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

Diego O. Croci, Juan P. Cerliani, Tomas Dalotto-Moreno, Santiago P. Méndez-Huergo, Ivan D. 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

Research output: Contribution to journalArticle

273 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)744-758
Number of pages15
JournalCell
Volume156
Issue number4
DOIs
StatePublished - Feb 13 2014

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Croci, D. O., Cerliani, J. P., Dalotto-Moreno, T., Méndez-Huergo, S. P., Mascanfroni, I. D., Dergan-Dylon, S., Toscano, M. A., Caramelo, J. J., García-Vallejo, J. J., Ouyang, J., Mesri, E. A., Junttila, M. R., Bais, C., Shipp, M. A., Salatino, M., & Rabinovich, G. A. (2014). Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell, 156(4), 744-758. https://doi.org/10.1016/j.cell.2014.01.043