c-Met-mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma Academic Article uri icon

Overview

MeSH Major

  • Drug Resistance, Neoplasm
  • Endothelial Cells
  • Glioblastoma
  • Neovascularization, Pathologic
  • Proto-Oncogene Proteins c-met

abstract

  • Aberrant vascularization is a hallmark of cancer progression and treatment resistance. Here, we have shown that endothelial cell (EC) plasticity drives aberrant vascularization and chemoresistance in glioblastoma multiforme (GBM). By utilizing human patient specimens, as well as allograft and genetic murine GBM models, we revealed that a robust endothelial plasticity in GBM allows acquisition of fibroblast transformation (also known as endothelial mesenchymal transition [Endo-MT]), which is characterized by EC expression of fibroblast markers, and determined that a prominent population of GBM-associated fibroblast-like cells have EC origin. Tumor ECs acquired the mesenchymal gene signature without the loss of EC functions, leading to enhanced cell proliferation and migration, as well as vessel permeability. Furthermore, we identified a c-Met/ETS-1/matrix metalloproteinase-14 (MMP-14) axis that controls VE-cadherin degradation, Endo-MT, and vascular abnormality. Pharmacological c-Met inhibition induced vessel normalization in patient tumor-derived ECs. Finally, EC-specific KO of Met inhibited vascular transformation, normalized blood vessels, and reduced intratumoral hypoxia, culminating in suppressed tumor growth and prolonged survival in GBM-bearing mice after temozolomide treatment. Together, these findings illustrate a mechanism that controls aberrant tumor vascularization and suggest that targeting Endo-MT may offer selective and efficient strategies for antivascular and vessel normalization therapies in GBM, and possibly other malignant tumors.

publication date

  • May 2, 2016

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4855929

Digital Object Identifier (DOI)

  • 10.1172/JCI84876

PubMed ID

  • 27043280

Additional Document Info

start page

  • 1801

end page

  • 14

volume

  • 126

number

  • 5