A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 28205552.
- Also identified by DOI 10.1038/ncomms14450 and PMC identifier 5316898.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
Non-classical secretory vesicles, collectively referred to as extracellular vesicles (EVs), have been implicated in different aspects of cancer cell survival and metastasis. Here, we describe how a specific class of EVs, called microvesicles (MVs), activates VEGF receptors and tumour angiogenesis through a unique 90 kDa form of VEGF (VEGF<sub>90K</sub>). We show that VEGF<sub>90K</sub> is generated by the crosslinking of VEGF<sub>165</sub>, catalysed by the enzyme tissue transglutaminase, and associates with MVs through its interaction with the chaperone Hsp90. We further demonstrate that MV-associated VEGF<sub>90K</sub> has a weakened affinity for Bevacizumab, causing Bevacizumab to be ineffective in blocking MV-dependent VEGF receptor activation. However, treatment with an Hsp90 inhibitor releases VEGF<sub>90K</sub> from MVs, restoring the sensitivity of VEGF<sub>90K</sub> to Bevacizumab. These findings reveal a novel mechanism by which cancer cell-derived MVs influence the tumour microenvironment and highlight the importance of recognizing their unique properties when considering drug treatment strategies.
Medical subject headings
- Benzoquinones
- Bevacizumab
- Breast Neoplasms
- Extracellular Vesicles
- Lactams, Macrocyclic
- Neovascularization, Pathologic
- Receptors, Vascular Endothelial Growth Factor