Department of Pathology, School of Basic Medical Sciences, Fudan University, Yixueyuan Rd. 138, Shanghai, 20032, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Yixueyuan Rd. 138, Shanghai, 20032, China.
Neurosurgical Department of Huashan Hospital, Shanghai Medical College, Fudan University, Yixueyuan Rd. 138, Shanghai, 20032, China.
Cancer Lett. 2021 Aug 10;513:1-13. doi: 10.1016/j.canlet.2021.05.002. Epub 2021 May 16.
Glioblastoma (GBM) is one of the most highly vascularized human cancers. The role of exosomes in cancer angiogenesis has attracted recent interest. However, proangiogenic biomolecules transported by exosomes to facilitate angiogenesis in GBM have not yet been identified. Here, we found a specific 120-kDa isoform of vascular endothelial growth factor (VEGF) in GBM-derived exosomes and confirmed it as VEGF-C. By binding to VEGF receptor 2 (VEGFR2), VEGF-C from GBM-derived exosomes showed a strong stimulatory effect on tafazzin (TAZ) expression in endothelial cells by inhibiting the Hippo signaling pathway, which eventually stimulates endothelial cell viability, migration, and tubulation. In human glioma samples, the expression of VEGF-C in tumor cells positively correlated with TAZ expression in endothelial cells. We further demonstrated that an inhibitor of exosomal release had a cooperative inhibitory effect with bevacizumab on GBM xenograft subcutaneous tumor growth and angiogenesis. Taken together, our findings revealed a novel VEGF-C isoform in GBM-derived exosomes with a role in angiogenesis and highlighted the importance of recognizing its unique signaling pathway when considering drug treatment strategies for GBM.
胶质母细胞瘤（GBM）是人类癌症中血管化程度最高的肿瘤之一。外泌体在癌症血管生成中的作用引起了最近的关注。然而，外泌体运输的促血管生成生物分子，以促进 GBM 中的血管生成，尚未被鉴定。在这里，我们在 GBM 来源的外泌体中发现了一种特定的 120 kDa 血管内皮生长因子（VEGF）同工型，并证实其为 VEGF-C。通过与血管内皮生长因子受体 2（VEGFR2）结合，GBM 来源的外泌体中的 VEGF-C 通过抑制 Hippo 信号通路，对内皮细胞中的 tafazzin（TAZ）表达表现出强烈的刺激作用，最终刺激内皮细胞活力、迁移和管腔形成。在人类神经胶质瘤样本中，肿瘤细胞中 VEGF-C 的表达与内皮细胞中 TAZ 的表达呈正相关。我们进一步证明，外泌体释放抑制剂与贝伐单抗联合使用对 GBM 异种移植皮下肿瘤生长和血管生成具有协同抑制作用。总之，我们的研究结果揭示了 GBM 来源的外泌体中一种新型的 VEGF-C 同工型在血管生成中的作用，并强调了在考虑 GBM 药物治疗策略时，识别其独特信号通路的重要性。
