Anti-angiogenic therapy targeting vascular endothelial growth factor (VEGF) is used to treat several types of cancers, but the clinical benefit of this therapy is variable. Gabriel Rabinovich and his colleagues demonstrate that, in mice, tumors resistant to anti-VEGF therapy deploy galectin-1 as a VEGF-mimicking ligand (Cell 156, 744–758, 2014 ).

Credit: Clouds Hill Imaging Ltd. / Science Source

The researchers found that galectin-1 binds to and signals through the VEGF receptor VEGFR2 on endothelial cells, but only when the receptor is suitably modified by N-glycosylation. Tumors in mice that produced high levels of galectin-1 were resistant to anti-VEGF therapy, and this resistance was overcome by treating the animals with antibodies targeting galectin-1. Resistant tumors challenged with anti-VEGF therapy also reset the glycan composition on the surface of endothelial cells to favor the interaction of galectin-1 with VEGFR2. The authors then showed the impact of the glycosylation pattern on endothelial cells to tumor resistance by implanting sensitive or resistant tumors into mutant mice with altered glycosylation pathways. Deficiency of the glycosyltransferase MGAT5 blocked tumor resistance, whereas deficiency of the sialyltransferase ST6GAL1 conferred resistance.

If galectin-1 promotes tumor resistance to anti-VEGF treatment also in humans, the galectin-1–VEGFR2 interaction could be targeted to increase the efficacy of this treatment.