Regulation of Angiogenesis by MYCN

MYCN amplification is a poor prognostic factor in children with neuroblastoma, and is associated with advanced tumor stage and metastasis. MYCN appears to play a significant role in neuroblastoma angiogenesis. Amplification of MYCN has been shown to correlate with mean vascular density (Meitar et al. 1996), and the expression of PDGF (but not with VEGF-A) (Eggert et al. 2000). Angiogenic activity of biopsy samples was significantly higher in those with MYCN-amplified tumors when tested in a chick embryo chorioallantoic membrane assay (Ribatti et al. 2002). It remains unclear if MYCN directly upregulates cytokines that promote neovascular development.

MYCN may also decrease the expression of endogenous inhibitors of angiogenesis. In cultured neuroblastoma cells MYCN causes decreased expression of interleukin-6 (IL-6), leukemia inhibitory factor, and activin A (Breit et al. 2000; Hatzi et al. 2000, 2002a,b). Over-expression of IL-6 in neuroblastoma xenografts results in decreased tumor angiogenesis and growth inhibition (Hatzi et al. 2002b); thus, current evidence suggests that MYCN promotes angio-genesis in neuroblastoma at least in part by decreasing expression of genes that normally function to restrain new blood vessel growth.

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