PDGF-mediated mesenchymal transformation renders endothelial resistance to anti-VEGF treatment in glioblastoma.
Tianrun LiuWenjuan MaHaineng XuMenggui HuangDuo ZhangZhenqiang HeLin ZhangSteven BremDonald M O'RourkeYanqing GongYonggao MouZhenfeng ZhangYi FanPublished in: Nature communications (2018)
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.
Keyphrases
- endothelial cells
- vascular endothelial growth factor
- poor prognosis
- high glucose
- bone marrow
- gene expression
- stem cells
- induced apoptosis
- binding protein
- papillary thyroid
- signaling pathway
- dna methylation
- epithelial mesenchymal transition
- long non coding rna
- type diabetes
- metabolic syndrome
- zika virus
- mesenchymal stem cells
- endoplasmic reticulum stress
- genome wide
- squamous cell
- skeletal muscle
- smoking cessation
- childhood cancer