Most of the angiogenesis inhibitors clinically used in cancer treatment target the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway. However, the current strategies for treating angiogenesis have limited efficacy. The issue of how to treat angiogenesis and endothelial dysfunction in cancer remains a matter of substantial debate. Here we demonstrate a glycosylation-dependent regulatory mechanism for tumor angiogenesis. St6gal1^-/- mice, lacking the α2,6-sialylation enzyme, were shown to exhibit impaired tumor angiogenesis through enhanced endothelial apoptosis. In a previous study, St6gal1^-/- endothelial cells exhibited a reduction in the cell surface residency of platelet endothelial cell adhesion molecule (PECAM). In this study, we found that cooperative functionality of PECAM-VEGFR2-integrin β3 was disturbed in St6gal1^-/- mice. First, cell surface PECAM-VEGFR2 complexes were lost, and both VEGFR2 internalization and the VEGFR-dependent signaling pathway were enhanced. Second, enhanced anoikis was observed, suggesting that the absence of α2,6-sialic acid leads to dysregulated integrin signaling. Notably, ectopic expression of PECAM increased cell surface integrin-β3, indicating that the reduction of cell surface integrin-β3 involves loss-of-endothelial PECAM. The results suggest that the cell surface stability of these glycoproteins is significantly reduced by the lack of α2,6-sialic acid, leading to abnormal signal transduction. The present findings highlight that α2,6-sialylation is critically involved in endothelial survival by controlling the cell surface stability and signal transduction of angiogenic molecules, and could be a novel target for anti-angiogenesis therapy.

中文翻译：

---

糖基化控制内皮表面上的协同PECAM-VEGFR2-β3整联蛋白功能，从而促进肿瘤血管生成。

临床上用于癌症治疗的大多数血管生成抑制剂均靶向血管内皮生长因子（VEGF）/ VEGF受体（VEGFR）途径。然而，目前用于治疗血管生成的策略具有有限的功效。如何治疗癌症中的血管生成和内皮功能障碍的问题仍然是一个充满争议的问题。在这里，我们证明了肿瘤血管生成的糖基化依赖性调节机制。缺乏α2，6-唾液酸化酶的St6gal1 ^-/-小鼠显示出通过增强的内皮细胞凋亡而损害了肿瘤血管生成。在以前的研究中，St6gal1 ^-/-内皮细胞在血小板内皮细胞粘附分子（PECAM）的细胞表面停留时间降低。在这项研究中，我们发现St6gal1 ^-/-中PECAM-VEGFR2-integrinβ3的协同功能受到干扰老鼠。首先，细胞表面PECAM-VEGFR2复合物丢失，并且VEGFR2内在化和VEGFR依赖性信号通路均得到增强。其次，观察到了增强的无神经，这表明缺乏α2，6-唾液酸会导致整联蛋白信号传导失调。值得注意的是，PECAM的异位表达增加了细胞表面整合素β3的表达，表明细胞表面整合素β3的减少涉及内皮PECAM的丧失。结果表明，由于缺乏α2，6-唾液酸，这些糖蛋白的细胞表面稳定性显着降低，从而导致异常的信号转导。目前的发现突显出，α2,6-唾液酸化通过控制细胞表面稳定性和血管生成分子的信号转导而在内皮细胞存活中起着至关重要的作用，