Despite aggressive
therapy, survival for advanced stage
neuroblastoma remains poor with significant long-term morbidity in disease survivors. High-risk disease features are strongly correlated with
tumor vascularity, suggesting that
angiogenesis inhibitors may be a useful addition to current therapeutic strategies. However, challenges include the well-known clinical heterogeneity and embryonal origins of this disease, which suggests a complex regulation of neovascularization that may be distinct from epithelial-derived
carcinomas. We will review what is understood about angiogenesis-related signaling in
neuroblastoma. In particular, we will present evidence that angiogenesis-related molecules are differentially expressed in primary
neuroblastomas in a pattern suggesting promotion of a pro-angiogenic phenotype in high-risk
tumors and an anti-angiogenic phenotype in low-risk
tumors. 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). Recent observations that the combination of
angiogenesis inhibitors with conventional
chemotherapy provides synergy without additive toxicity, suggests the potential use of
angiogenesis inhibitors as an adjunct between cycles of conventional cytotoxic
therapy. Further identification of critical angiogenic signaling pathways and evaluation of specific inhibitors in preclinical
neuroblastoma models should provide justification for future selection and evaluation of
angiogenesis inhibitors in clinical trials for high-risk
neuroblastoma patients.