Journal Article

PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma

Zhang, Duo, Gong, Yanqing, Fan, Yi, Zhang, Lin, Ma, Wenjuan, Huang, Menggui, He, Zhenqiang, Xu, Haineng, Brem, Steven, Liu, Tianrun, Mou, Yonggao, O’Rourke, Donald M., Zhang, Zhenfeng

2018

Overview

Angiogenesis is a hallmark of cancer. However, most malignant solid tumors exhibit robust resistance to current anti-angiogenic therapies that primarily target VEGF pathways. Here we report that endothelial-mesenchymal transformation induces glioblastoma (GBM) resistance to anti-angiogenic therapy by downregulating VEGFR-2 expression in tumor-associated endothelial cells (ECs). We show that VEGFR-2 expression is markedly reduced in human and mouse GBM ECs. Transcriptome analysis verifies reduced VEGFR-2 expression in ECs under GBM conditions and shows increased mesenchymal gene expression in these cells. Furthermore, we identify a PDGF/NF-κB/Snail axis that induces mesenchymal transformation and reduces VEGFR-2 expression in ECs. Finally, dual inhibition of VEGFR and PDGFR eliminates tumor-associated ECs and improves animal survival in GBM-bearing mice. Notably, EC-specific knockout of PDGFR-β sensitizes tumors to VEGF-neutralizing treatment. These findings reveal an endothelial plasticity-mediated mechanism that controls anti-angiogenic therapy resistance, and suggest that vascular de-transformation may offer promising opportunities for anti-vascular therapy in cancer. Resistance to anti-angiogenic therapies often occurs in patients. Here, the authors demonstrate the role of PDGF signaling in GBM resistance to anti-VEGF treatment via a mechanism that involves endothelial-mesenchymal transformation and transcriptional regulation of VEGFR-2.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 13/109 / 13/31 / 13/89 / 14/63 / 38/91 / 45/15 / 631/67/1922 / 631/67/2328 / 631/67/327 / 64/60 / Angiogenesis / Animals / Brain cancer / Cancer / Cell Line, Tumor / Cell Proliferation / Cells, Cultured / Chickens / Chromatin Immunoprecipitation / Endothelial cells / Endothelial Cells - drug effects / Endothelial Cells - metabolism / Flow Cytometry / Fluorescent Antibody Technique / Gene expression / Genetic transformation / Glioblastoma / Glioblastoma - drug therapy / Glioblastoma - metabolism / Humanities and Social Sciences / Humans / Immunoblotting / Mesenchyme / Mice / Mice, Knockout / multidisciplinary / NF-kappa B - metabolism / NF-κB protein / Platelet-derived growth factor / Platelet-Derived Growth Factor - antagonists & inhibitors / Platelet-Derived Growth Factor - metabolism / Real-Time Polymerase Chain Reaction / Science / Science (multidisciplinary) / Snail Family Transcription Factors / Solid tumors / Therapy / Tumors / Vascular endothelial growth factor / Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors / Vascular Endothelial Growth Factor Receptor-2 - metabolism / Vascular endothelial growth factor receptors