Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
J Exp Med. 2018 Mar 5;215(3):963-983. doi: 10.1084/jem.20170123. Epub 2018 Feb 14.
High-grade glioma (HGG) is highly angiogenic, but antiangiogenic therapy has transient clinical benefit in only a fraction of patients. Vascular regulators of these heterogeneous responses remain undetermined. We found up-regulation of Sox7 and down-regulation of Sox17 in tumor endothelial cells (tECs) in mouse HGG. deletion suppressed VEGFR2 expression, vascular abnormality, hypoxia-driven invasion, regulatory T cell infiltration, and tumor growth. Conversely, deletion exacerbated these phenotypes by up-regulating Sox7 in tECs. Anti-VEGFR2 antibody treatment delayed tumor growth by normalizing -deficient abnormal vessels with high Sox7 levels but promoted it by regressing -deficient vessels, recapitulating variable therapeutic responses to antiangiogenic therapy in HGG patients. Our findings establish that Sox7 promotes tumor growth via vessel abnormalization, and its level determines the therapeutic outcome of VEGFR2 inhibition in HGG. In 189 HGG patients, Sox7 expression was heterogeneous in tumor vessels, and high Sox7 levels correlated with poor survival, early recurrence, and impaired vascular function, emphasizing the clinical relevance of Sox7 in HGG.
高级别神经胶质瘤（HGG）具有高度血管生成性，但抗血管生成治疗仅在一小部分患者中具有短暂的临床获益。这些异质性反应的血管调节因子仍未确定。我们在小鼠 HGG 的肿瘤内皮细胞（tEC）中发现 Sox7 上调和 Sox17 下调。 缺失抑制了 VEGFR2 的表达、血管异常、缺氧驱动的侵袭、调节性 T 细胞浸润和肿瘤生长。相反， 缺失通过在 tEC 中上调 Sox7 加剧了这些表型。抗 VEGFR2 抗体治疗通过使 Sox7 水平升高的 - 缺陷异常血管正常化来延迟肿瘤生长，但通过消退 - 缺陷血管来促进肿瘤生长，从而再现了 HGG 患者抗血管生成治疗的可变治疗反应。我们的研究结果表明 Sox7 通过血管异常化促进肿瘤生长，其水平决定了 VEGFR2 抑制在 HGG 中的治疗效果。在 189 名 HGG 患者中，肿瘤血管中的 Sox7 表达具有异质性，高 Sox7 水平与不良预后、早期复发和血管功能受损相关，强调了 Sox7 在 HGG 中的临床相关性。
