Neuroblastoma (NB), which arises from embryonic neural crest cells, is the most common extra-cranial solid
tumor of childhood. Approximately half of NB patients manifest bone
metastasis accompanied with bone
pain, fractures and
bone marrow failure, leading to disturbed quality of life and poor survival. To study the mechanism of bone
metastasis of NB, we established an animal model in which intracardiac inoculation of the SK-N-AS human NB cells in nude mice developed osteolytic bone
metastases with increased osteoclastogenesis. SK-N-AS cells induced the expression of receptor activator of NF-κB
ligand and osteoclastogenesis in mouse bone marrow cells in the co-culture. SK-N-AS cells expressed COX-2
mRNA and produced substantial amounts of
prostaglandin E2 (
PGE2). In contrast, the SK-N-DZ and SK-N-FI human NB cells failed to develop bone
metastases, induce osteoclastogenesis, express COX-2
mRNA and produce
PGE2. Immunohistochemical examination of SK-N-AS bone
metastasis and subcutaneous
tumor showed strong expression of COX-2. The selective
COX-2 inhibitor NS-398 inhibited
PGE2 production and suppressed bone
metastases with reduced osteoclastogenesis.
NS-398 also inhibited subcutaneous SK-N-AS
tumor development with decreased angiogenesis and
vascular endothelial growth factor-A expression. Of interest,
metastasis to the adrenal gland, a preferential site for NB development, was also diminished by
NS-398. Our results suggest that COX2/
PGE2 axis plays a critical role in the pathophysiology of osteolytic bone
metastases and
tumor development of the SK-NS-AS human NB. Inhibition of angiogenesis by suppressing COX-2/
PGE2 may be an effective therapeutic approach for children with NB.