title: Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors.
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.
authors: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Buenos Aires, Argentina.
authors: Diego O
authors: DO
authors: Croci
authors: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Buenos Aires, Argentina.
authors: Juan P
authors: JP
authors: Cerliani
authors: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Buenos Aires, Argentina.
authors: Tomas
authors: T
authors: Dalotto-Moreno
authors: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Buenos Aires, Argentina.
authors: Santiago P
authors: SP
authors: Méndez-Huergo
authors: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Buenos Aires, Argentina.
authors: Ivan D
authors: ID
authors: Mascanfroni
authors: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Buenos Aires, Argentina.
authors: Sebastián
authors: S
authors: Dergan-Dylon
authors: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Buenos Aires, Argentina.
authors: Marta A
authors: MA
authors: Toscano
authors: Laboratorio de Biología Estructural y Celular, Fundación Instituto Leloir, CONICET, 1405 Buenos Aires, Argentina.
authors: Julio J
authors: JJ
authors: Caramelo
authors: Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081BT Amsterdam, The Netherlands.
authors: Juan J
authors: JJ
authors: García-Vallejo
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
authors: Jing
authors: J
authors: Ouyang
authors: 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.
authors: Enrique A
authors: EA
authors: Mesri
authors: Genentech, Inc., South San Francisco, CA 94080, USA.
authors: Melissa R
authors: MR
authors: Junttila
authors: Genentech, Inc., South San Francisco, CA 94080, USA.
authors: Carlos
authors: C
authors: Bais
authors: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA.
authors: Margaret A
authors: MA
authors: Shipp
authors: Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME), Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), 1428 Buenos Aires, Argentina.
authors: Mariana
authors: M
authors: Salatino
authors: 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.
authors: Gabriel A
authors: GA
authors: Rabinovich
mesh_terms: D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism; D037483:Galectin 1 / Q000235:genetics / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D000860:Hypoxia; D051379:Mice; D009369:Neoplasms / Q000098:blood supply* / Q000188:drug therapy*; D009389:Neovascularization, Pathologic; D011975:Receptors, Mitogen / Q000378:metabolism; D042442:Vascular Endothelial Growth Factors / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D037483:Galectin 1; D011975:Receptors, Mitogen; D042442:Vascular Endothelial Growth Factors