糖基化
生物
血管生成
聚糖
癌症研究
血管生成素受体
细胞生物学
血管内皮生长因子
唾液酸
受体
生物化学
糖蛋白
血管内皮生长因子受体
作者
Diego O. Croci,Juan P. Cerliani,Tomás Dalotto-Moreno,Santiago P. Méndez-Huergo,Iván Mascanfroni,Sebastián Dergan-Dylon,Marta A. Toscano,Julio J. Caramelo,Juan J. García-Vallejo,Jing Ouyang,Enrique A. Mesri,Melissa R. Junttila,Carlos Bais,Margaret A. Shipp,Mariana Salatino,Gabriel A. Rabinovich
出处
期刊:Cell
[Elsevier]
日期:2014-02-01
卷期号:156 (4): 744-758
被引量:423
标识
DOI:10.1016/j.cell.2014.01.043
摘要
The clinical benefit conferred by vascular endothelial growth factors (VEGF)-targeted therapies is variable, and tumors from treated patients eventually reinitiate growth. Here, we identify a glycosylation-dependent pathway that compensates for the absence of cognate ligand and preserves angiogenesis in response to VEGF blockade. Remodeling of the endothelial cell (EC) surface glycome selectively regulated binding of galectin-1 (Gal1), which upon recognition of complex N-glycans on VEGFR2, activated VEGF-like signaling. Vessels within anti-VEGF-sensitive tumors exhibited high levels of α2-6-linked sialic acid, which prevented Gal1 binding. In contrast, anti-VEGF refractory tumors secreted increased Gal1 and their associated vasculature displayed glycosylation patterns that facilitated Gal1-EC interactions. Interruption of β1-6GlcNAc branching in ECs or silencing of tumor-derived Gal1 converted refractory into anti-VEGF-sensitive tumors, whereas elimination of α2-6-linked sialic acid conferred resistance to anti-VEGF. Disruption of the Gal1-N-glycan axis promoted vascular remodeling, immune cell influx and tumor growth inhibition. Thus, targeting glycosylation-dependent lectin-receptor interactions may increase the efficacy of anti-VEGF treatment.
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