Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors

CROCI DO; CERLIANI JP; DALOTTO-MORENO T; MÉNDEZ-HUERGO SP; MASCANFRONI ID; DERGAN-DYLON S; TOSCANO MA; CARAMELO JJ; GARCÍA-VALLEJO JJ; OUYANG J; MESRI EA; JUNTTILA MR; BAIS C; SHIPP MA; SALATINO M; RABINOVICH GA

CELL

CELL PRESS

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

0092-8674

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 a2-6-linkedsialic acid,which prevented Gal1 binding. In contrast, anti-VEGF refractory tumors secreted increased Gal1 and their associated vasculature displayed glycosylation patterns that facilitated Gal1-ECinteractions. Interruption of b1-6GlcNAc branching in ECs or silencing of tumor-derived Gal1 converted refractory into anti-VEGF-sensitive tumors, whereas elimination of a2-6-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 interactionsay increase the efficacy of anti-VEGF treatment.