title: COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset.
abstract: The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E2 (PGE2) 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 PGE2. 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 PGE2 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 PGE2 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.
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
authors.forename: Karin
authors.initials: K
authors.lastname: Larsson
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, SE-171 76 Stockholm, Sweden;
authors.forename: Anna
authors.initials: A
authors.lastname: Kock
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
authors.forename: Helena
authors.initials: H
authors.lastname: Idborg
authors.affiliation: Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;
authors.forename: Marie
authors.initials: M
authors.lastname: Arsenian Henriksson
authors.affiliation: Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden;
authors.forename: Tommy
authors.initials: T
authors.lastname: Martinsson
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, SE-171 76 Stockholm, Sweden;
authors.forename: John I
authors.initials: JI
authors.lastname: Johnsen
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden;
authors.forename: Marina
authors.initials: M
authors.lastname: Korotkova
authors.affiliation: Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, SE-171 76 Stockholm, Sweden; Per.Kogner@ki.se Per-Johan.Jakobsson@ki.se.
authors.forename: Per
authors.initials: P
authors.lastname: Kogner
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; Rheumatology Clinic, Karolinska University Hospital, SE-171 76 Stockholm, Sweden Per.Kogner@ki.se Per-Johan.Jakobsson@ki.se.
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Jakobsson
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11; D015232:Dinoprostone / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D059016:Tumor Microenvironment
chemical_list: D012333:RNA, Messenger; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone
keywords: PGE2; cancer-associated fibroblasts; mPGES-1; neuroblastoma; tumor microenvironment