Gain-of-function mutations in isocitrate dehydrogenase (IDH) genes result in excessive production of (D)-2-hydroxyglutarate (D-2HG) which intrinsically modifies tumor cell epigenetics and impacts surrounding noncancerous cells through nonepigenetic pathways. However, whether D-2HG has a paracrine effect on endothelial cells in the tumor microenvironment needs further clarification. We quantified microvessel density by immunohistochemistry using tissue sections from 60 high-grade astrocytic gliomas with or without IDH mutation. Microvessel density was found to be reduced in tumors carrying an IDH mutation. Ex vivo experiments showed that D-2HG inhibited endothelial cell migration, wound healing, and tube formation by suppressing cell proliferation but not viability, possibly through reduced activation of the mTOR/STAT3 pathway. Further, D-2HG reduced fluorescent dextran permeability and decreased paracellular T-cell transendothelial migration by augmenting expression of junctional proteins thereby collectively increasing endothelial barrier function. These results indicate that D-2HG may influence the tumor vascular microenvironment by reducing the intratumoral vasculature density and by inhibiting the transport of metabolites and extravasation of circulating cells into the astrocytoma microenvironment. These observations provide a rationale for combining IDH inhibition with antitumor immunological/angiogenic approaches and suggest a molecular basis for resistance to antiangiogenic drugs in patients whose tumors express a mutant IDH allele.

中文翻译：

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D-2-羟基戊二酸调节人脑血管内皮细胞增殖和屏障功能

异柠檬酸脱氢酶 (IDH) 基因的功能获得性突变导致 (D)-2-羟基戊二酸 (D-2HG) 过量产生，从本质上改变肿瘤细胞表观遗传学，并通过非表观遗传途径影响周围的非癌细胞。然而，D-2HG是否对肿瘤微环境中的内皮细胞具有旁分泌作用还需要进一步阐明。我们使用来自 60 个有或没有 IDH 突变的高级星形细胞胶质瘤的组织切片，通过免疫组织化学量化了微血管密度。发现携带 IDH 突变的肿瘤中微血管密度降低。离体实验表明，D-2HG 通过抑制细胞增殖而非活力来抑制内皮细胞迁移、伤口愈合和管形成，这可能是通过减少 mTOR/STAT3 通路的激活来实现的。此外，D-2HG 通过增强连接蛋白的表达来降低荧光右旋糖酐通透性并减少细胞旁 T 细胞跨内皮迁移，从而共同增强内皮屏障功能。这些结果表明，D-2HG可能通过降低瘤内血管密度和抑制代谢物的转运和循环细胞外渗到星形细胞瘤微环境中来影响肿瘤血管微环境。这些观察结果为将 IDH 抑制与抗肿瘤免疫/血管生成方法相结合提供了基本原理，并提出了肿瘤表达突变 IDH 等位基因的患者对抗血管生成药物耐药的分子基础。