IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas.
IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas.
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IDH 突变状态与低级别胶质瘤中独特的血管基因表达特征相关。
DOI：
10.1093/neuonc/noy088
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发表时间：
2018-10-09
期刊：
影响因子：
15.9
通讯作者：
Dimberg A
中科院分区：
文献类型：
--
作者：
Zhang L;He L;Lugano R;Roodakker K;Bergqvist M;Smits A;Dimberg A
低级别胶质瘤（LGG；弥漫性世界卫生组织 [WHO] II-III 级胶质瘤）中的血管基因表达模式尚未得到彻底研究。本研究的目的是从分子角度表征 LGG 血管并确定肿瘤异柠檬酸脱氢酶 (IDH) 突变状态是否影响血管表型。使用源自显微解剖血管和人类神经胶质瘤总肿瘤样本的内部数据集，结合癌症基因组图谱数据库中 289 个 LGG 样本的表达数据，对基因表达进行了分析。通过免疫组织化学检查代表 WHO II-IV 级神经胶质瘤和非恶性脑样本的人脑肿瘤组织微阵列 (TMA) 中的血管蛋白表达。在体外检查原代内皮细胞中基因表达的调节。 WHO II级胶质瘤的基因表达分析表明血管异常处于中间阶段，其严重程度低于胶质母细胞瘤血管，但与正常血管不同。通过人 TMA 染色证实了 WHO II 级神经胶质瘤中层粘连蛋白亚基 α 4 (LAMA4) 和血管生成素 2 (ANGPT2) 的表达增强。 IDH野生型LGG表现出特定的血管生成基因表达特征，包括ANGPT2和丝氨酸蛋白酶抑制剂家族H (SERPINH1)的上调，与增强的内皮细胞迁移和基质重塑有关。转录因子分析表明 IDH 野生型 LGG 中转化生长因子 β (TGFβ) 和缺氧信号传导增加。在体外用 TGFβ2、血管内皮生长因子或氯化钴刺激内皮细胞，IDH 野生型 LGG 血管中特异性诱导的基因子集上调。 IDH 野生型 LGG 血管在分子上与 IDH 突变 LGG 的血管系统不同。 TGFβ 和缺氧相关信号通路可能是 IDH 野生型 LGG 抗血管生成治疗的潜在靶点。
Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II–III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype. Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II–IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro. Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro. IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.
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影响因子：
--
作者：
Kelly PJ
通讯作者：
Kelly PJ
影响因子：
6.4
作者：
Popova SN;Bergqvist M;Dimberg A;Edqvist PH;Ekman S;Hesselager G;Ponten F;Smits A;Sooman L;Alafuzoff I
通讯作者：
Alafuzoff I
影响因子：
28.2
作者：
Rodon, Laura;Gonzalez-Junca, Alba;Seoane, Joan
通讯作者：
Seoane, Joan
影响因子：
8.8
作者：
Elsir, T.;Qu, M.;Berntsson, S. G.;Orrego, A.;Olofsson, T.;Lindstrom, M. S.;Nister, M.;von Deimling, A.;Hartmann, C.;Ribom, D.;Smits, A.
通讯作者：
Smits, A.
影响因子：
3.2
作者：
Hwang, Eugene I.;Jakacki, Regina I.;Packer, Roger J.
通讯作者：
Packer, Roger J.