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

Author(s)

dos Santos, Sofia Nascimento ; Sheldon, Helen ; Pereira, Jonathas Xavier ; Paluch, Christopher ; Bridges, Esther M. ; El-Cheikh, Marcia Curry ; Harris, Adrian L. ; Bernardes, Emerson Soares

• Document type: Journal article
• Source: ONCOTARGET; v. 8, n. 30, p. 49484-49501, JUL 25 2017.
• Web of Science Citations: 16

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. (AU)

• FAPESP's process: 12/06875-6 - Development and production of positron emission tomography radiopharmaceuticals for diagnostic purposes in oncology
• Grantee: Emerson Soares Bernardes
• Support Opportunities: Research Grants - Young Investigators Grants