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

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.

SUBMITTER: Ko SY

PROVIDER: S-EPMC6802217 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Ko Song Yi SY Lee WonJae W Kenny Hilary A HA Dang Long H LH Ellis Lee M LM Jonasch Eric E Lengyel Ernst E Naora Honami H

Communications biology 20191018

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 ...[more]

PMID: 31646189

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Project description:Although cell survival post-transplantation is very low, emerging evidence using stem cell therapy for myocardial repair points toward a primary role of paracrine signaling mechanisms as the basis for improved cardiac function, decreased fibrosis, and increased angiogenesis. Recent studies have demonstrated that extracellular vesicles (EVs) such as exosomes secreted by stem cells stimulate angiogenesis, provide cytoprotection, and modulate apoptosis. However, the angiogenic potential of EVs secreted from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), a terminally differentiated cell type, has not been elucidated yet. Therefore, the main objective of this study is to isolate, characterize, and evaluate the in vitro angiogenic potential of EVs collected from hiPSC-CM conditioned media. The hiPSC-CM were cultured for 2 weeks and EVs were isolated from cell culture medium. Isolated EVs were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis, and immunoblotting. Furthermore, the angiogenic potential of these EVs was evaluated by tube formation, wound-healing, and cell-proliferation assays in bovine aortic endothelial cells (BAEC). In addition, gene expression levels of growth factors was evaluated in hiPSC-derived endothelial cells (hiPSC-EC) treated with hiPSC-CM-derived EV (CM-EVs) to assess their role in promoting angiogenesis. TEM imaging of CM-EVs showed a presence of a double-membrane bound structure, which is a characteristic of EV. Nanoparticle tracking analysis further confirmed the size and shape of the secreted particles to be consistent with EVs. Furthermore, EV-specific markers (CD63 and HSP70) were enriched in these particles as illustrated by immunoblotting. Most importantly, BAEC treated with 100 ?g/ml of CM-EVs showed significant increases in tube formation, wound closure, and cell proliferation as compared to control (no-EVs). Finally, treatment of hiPSC-EC with CM-EVs induced increased expression of pro-angiogenic growth factors by the endothelial cells. Overall, our results demonstrated that EVs isolated from hiPSC-CM enhance angiogenesis in endothelial cells. This acellular/cell-free approach constitutes a potential translational therapeutic to induce angiogenesis in patients with myocardial infarction.

Dataset Information

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

Publications

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

Similar Datasets

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