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.
Highlights
As the major regulator of angiogenesis, vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) mediates the almost all endothelial cells (ECs) responses to VEGFs, while VEGFR-1 acts as a decoy receptor to modulate VEGFR-2 activity, and VEGFR-3 has a limited role in regulating lymphangiogenesis[22,23,24]
Cell viability analyses showed that GBM tumor-derived ECs were resistant to pharmacological inhibition of VEGFR (Fig. 1a) and B20 antibody-mediated blockade of VEGF (Fig. 1b)
VEGFR inhibitor and VEGF-neutralizing antibody completely abolished cell proliferation in normal brain microvascular ECs. Immunoblot analysis of these cells showed that compared to normal ECs, GBM-associated ECs, isolated from either intratumor or peri-tumor tissue, exhibited diminished expression of VEGFR-2, a receptor that mediates almost all of the known cellular responses to VEGF, while expression of VEGFR-1, a receptor that acts as a decoy receptor sequestering VEGF from VEGFR-2 binding, was at similar level in normal and GBM ECs (Fig. 1c), providing a possible mechanism for the anti-VEGF resistance in GBM ECs
Summary
Most malignant solid tumors exhibit robust resistance to current anti-angiogenic therapies that primarily target VEGF pathways. 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). EC-specific knockout of PDGFR-β sensitizes tumors to VEGF-neutralizing treatment These findings reveal an endothelial plasticity-mediated mechanism that controls antiangiogenic therapy resistance, and suggest that vascular de-transformation may offer promising opportunities for anti-vascular therapy in cancer. Our recent work reveals robust EC plasticity in tumor microenvironment, e.g., ECs acquire mesenchymal phenotypes to promote their ability to proliferate and migrate[14], which may alternatively induce primary and acquired resistance to anti-angiogenic treatment in cancer. We show that platelet-derived growth factor (PDGF)-mediated endothelial-mesenchymal transformation (Endo-MT) induces EC resistance to anti-angiogenic treatment through downregulation of VEGFR-2 expression. Combination of vascular de-transformation with conventional anti-angiogenic treatment may serve as an efficient strategy for anti-vascular therapy in GBM and possibly other malignant solid tumors
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
