c-Met–mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma
Menggui Huang, … , Constantinos Koumenis, Yi Fan
Menggui Huang, … , Constantinos Koumenis, Yi Fan
Published April 4, 2016
Citation Information: J Clin Invest. 2016;126(5):1801-1814. https://doi.org/10.1172/JCI84876.
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Research Article Oncology

c-Met–mediated endothelial plasticity drives aberrant vascularization and chemoresistance in glioblastoma

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.

Authors

Menggui Huang, Tianrun Liu, Peihong Ma, R. Alan Mitteer Jr., Zhenting Zhang, Hyun Jun Kim, Eujin Yeo, Duo Zhang, Peiqiang Cai, Chunsheng Li, Lin Zhang, Botao Zhao, Laura Roccograndi, Donald M. O’Rourke, Nadia Dahmane, Yanqing Gong, Constantinos Koumenis, Yi Fan

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Figure 2

Robust Endo-MT in GBM vasculature.

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Robust Endo-MT in GBM vasculature. (A and B) GBM was induced by orthotop...
(A and B) GBM was induced by orthotopic injection of retrovirus or GL26 tumor cells. The GBM in Ntv-a Ink4a–/–Ptenfl/fl LSL-Luc mice is induced by PDGF overexpression and Cre-mediated Pten deletion in neural stem and progenitor cells through RCAS-mediated somatic gene transfer. (A) Schematic approach. (B) Single-cell suspension from normal brain and tumors was stained with anti-CD31 and anti–FSP-1 antibodies and analyzed by flow cytometry. Left, representative cell sorting. Right, quantitative analysis (mean ± SEM, n = 6–8, unpaired t test). (C–E) The primary GBM in Ntv-a Ink4a–/–Ptenfl/fl LSL-Luc donor mice is induced by RCAS-mediated somatic gene transfer. Recipient mice were WT and Tie2-Cre mice. (C) Schematic approach. (D) Single-cell suspensions derived from tumors were stained with anti-Cre and anti–FSP-1 antibodies and analyzed by flow cytometry. Left, representative cell sorting. Right, quantitative analysis (mean ± SEM, n = 6, unpaired t test). (E) Tumor sections were subjected to immunofluorescence analyses. Right, enlarged images of left rectangles. Representative data are shown from 4–5 mice. Scale bars: 100 μm.