异柠檬酸脱氢酶（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。
IDH mutation status is associated with distinct vascular gene expression signatures in lower-grade gliomas.
机构信息
Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, China.
Department of Immunology, Genetics, and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden.
出版信息
Neuro Oncol. 2018 Oct 9;20(11):1505-1516. doi: 10.1093/neuonc/noy088.
BACKGROUND
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.
METHODS
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.
RESULTS
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.
CONCLUSION
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.
背景
低级别胶质瘤（LGG；弥漫性世界卫生组织 [WHO] 分级 II-III 级胶质瘤）的血管基因表达模式尚未得到充分研究。本研究旨在对 LGG 血管进行分子特征分析，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。
方法
采用内部数据集对取自人类脑肿瘤的微血管和总肿瘤样本进行基因表达分析，同时结合癌症基因组图谱数据库中 289 例 LGG 样本的表达数据。通过免疫组织化学染色在代表 WHO 分级 II-IV 级胶质瘤和非恶性脑组织的人类脑肿瘤组织微阵列（TMA）上检测血管蛋白表达。在体外原代内皮细胞中检测基因表达的调控。
结果
WHO 分级 II 级胶质瘤的基因表达分析表明血管异常处于中间阶段，比胶质母细胞瘤血管的严重程度低，但与正常血管不同。通过对人类 TMA 的染色，证实了 WHO 分级 II 级胶质瘤中层粘连蛋白亚单位 alpha 4（LAMA4）和血管生成素 2（ANGPT2）的表达增强。IDH 野生型 LGG 显示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 TGFβ 和缺氧信号增加。体外用 TGFβ2、血管内皮生长因子或氯化钴刺激内皮细胞，可诱导 IDH 野生型 LGG 血管中特定的一组基因上调。
结论
IDH 野生型 LGG 血管在分子上与 IDH 突变型 LGG 的血管不同。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。
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