Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
FASEB J. 2018 Jun;32(6):2934-2949. doi: 10.1096/fj.201700867RR. Epub 2018 Jan 11.
Endoglin, a TGF-β coreceptor predominantly expressed in endothelial cells, plays an important role in vascular development and tumor-associated angiogenesis. However, the mechanism by which endoglin regulates angiogenesis, especially during tip cell formation, remains largely unknown. In this study, we report that endoglin promoted VEGF-induced tip cell formation. Mechanistically, endoglin interacted with VEGF receptor (VEGFR)-2 in a VEGF-dependent manner, which sustained VEGFR2 on the cell surface and prevented its degradation. Endoglin mutants deficient in the ability to interact with VEGFR2 failed to sustain VEGFR2 on the cell surface and to promote VEGF-induced tip cell formation. Further, an endoglin-targeting monoclonal antibody (mAb), TRC105, cooperated with a VEGF-A targeting mAb, bevacizumab, to inhibit VEGF signaling and tip cell formation in vitro and to inhibit tumor growth, metastasis, and tumor-associated angiogenesis in a murine tumor model. This study demonstrate a novel mechanism by which endoglin initiates and regulates VEGF-driven angiogenesis while providing a rationale for combining anti-VEGF and anti-endoglin therapy in patients with cancer.-Tian, H., Huang, J. J., Golzio, C., Gao, X., Hector-Greene, M., Katsanis, N., Blobe, G. C. Endoglin interacts with VEGFR2 to promote angiogenesis.
内皮糖蛋白，一种主要在血管内皮细胞中表达的 TGF-β 核心受体，在血管发育和肿瘤相关血管生成中发挥重要作用。然而，内皮糖蛋白调节血管生成的机制，特别是在尖端细胞形成过程中的机制，在很大程度上仍然未知。在这项研究中，我们报告内皮糖蛋白促进了 VEGF 诱导的尖端细胞形成。在机制上，内皮糖蛋白以 VEGF 依赖的方式与 VEGF 受体 (VEGFR)-2 相互作用，从而维持 VEGFR2 在细胞表面并防止其降解。缺乏与 VEGFR2 相互作用能力的内皮糖蛋白突变体无法维持 VEGFR2 在细胞表面的位置，也无法促进 VEGF 诱导的尖端细胞形成。此外，一种内皮糖蛋白靶向的单克隆抗体 (mAb)，TRC105，与一种 VEGF-A 靶向的 mAb，bevacizumab，协同作用，在体外抑制 VEGF 信号和尖端细胞形成，并在小鼠肿瘤模型中抑制肿瘤生长、转移和肿瘤相关血管生成。这项研究证明了内皮糖蛋白启动和调节 VEGF 驱动的血管生成的新机制，为在癌症患者中联合抗 VEGF 和抗内皮糖蛋白治疗提供了依据。-Tian, H., Huang, J. J., Golzio, C., Gao, X., Hector-Greene, M., Katsanis, N., Blobe, G. C. Endoglin interacts with VEGFR2 to promote angiogenesis.
