TY - JOUR
T1 - Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors
AU - Croci, Diego O.
AU - Cerliani, Juan P.
AU - Dalotto-Moreno, Tomas
AU - Méndez-Huergo, Santiago P.
AU - Mascanfroni, Ivan D.
AU - Dergan-Dylon, Sebastián
AU - Toscano, Marta A.
AU - Caramelo, Julio J.
AU - García-Vallejo, Juan J.
AU - Ouyang, Jing
AU - Mesri, Enrique A.
AU - Junttila, Melissa R.
AU - Bais, Carlos
AU - Shipp, Margaret A.
AU - Salatino, Mariana
AU - Rabinovich, Gabriel A.
N1 - Funding Information:
We thank J. Dennis for Mgat5 −/− mice; J. Paulson for St6gal1 −/− mice; F. Poirier for Lgals1 −/− mice; J. Wang for Gal1 N46D ; C. Tran for PDAC tumors; J. Stupirski, H. Kalay, C. Leishman, and R. Morales for technical assistance; and J. Ilarregui and A. Góngora for advice. Supported by the Argentinean Agency for Promotion of Science and Technology, CONICET, University of Buenos Aires, Sales Foundation, and donations from Ferioli and Ostry families (to G.A.R.).
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2014/2/13
Y1 - 2014/2/13
N2 - 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. PaperFlick
AB - 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. PaperFlick
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U2 - 10.1016/j.cell.2014.01.043
DO - 10.1016/j.cell.2014.01.043
M3 - Article
C2 - 24529377
AN - SCOPUS:84894136530
VL - 156
SP - 744
EP - 758
JO - Cell
JF - Cell
SN - 0092-8674
IS - 4
ER -