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

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 b...

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Veröffentlicht in:Nature communications 2018-08, Vol.9 (1), p.3439-13, Article 3439
Hauptverfasser: Liu, Tianrun, Ma, Wenjuan, Xu, Haineng, Huang, Menggui, Zhang, Duo, He, Zhenqiang, Zhang, Lin, Brem, Steven, O’Rourke, Donald M., Gong, Yanqing, Mou, Yonggao, Zhang, Zhenfeng, Fan, Yi
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Sprache:eng
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Zusammenfassung: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.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-018-05982-z