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 (VEGF90K). We show that VEGF90K is generated by the crosslinking of VEGF165, catalysed by the enzyme tissue transglutaminase, and associates with MVs through its interaction with the chaperone Hsp90. We further demonstrate that MV-associated VEGF90K 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 VEGF90K from MVs, restoring the sensitivity of VEGF90K 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.
Highlights
Non-classical secretory vesicles, collectively referred to as extracellular vesicles (EVs), have been implicated in different aspects of cancer cell survival and metastasis
During experiments aimed at identifying drug combinations that exhibit beneficial effects in blocking tumour growth in MDAMB231 cell xenografts in mice, we found that the combination of the VEGF drug Bevacizumab with an Hsp[90] inhibitor gave striking results
We found that the same VEGF species observed in the conditioned medium from MDAMB231 cells were present in the conditioned medium from a number of the patient-derived mouse xenograft (PDX) samples (Supplementary Fig. 7A; Supplementary Fig. 7B shows the levels of tissue transglutaminase (tTG) and Hsp[90] in whole cell lysates of the PDX samples HCI-001-HCI-003, and HCI-005-HCI-010)
Summary
Non-classical secretory vesicles, collectively referred to as extracellular vesicles (EVs), have been implicated in different aspects of cancer cell survival and metastasis. We set out to determine the underlying mechanisms by which the combination of Bevacizumab and an Hsp[90] inhibitor gave rise to a striking synergistic inhibition of tumour growth and blood vessel formation in xenograft models for breast cancer This led us to discover how a specific class of EVs (MVs) derived from breast cancer cells provides a sustained activation of VEGFRs on endothelial cells. Treatment with Hsp[90] inhibitors causes the release of VEGF90K from MVs, enabling it to bind to Bevacizumab, restoring its sensitivity to the drug Taken together, these findings illustrate the roles played by cancer cell-derived MVs and their associated VEGF90K in the tumour microenvironment, and how they can contribute to tumour angiogenesis in a unique way that limits the effectiveness of Bevacizumab therapy
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