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Linking tumor hypoxia with VEGFR2 signaling and compensatory angiogenesis: Glycans make the difference.

Croci DO, Rabinovich GA - Oncoimmunology (2014)

Bottom Line: Although blocking vascular endothelial growth factor (VEGF) signaling is clinically beneficial in certain cancers, tumor regrowth in treated patients suggests that compensatory angiogenic programs may limit the efficacy of anti-VEGF treatment.We found that association of galectin-1 with complex N-glycans on VEGFR2 links tumor hypoxia to VEGFR2 signaling and preserves angiogenesis in response to VEGF blockade.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Inmunopatología; Instituto de Biología y Medicina Experimental (IBYME); Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Buenos Aires, Argentina.

ABSTRACT
Although blocking vascular endothelial growth factor (VEGF) signaling is clinically beneficial in certain cancers, tumor regrowth in treated patients suggests that compensatory angiogenic programs may limit the efficacy of anti-VEGF treatment. We found that association of galectin-1 with complex N-glycans on VEGFR2 links tumor hypoxia to VEGFR2 signaling and preserves angiogenesis in response to VEGF blockade.

No MeSH data available.


Related in: MedlinePlus

Figure 1. Association of Gal1 with complex N-gycans on VEGFR2 compensates for the absence of cognate ligand in anti-VEGF refractory tumors. In response to VEGF blockade, anti-VEGF refractory tumors (upper pannel) secrete higher amounts of Gal1 and their associated endothelial cells (ECs) express all the repertoire of glycans that are critical for Gal1 binding (increased β1,6 N-glycan branching, augmented poly-N-acetyllactosamine extension and lower α2,6 sialylation). This inducible EC glycophenotype facilitated Gal1 signaling, compensatory angiogenesis and tumor growth. In contrast, blood vessels associated with anti-VEGF sensitive tumors (lower panel) displayed higher amounts of α2,6-linked sialic acid which prevented Gal-1-VEGFR2 interactions.
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Figure 1: Figure 1. Association of Gal1 with complex N-gycans on VEGFR2 compensates for the absence of cognate ligand in anti-VEGF refractory tumors. In response to VEGF blockade, anti-VEGF refractory tumors (upper pannel) secrete higher amounts of Gal1 and their associated endothelial cells (ECs) express all the repertoire of glycans that are critical for Gal1 binding (increased β1,6 N-glycan branching, augmented poly-N-acetyllactosamine extension and lower α2,6 sialylation). This inducible EC glycophenotype facilitated Gal1 signaling, compensatory angiogenesis and tumor growth. In contrast, blood vessels associated with anti-VEGF sensitive tumors (lower panel) displayed higher amounts of α2,6-linked sialic acid which prevented Gal-1-VEGFR2 interactions.

Mentions: In vitro, serum-free conditioned medium from anti-VEGF refractory, but not anti-VEGF sensitive tumors, induced endothelial cell exposure of Gal1-specific ligands. More importantly, tumor-associated vessels from mice inoculated with tumors that were sensitive to anti-VEGF (B16-F0 melanoma and CT26 colon carcinoma), expressed high amounts of α2,6-linked sialic acid in response to VEGF blockade, which prevented Gal1 binding and angiogenesis (Fig. 1). In contrast, mice inoculated with anti-VEGF refractory tumors (Lewis lung adenocarcinoma; LLC1 and R1.1 T cell lymphoma) secreted increased Gal1 and their associated vasculature expressed higher amounts of β1–6GlcNAc-branched complex N-glycans and decreased α2,6 sialylation in response to VEGF blockade (Fig. 1). Programmed remodeling of the EC glycome facilitated Gal-1-N-glycan interactions and promoted compensatory angiogenesis in tumors with limited sensitivity to anti-VEGF.10 Lack of β1–6GlcNAc-branched N-glycans in endothelial cells or silencing of tumor-derived Gal1 converted refractory into anti-VEGF-sensitive tumors, whereas elimination of α2,6-linked sialic acid limited the efficacy of anti-VEGF treatment in sensitive tumors. This effect involved Gal1-VEGFR2 interactions, as it was prevented when Gal1 was silenced in tumor cells or when mice were treated with anti-VEGF monoclonal antibodies plus axitinib, a receptor tyrosine kinase inhibitor that preferentially perturbs VEGFR signaling.10


Linking tumor hypoxia with VEGFR2 signaling and compensatory angiogenesis: Glycans make the difference.

Croci DO, Rabinovich GA - Oncoimmunology (2014)

Figure 1. Association of Gal1 with complex N-gycans on VEGFR2 compensates for the absence of cognate ligand in anti-VEGF refractory tumors. In response to VEGF blockade, anti-VEGF refractory tumors (upper pannel) secrete higher amounts of Gal1 and their associated endothelial cells (ECs) express all the repertoire of glycans that are critical for Gal1 binding (increased β1,6 N-glycan branching, augmented poly-N-acetyllactosamine extension and lower α2,6 sialylation). This inducible EC glycophenotype facilitated Gal1 signaling, compensatory angiogenesis and tumor growth. In contrast, blood vessels associated with anti-VEGF sensitive tumors (lower panel) displayed higher amounts of α2,6-linked sialic acid which prevented Gal-1-VEGFR2 interactions.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4125380&req=5

Figure 1: Figure 1. Association of Gal1 with complex N-gycans on VEGFR2 compensates for the absence of cognate ligand in anti-VEGF refractory tumors. In response to VEGF blockade, anti-VEGF refractory tumors (upper pannel) secrete higher amounts of Gal1 and their associated endothelial cells (ECs) express all the repertoire of glycans that are critical for Gal1 binding (increased β1,6 N-glycan branching, augmented poly-N-acetyllactosamine extension and lower α2,6 sialylation). This inducible EC glycophenotype facilitated Gal1 signaling, compensatory angiogenesis and tumor growth. In contrast, blood vessels associated with anti-VEGF sensitive tumors (lower panel) displayed higher amounts of α2,6-linked sialic acid which prevented Gal-1-VEGFR2 interactions.
Mentions: In vitro, serum-free conditioned medium from anti-VEGF refractory, but not anti-VEGF sensitive tumors, induced endothelial cell exposure of Gal1-specific ligands. More importantly, tumor-associated vessels from mice inoculated with tumors that were sensitive to anti-VEGF (B16-F0 melanoma and CT26 colon carcinoma), expressed high amounts of α2,6-linked sialic acid in response to VEGF blockade, which prevented Gal1 binding and angiogenesis (Fig. 1). In contrast, mice inoculated with anti-VEGF refractory tumors (Lewis lung adenocarcinoma; LLC1 and R1.1 T cell lymphoma) secreted increased Gal1 and their associated vasculature expressed higher amounts of β1–6GlcNAc-branched complex N-glycans and decreased α2,6 sialylation in response to VEGF blockade (Fig. 1). Programmed remodeling of the EC glycome facilitated Gal-1-N-glycan interactions and promoted compensatory angiogenesis in tumors with limited sensitivity to anti-VEGF.10 Lack of β1–6GlcNAc-branched N-glycans in endothelial cells or silencing of tumor-derived Gal1 converted refractory into anti-VEGF-sensitive tumors, whereas elimination of α2,6-linked sialic acid limited the efficacy of anti-VEGF treatment in sensitive tumors. This effect involved Gal1-VEGFR2 interactions, as it was prevented when Gal1 was silenced in tumor cells or when mice were treated with anti-VEGF monoclonal antibodies plus axitinib, a receptor tyrosine kinase inhibitor that preferentially perturbs VEGFR signaling.10

Bottom Line: Although blocking vascular endothelial growth factor (VEGF) signaling is clinically beneficial in certain cancers, tumor regrowth in treated patients suggests that compensatory angiogenic programs may limit the efficacy of anti-VEGF treatment.We found that association of galectin-1 with complex N-glycans on VEGFR2 links tumor hypoxia to VEGFR2 signaling and preserves angiogenesis in response to VEGF blockade.

View Article: PubMed Central - PubMed

Affiliation: Laboratorio de Inmunopatología; Instituto de Biología y Medicina Experimental (IBYME); Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET); Buenos Aires, Argentina.

ABSTRACT
Although blocking vascular endothelial growth factor (VEGF) signaling is clinically beneficial in certain cancers, tumor regrowth in treated patients suggests that compensatory angiogenic programs may limit the efficacy of anti-VEGF treatment. We found that association of galectin-1 with complex N-glycans on VEGFR2 links tumor hypoxia to VEGFR2 signaling and preserves angiogenesis in response to VEGF blockade.

No MeSH data available.


Related in: MedlinePlus