Galectin-1 Maintains Angiogenesis in Anti-VEGF–Refractory Tumors

Antibody therapy targeting vascular endothelial growth factor (VEGF-A) slows cancer progression by blocking abnormal angiogenesis, but tumors frequently are refractory or become resistant to anti-VEGF treatment through mechanisms that remain unclear. Croci and colleagues hypothesized that galectin-1 (GAL1, encoded by the LGALS1 gene), a hypoxia-regulated glycan-binding lectin with known roles in endothelial cell signaling, tumor progression, and angiogenesis, may activate compensatory mechanisms in tumors refractory to anti-VEGF treatment. Examination of cultured human endothelial cells revealed that GAL1 could stimulate proangiogenic activity by specifically binding to neutral branched N-glycans on VEGF receptor 2 (VEGFR2), which activated VEGFR2 signaling and enhanced VEGFR2 retention at the cell surface. Hypoxia boosted the prevalence of GAL1-binding N-glycan moieties on endothelial cells, and conditioned media from refractory tumors cultured under hypoxic conditions increased GAL1 binding to endothelial cells in vitro, indicating that hypoxia alters the endothelial cell glycome in anti-VEGF–refractory tumors. Consistent with these findings, anti-VEGF–refractory tumor cells implanted into syngeneic mice and treated with anti-VEGF exhibited tumor hypoxia, and these tumors strongly upregulated expression of GAL1 and displayed enhanced N-glycan branching on tumor-associated blood vessels whereas anti-VEGF–sensitive tumors did not. Disrupting this pathway by silencing expression of GAL1 or through genetic deficiency of N-glycan branching in host animals rendered implanted refractory tumors sensitive to anti-VEGF and improved anti-VEGF effectiveness in sensitive tumors. Further, administration of a GAL1-blocking antibody alongside anti-VEGF reversed refractoriness and also improved sensitive tumors' responsiveness to anti-VEGF by normalizing blood vessel architecture and improving tumor surveillance by the immune system. Together, these data demonstrate that changes in the glycosylation signature of blood vessels affect tumor progression and suggest that coadministration of anti-GAL1 and anti-VEGF could be therapeutically beneficial.

Croci DO, Cerliani JP, Dalotto-Moreno T, Méndez-Huergo SP, Mascanfroni ID, Dergan-Dylon S, et al. Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell 2014;156:744–58.

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