Glioma-Derived miRNA-Containing Extracellular Vesicles Induce Angiogenesis by Reprogramming Brain Endothelial Cells

Cell Rep. 2020 Feb 18;30(7):2065-2074.e4. doi: 10.1016/j.celrep.2020.01.073.


Glioblastoma (GBM) is characterized by aberrant vascularization and a complex tumor microenvironment. The failure of anti-angiogenic therapies suggests pathways of GBM neovascularization, possibly attributable to glioblastoma stem cells (GSCs) and their interplay with the tumor microenvironment. It has been established that GSC-derived extracellular vesicles (GSC-EVs) and their cargoes are proangiogenic in vitro. To further elucidate EV-mediated mechanisms of neovascularization in vitro, we perform RNA-seq and DNA methylation profiling of human brain endothelial cells exposed to GSC-EVs. To correlate these results to tumors in vivo, we perform histoepigenetic analysis of GBM molecular profiles in the TCGA collection. Remarkably, GSC-EVs and normal vascular growth factors stimulate highly distinct gene regulatory responses that converge on angiogenesis. The response to GSC-EVs shows a footprint of post-transcriptional gene silencing by EV-derived miRNAs. Our results provide insights into targetable angiogenesis pathways in GBM and miRNA candidates for liquid biopsy biomarkers.

Keywords: angiogenesis; biomarker; cancer stem cell; deconvolution; exRNA; extracellular vesicle; glioblastoma; miRNA; reprogramming; tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Brain / physiopathology*
  • Endothelial Cells / metabolism*
  • Extracellular Vesicles / metabolism*
  • Glioblastoma / genetics*
  • Glioblastoma / pathology
  • Glioma / genetics*
  • Glioma / pathology
  • Humans
  • MicroRNAs / metabolism*
  • Neovascularization, Pathologic


  • MicroRNAs