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Neuroblastoma (NB), the most common extracranial solid tumor in children, is characterized by a heterogeneous clinical behaviour. Some tumors may undergo spontaneous regression or differentiation while the majority of metastatic NB have poor prognosis despite intensive therapy. Cyclooxygenases (COX) catalyse the conversion of arachidonic acid to prostaglandins. We have previously shown that COX-2 is highly expressed in NB and treatment of established NB xenografts with COX-2 inhibitors reduces tumour growth in vivo. The role of COX-2 in cancer is not fully understood but it appears that COX-2 derived prostaglandin E2 (PGE2) and its receptors play a predominant role. The effect of PGE2 is mediated through four G-protein coupled receptors EP1, EP2, EP3 and EP4 that activates distinct intracellular signaling pathways. To evaluate the importance of PGE2 and its receptors in NB, we analyzed the expression of EP1-EP4 in clinical primary NB tumors and cell lines and examined the effect of EP receptor antagonists on cell viability. All four EP receptor subtypes were detected at both the mRNA and protein level in human NB cell lines, as well as in NB primary tumors using immunohistochemistry. Treatment with a receptor antagonist against EP4 but not against EP1 induced a dose-dependent reduction in cell viability in vitro. These results indicate that agents targeting prostaglandin E2 receptors may have a potential therapeutic significance in neuroblastoma treatment. Complementary studies are in progress, to fully elucidate the significance of PGE2 and its receptors in neuroblastoma carcinogenesis.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]