A class of extracellular vesicles from breast cancer cells activates VEGF receptors and tumour angiogenesis

Nat Commun. 2017 Feb 16;8:14450. doi: 10.1038/ncomms14450.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiogenesis Inducing Agents / metabolism
  • Animals
  • Benzoquinones / metabolism
  • Benzoquinones / pharmacology*
  • Bevacizumab / metabolism
  • Bevacizumab / pharmacology*
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor / drug effects
  • Cell Line, Tumor / metabolism
  • Cell-Derived Microparticles / classification
  • Cell-Derived Microparticles / metabolism
  • Disease Models, Animal
  • Drug Combinations
  • Extracellular Vesicles / classification*
  • Extracellular Vesicles / metabolism*
  • Female
  • HSP90 Heat-Shock Proteins / drug effects
  • HSP90 Heat-Shock Proteins / metabolism
  • HeLa Cells
  • Humans
  • Lactams, Macrocyclic / metabolism
  • Lactams, Macrocyclic / pharmacology*
  • Mice
  • Neovascularization, Pathologic / metabolism*
  • Neovascularization, Pathologic / pathology
  • Receptors, Vascular Endothelial Growth Factor / metabolism*
  • Secretory Vesicles
  • Signal Transduction
  • Transglutaminases
  • Transplantation, Heterologous
  • Tumor Microenvironment
  • Vascular Endothelial Growth Factor A / drug effects
  • Vascular Endothelial Growth Factor A / metabolism

Substances

  • Angiogenesis Inducing Agents
  • Benzoquinones
  • Drug Combinations
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • tanespimycin
  • Transglutaminases
  • Receptors, Vascular Endothelial Growth Factor