In this study, we analyzed the effects of hypoxia, a common feature of solid tumors and a major drive to tumor angiogenesis, and of PA, a tryptophan catabolite produced under inflammatory conditions and endowed with several biologic properties, on the production of the angiogenic activator VEGF by advanced-stage human NB cell lines.
The redundancy in angiogenic factor expression suggests that inhibition of VEGF bioactivity alone might not be a sufficient approach for antiangiogenic therapy of human NB.
Patients with high miR-337-3p expression had greater survival probability. miR-337-3p suppressed the promoter activity, nascent transcription, and expression of MMP-14, resulting in decreased levels of vascular endothelial growth factor, in cultured NB cell lines.
Since BDNF is reported to stimulate VEGF expression and/or release in neuroblastoma cells, the present study tested the hypothesis that the actions of BDNF are mediated by VEGF.
In vivo, h10H5 shows single-agent antitumor efficacy in human SK-N-AS neuroblastoma and SW527 breast cancer xenograft models and even greater efficacy in combination with the chemotherapeutic agent docetaxel or an anti-vascular endothelial growth factor antibody.
ALK knockdown was associated with marked reductions in vascular endothelial growth factor (VEGF) secretion, blood vessel density, and matrix metalloproteinases (MMPs) expression in vivo, suggesting a role for ALK in NB-induced neoangiogenesis and tumor invasion, confirming this gene as a fundamental oncogene in NB.
Recently, BDNF was identified as a potential proangiogenic factor for the promotion of endothelial cell survival, induction of neoangiogenesis in ischemic tissues, and increase of VEGF expression in neuroblastoma.
Our results further suggest that a persistent blocker of stroma-derived VEGF will need to be combined with CPT-11 to completely inhibit the growth of chemosensitive NB, and that administration of CPT-11 at higher doses will be required to inhibit the growth of multidrug-resistant NB.
Overexpression or knockdown of miR-9 responsively altered both the mRNA and protein levels of MMP-14 and its downstream gene, vascular endothelial growth factor, in cultured neuroblastoma cell lines SH-SY5Y and SK-N-SH.
These results indicate that VEGF(165) is up-regulated in NB and that there is a difference in the balance of isoform expression from anti-angiogenic VEGF(165)b to angiogenic VEGF(165).
We will also discuss a variety of vascular inhibition strategies that have been used in neuroblastoma preclinical models including specific inhibition of vascular endothelial growth factor (VEGF) and methionine aminopeptidase 2 (MetAP2).
Upregulation of macrophage migration inhibitory factor contributes to induced N-Myc expression by the activation of ERK signaling pathway and increased expression of interleukin-8 and VEGF in neuroblastoma.
This conclusion was based on in vitro transfection with pre-miR-93-5p and anti-miR-93-5p; these treatments inversely modulated both VEGF and IL-8 gene expression and protein release in the neuroblastoma SK-N-AS cell line.
Gain- and loss-of-function studies indicated that secretory ITLN1 facilitated the NDRG2 expression, resulting in down-regulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9), in NB cell lines SH-SY5Y, SK-N-BE(2), and SK-N-SH.
We have thus demonstrated that NB cell adaptation to hypoxia, in addition to the modulation of HIF1alpha and VEGF expression and nuclear translocation of ID1 and ID2 transcription factors, involve in the activation of a gene expression program consistent with the pro-metastatic events.
We show here that this engineered ZFP-TF activates VEGF-A in appropriate cells in culture and that the secreted VEGF-A protein induced by the ZFP protects neuroblastoma cell lines from a serum starvation insult in vitro.
The present findings indicated that the interplay between the p53/caspase pathway and the linc01105/miR‑6769b‑5p/VEGFA axis may have important roles in the development of neuroblastoma.