Targeting the COX/mPGES-1/PGE₂ Pathway in Neuroblastoma

The importance of prostaglandin E₂ in cancer progression is well established, but research on its role in cancer has so far mostly been focused on epithelial cancer in adults while the knowledge about the contribution of prostaglandin E₂ to childhood malignancies is limited. Neuroblastoma, an extracranial solid tumor of the sympathetic nervous system, mainly affects young children. Patients with tumors classified as high-risk have poor survival despite receiving intensive treatment, illustrating a need for new treatments complimenting existing ones. The basis of neuroblastoma treatment e.g. chemotherapy and radiation therapy, target the proliferating genetically unstable tumor cells leading to treatment resistance and relapses. The tumor microenvironment is an avenue, still to a great extent, unexplored and lacking effective targeted therapies. Cancer-associated fibroblasts is the main source of prostaglandin E₂ in neuroblastoma contributing to angiogenesis, immunosuppression and tumor growth. Prostaglandin E₂ is formed from its precursor arachidonic acid in a two-step enzymatic reaction. Arachidonic acid is first converted by cyclooxygenases into prostaglandin H₂ and then further converted by microsomal prostaglandin E synthase-1 into prostaglandin E₂. We believe targeting of microsomal prostaglandin E synthase-1 in cancer-associated fibroblasts will be an effective future therapeutic strategy in fighting neuroblastoma.