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 8

c-Met is critical for Endo-MT and aberrant vascularization in GBM.

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c-Met is critical for Endo-MT and aberrant vascularization in GBM. The g...
The genetic GBM model was induced in Metfl/fl and Tie2-Cre Metfl/fl mice and treated with saline or 100 mg/kg TMZ 14 days after tumor transplantation. (A) Tumor sections were probed with anti-CD31 and anti–FSP-1 antibodies. Representative data are shown from 5 mice/group. Scale bar: 100 μm. Right, FSP-1 fluorescence intensity in CD31+ cells was quantified and expressed as percentage of the intensity in Metfl/fl mice treated with saline (n = 5, unpaired t test). (B) Tumor sections were fixed, probed with anti-CD31 and anti–NG-2 antibodies, and stained with Alexa Fluor 488– and 568–conjugated secondary IgGs (n = 3–5, representative data shown). Scale bar: 100 μm. (C) Mice were perfused i.v. with FITC-dextran. Tumors were excised, and the sections were imaged (n = 3–5, representative data shown). Scale bar: 50 μm. (D) Mice were injected with Hypoxyprobe-1 (pimonidazole HCl), and tumor sections were probed with antibody against pimonidazole adducts (n = 3–5, representative data shown). Scale bar: 100 μm.