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

Tianrun Liu, Wenjuan Ma, Haineng Xu, Menggui Huang, Duo Zhang, Zhenqiang He, Lin Zhang, Steven Brem, Donald M. O’Rourke, Yanqing Gong, Yonggao Mou (), Zhenfeng Zhang () and Yi Fan ()
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Tianrun Liu: University of Pennsylvania Perelman School of Medicine
Wenjuan Ma: University of Pennsylvania Perelman School of Medicine
Haineng Xu: University of Pennsylvania Perelman School of Medicine
Menggui Huang: University of Pennsylvania Perelman School of Medicine
Duo Zhang: University of Pennsylvania Perelman School of Medicine
Zhenqiang He: University of Pennsylvania Perelman School of Medicine
Lin Zhang: University of Pennsylvania Perelman School of Medicine
Steven Brem: University of Pennsylvania Perelman School of Medicine
Donald M. O’Rourke: University of Pennsylvania Perelman School of Medicine
Yanqing Gong: University of Pennsylvania Perelman School of Medicine
Yonggao Mou: Sun Yat-sen University Cancer Center
Zhenfeng Zhang: The Second Affiliated Hospital of Guangzhou Medical University
Yi Fan: University of Pennsylvania Perelman School of Medicine

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-05982-z

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