The Hippo-TAZ axis mediates vascular endothelial growth factor C in glioblastoma-derived exosomes to promote angiogenesis.

Abstract

Glioblastoma (GBM) is one of the most highly vascularized human cancers. The role of exosomes in cancer angiogenesis has attracted recent interest. However, proangiogenic biomolecules transported by exosomes to facilitate angiogenesis in GBM have not yet been identified. Here, we found a specific 120-kDa isoform of vascular endothelial growth factor (VEGF) in GBM-derived exosomes and confirmed it as VEGF-C. By binding to VEGF receptor 2 (VEGFR2), VEGF-C from GBM-derived exosomes showed a strong stimulatory effect on tafazzin (TAZ) expression in endothelial cells by inhibiting the Hippo signaling pathway, which eventually stimulates endothelial cell viability, migration, and tubulation. In human glioma samples, the expression of VEGF-C in tumor cells positively correlated with TAZ expression in endothelial cells. We further demonstrated that an inhibitor of exosomal release had a cooperative inhibitory effect with bevacizumab on GBM xenograft subcutaneous tumor growth and angiogenesis. Taken together, our findings revealed a novel VEGF-C isoform in GBM-derived exosomes with a role in angiogenesis and highlighted the importance of recognizing its unique signaling pathway when considering drug treatment strategies for GBM.