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 3

Endo-MT induces vascular abnormality in vitro.

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Endo-MT induces vascular abnormality in vitro. (A–F, and H) Human brain ...
(A–F, and H) Human brain microvascular ECs were treated with control ECM or U251 glioma-CM. (A) Twenty-four hours after treatment, cells were stained with anti–VE-cadherin antibody and costained with Alexa Fluoro 567–labeled phalloidin for visualization of F-actin. Representative data are shown from 2 independent experiments. Scale bars: 100 μm. (B) ECs were lysed. Cell lysates were resolved by SDS-PAGE and immunoblotted. Representative data are shown from 3 independent experiments. (C) mRNA was isolated from ECs 24 hours after treatment and analyzed by qPCR (mean ± SEM, n = 3). (D–F) ECs pretreated with control medium or glioma-CM for 24 hours were trypsinized and cultured in normal culture medium. (D) Cell proliferation was determined with MTT assay. Cell migration was determined with transwell assay. Cell invasion across Matrigel-coated membranes in tranwells was determined. Data expressed as the percentage of control (mean ± SEM, n = 5, paired t test). (E) EC monolayer permeability was analyzed by measuring the fluorescence of diffused FITC-dextran across transwell membrane (mean ± SEM, n = 6, paired t test). (F) Tube formation was induced on Matrigel. Left, representative images. Right, quantified total tube length (mean ± SEM, n = 6, paired t test). Scale bar: 200 μm. (G) ECs isolated from normal brain or patient GBM tumor were subjected to cell viability analysis (mean ± SEM, n = 4, unpaired t test). (H) Cells pretreated with control medium or glioma-CM for 48 hours were incubated with Dil-Ac-LDL and stained with anti–FSP-1 antibody. Representative data are shown from 3 independent experiments. Scale bar: 50 μm.