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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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 6

c-Met activation induces ETS-dependent MMP-14 expression, leading to VE-cadherin cleavage and Endo-MT.

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c-Met activation induces ETS-dependent MMP-14 expression, leading to VE-...
(A) Human brain microvascular ECs were treated with U251 glioma-CM and analyzed by immunoblot. (B) Cells were lentivirally transduced with c-Met or control shRNA and treated with glioma-CM. Cell lysates were subjected to immunoblot analysis. (C and D) Glioma-CM–induced FSP-1 or α-SMA expression is inhibited by knockdown of MMP-14 but not MMP-2. Cells transduced with MMP-14 (C), MMP-2 (D), or control shRNA were treated with glioma-CM and analyzed by immunoblot. (E) Cells were transfected with NF-κB, ETS-1, or control siRNA and treated with 100 ng/ml HGF. Cell lysates were subjected to immunoblot analysis. (F and G) Cells were incubated with active MMP-14 for 18 hours. (F) Culture medium and cell lysates were immunoblotted with anti–VE-cadherin antibody. (G) MMP-14 induces VE-cadherin disorganization and downregulation. Cells were subjected to immunofluorescence analysis with an anti–VE-cadherin antibody. Scale bar: 20 μm. (H) Cells were lentivirally transduced with c-Met or control shRNA, treated with glioma-CM in the presence or absence of active MMP-14, and analyzed by immunoblot. (I) ECs isolated from normal brain and patient GBM tumors were treated with 5 μM SU11274 or 0.1% DMSO (vehicle) and subjected to immunoblot analysis. All representative data are shown from 2–3 independent experiments.