GLYCOSYLATION-DEPENDENT LECTIN-RECEPTOR INTERACTIONS PRESERVE ANGIOGENESIS IN ANTI-VEGF REFRACTORY TUMORS

CROCI DIEGO O; CERLIANI JUAN PABLO; DALOTTO MORENO TOMAS; MENDEZ HUERGO SANTIAGO P; MASCANFRONI IVAN D; DERGAN DYLON, SEBASTIÁN; TOSCANO MARTA; CARAMELO JULIO; GARCIA-VALLEJO JUAN J; OUYANG JING; MESRI ENRIQUE; JUNTTILA MELISSA; BAIS CARLOS; SHIPP MARGARET; SALATINO MARIANA; RABINOVICH GABRIEL

CELL

CELL PRESS

Lugar: United States; Año: 2014 vol. 156 p. 744 - 758

0092-8674

SUMMARY The clinical benefit conferred by 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 alpha2-6-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 alpha2-6-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.