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Cell. 2014 Feb 13;156(4):744-58. doi: 10.1016/j.cell.2014.01.043.

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

Author information

1
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Buenos Aires, Argentina.
2
Laboratorio de Biología Estructural y Celular, Fundación Instituto Leloir, CONICET, 1405 Buenos Aires, Argentina.
3
Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081BT Amsterdam, The Netherlands.
4
Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
5
Miami Center for AIDS Research, Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
6
Genentech, Inc., South San Francisco, CA 94080, USA.
7
Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Buenos Aires, Argentina; Laboratorio de Glicómica. Departamento de Química Biológica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, 1428 Buenos Aires, Argentina. Electronic address: gabyrabi@gmail.com.

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.

PMID:
24529377
DOI:
10.1016/j.cell.2014.01.043
[Indexed for MEDLINE]
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