis in the GBM patient cohort. Thus, we provide a robust and reliable combination of qPCR markers to characterize global microglia/macrophage status and the associated proteinase profiles in GBM patients that can be used to analyze the tumormicroenvironment, the patients' prognosis and preselect those GBM patients for which targeting the microglia/macrophage population by repolarization might be beneficial.