Galectin-3 acts as an angiogenic switch to induce tumor angiogenesis via Jagged-1/Notch activation

// Sofia Nascimento dos Santos 1 , Helen Sheldon 2 , Jonathas Xavier Pereira 3 , Christopher Paluch 4 , Esther M Bridges 2 , Marcia Curry El-Cheikh 5 , Adrian L Harris 2 and Emerson Soares Bernardes 1 1 Radiopharmacy Department, Nuclear Energy Research Institute, Sao Paulo, Brazil 2 Department of Medical Oncology, Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK 3 Department of Pathology, Faculty of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil 4 T-cell Biology Group, Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK 5 Institute for Biomedical Sciences, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil Correspondence to: Emerson Soares Bernardes, email: ebernardes@ipen.br Keywords: angiogenesis, cancer, galectin-3, Jagged-1, Notch Received: March 09, 2016      Accepted: April 25, 2017      Published: May 09, 2017 ABSTRACT Angiogenesis is a coordinated process tightly regulated by the balance between Delta-like-4 (DLL4) and Jagged-1 (JAG1) in endothelial cells. Here we show that galectin-3 (gal-3), a glycan-binding protein secreted by cancer cells under hypoxic conditions, triggers sprouting angiogenesis, assisted by hypoxic changes in the glycosylation status of endothelial cells that enhance binding to gal-3. Galectin-3’s proangiogenic functions were found to be predominantly dependent on the Notch ligand JAG1. Differential direct binding to JAG1 was shown by surface plasmon resonance assay. Upon binding to Notch ligands, gal-3 preferentially increased JAG1 protein half-life over DLL4 and preferentially activated JAG1/Notch-1 signaling in endothelial cells. JAG1 overexpression in Lewis lung carcinoma cells accelerated tumor growth in vivo , but this effect was prevented in Lgals3 −/− mice. Our findings establish gal-3 as a molecular regulator of the JAG1/Notch-1 signaling pathway and have direct implications for the development of strategies aimed at controlling tumor angiogenesis.