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

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.

AVNP2 protects against cognitive impairments induced by C6 glioma by suppressing tumour associated inflammation in rats

“…Western blotting assay of COX-2, iNOS and VEGF did not totally prove the anti-angiogenesis function of AVNP2 on gliomas but gave us a hint, which needs to be investigated deeper by means of ELISA and the tubule formation test in vivo and in vitro (Chen et al, 2016). The activation or suppression of endothelial cells (ECs), which play an important part in tumour angiogenesis, are worthy of study and discussion too (Liu et al, 2018). In our experiment, results corresponded to the inflammation-related proteins mentioned before.…”

Hypoxia-induced lncRNA PDIA3P1 promotes mesenchymal transition via sponging of miR-124-3p in glioma

“…In 2013, Bhat et al found that PN GSCs transformed to the MES state through the NF-κB pathway, with an elevated expression of CD44 and radioresistant phenotypes 37 . Thereafter, several studies were conducted to elucidate the potential mechanisms of how gliomas acquire the MES-signature through activating NF-κB transcriptional programs [38][39][40][41] . Furthermore, therapeutic approaches targeting the NF-κB pathway in GBM have (see figure on previous page) Fig.…”

Intravital 2-photon imaging reveals distinct morphology and infiltrative properties of glioblastoma-associated macrophages

“…Given their localization and protumor behavior, TAMs have been suggested to promote resistance to antiangiogenic agents, such as bevacizumab, but the underlying mechanisms remain unknown (29)(30)(31). Evidence suggests that resistance may be due to changes in the tumor microenvironment and the presence of myeloid-derived TAMs (32,33). Mechanisms of TAM infiltration may include passive migration due to a leaky BBB or active migration via chemokine gradients; however, which of these mechanisms is most responsible remains unclear.…”