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COX/mPGES-1/PGE₂ pathway depicts an inflammatory-dependent high-risk neuroblastoma subset

Larsson, Karin, Kock, Anna, Idborg, Helena, Arsenian Henriksson, Marie, Martinsson, Tommy, Johnsen, John I., Korotkova, Marina, Kogner, Per, Jakobsson, Per-Johan
Proceedings of the National Academy of Sciences of the United States of America 2015 v.112 no.26 pp. 8070-8075
adulthood, angiogenesis, childhood, chromosomes, fibroblasts, inflammation, metastasis, neoplasms, prognosis, prostaglandins, therapeutics
The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E ₂ (PGE ₂) contribute to the establishment of inflammation and have been linked to tumor growth and aggressiveness. Here we show that high-risk neuroblastoma with deletion of chromosome 11q represents an inflammatory subset of neuroblastomas. Analysis of enzymes involved in the production of proinflammatory lipid mediators showed that 11q-deleted neuroblastoma tumors express high levels of microsomal prostaglandin E synthase-1 (mPGES-1) and elevated levels of PGE ₂. High mPGES-1 expression also corresponded to poor survival of neuroblastoma patients. Investigation of the tumor microenvironment showed high infiltration of tumor-promoting macrophages with high expression of the M2-polarization markers CD163 and CD206. mPGES-1–expressing cells in tumors from different subtypes of neuroblastoma showed differential expression of one or several cancer-associated fibroblast markers such as vimentin, fibroblast activation protein α, α smooth muscle actin, and PDGF receptor β. Importantly, inhibition of PGE ₂ production with diclofenac, a nonselective COX inhibitor, resulted in reduced tumor growth in an in vivo model of 11q-deleted neuroblastoma. Collectively, these results suggest that PGE ₂ is involved in the tumor microenvironment of specific neuroblastoma subgroups and indicate that therapeutic strategies using existing anti-inflammatory drugs in combination with current treatment should be considered for certain neuroblastomas.