Cancer-derived small extracellular vesicles promote angiogenesis by heparin-bound, bevacizumab-insensitive VEGF, independent of vesicle uptake

Song Yi Ko,Honami Naora,Lee M Ellis,Eric Jonasch,Hilary A Kenny,Wonjae Lee,Ernst Lengyel,Long H Dang

doi:10.1038/s42003-019-0609-x

Abstract

Cancer-derived small extracellular vesicles (sEVs) induce stromal cells to become permissive for tumor growth. However, it is unclear whether this induction solely occurs through transfer of vesicular cargo into recipient cells. Here we show that cancer-derived sEVs can stimulate endothelial cell migration and tube formation independently of uptake. These responses were mediated by the 189 amino acid isoform of vascular endothelial growth factor (VEGF) on the surface of sEVs. Unlike other common VEGF isoforms, VEGF189 preferentially localized to sEVs through its high affinity for heparin. Interaction of VEGF189 with the surface of sEVs profoundly increased ligand half-life and reduced its recognition by the therapeutic VEGF antibody bevacizumab. sEV-associated VEGF (sEV-VEGF) stimulated tumor xenograft growth but was not neutralized by bevacizumab. Furthermore, high levels of sEV-VEGF were associated with disease progression in bevacizumab-treated cancer patients, raising the possibility that resistance to bevacizumab might stem in part from elevated levels of sEV-VEGF.

Highlights

Cancer-derived small extracellular vesicles induce stromal cells to become permissive for tumor growth
We identified that cancer cell-derived small EVs (sEVs) can stimulate endothelial cell migration and tube formation independently of uptake, and that these responses are mediated by the 189 amino acid, heparinbound isoform of vascular endothelial growth factor (VEGF) that, unlike other common isoforms of VEGF, is enriched on the surface of sEVs
VEGF has been implicated in the angiogenic activity of these sEVs19,20, but there has been no explanation as to how this ligand elicits its signals if it is encapsulated within sEVs and internalized in recipient cells

Summary

Introduction

Cancer-derived small extracellular vesicles (sEVs) induce stromal cells to become permissive for tumor growth. There is evidence that sEVs can deliver signals to various immune cells independently of uptake[4,13] These findings suggest that sEVs might mediate intercellular communication in the tumor microenvironment through mechanisms other than transferring their luminal cargo into recipient cells. We identified that cancer cell-derived sEVs can stimulate endothelial cell migration and tube formation independently of uptake, and that these responses are mediated by the 189 amino acid, heparinbound isoform of vascular endothelial growth factor (VEGF) that, unlike other common isoforms of VEGF, is enriched on the surface of sEVs. we found that sEV-associated VEGF (sEV-VEGF) is highly stable and is not neutralized by the therapeutic VEGF antibody bevacizumab, raising the possibility that elevated levels of sEV-VEGF contribute in part to the resistance of tumors to bevacizumab

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Conclusion