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.
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.
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.
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).
VEGF mRNA levels in neuroblastoma cells cultured in serum-free medium increased after 8 to 16 hours in serum, insulin-like growth factor-I (IGF-I), epidermal growth factor, or platelet-derived growth factor.
These data indicate that BDNF plays a role in regulating VEGF levels in neuroblastoma cells and that targeted therapies to BDNF/TrkB, PI3K, mTOR signal transduction pathways, and/or HIF-1alpha have the potential to inhibit VEGF expression and limit neuroblastoma tumor growth.
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.
Furthermore, high HIF-2alpha protein levels were correlated with advanced clinical stage and high VEGF expression and predicted poor prognosis in a clinical neuroblastoma material.
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.
We investigated the effects of the topoisomerase I inhibitor, topotecan, on vascular endothelial growth factor (VEGF) induction by hypoxia in advanced-stage human neuroblastoma cells.
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.
Our previous work demonstrated the overexpression of vascular endothelial growth factor (VEGF) in NB, and we showed that an anti-VEGF receptor (VEGFR-2) antibody could induce sustained NB tumor suppression and regression.
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.