Tags

Type your tag names separated by a space and hit enter

COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset.
Proc Natl Acad Sci U S A. 2015 Jun 30; 112(26):8070-5.PN

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+Show Affiliations

Rheumatology Unit, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden;Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, SE-171 76 Stockholm, Sweden;Rheumatology Unit, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden;Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden;Department of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden;Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Astrid Lindgren Children's Hospital, SE-171 76 Stockholm, Sweden;Rheumatology Unit, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden;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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26080408

Citation

Larsson, Karin, et al. "COX/mPGES-1/PGE2 Pathway Depicts an Inflammatory-dependent High-risk Neuroblastoma Subset." Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 26, 2015, pp. 8070-5.
Larsson K, Kock A, Idborg H, et al. COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset. Proc Natl Acad Sci USA. 2015;112(26):8070-5.
Larsson, K., Kock, A., Idborg, H., Arsenian Henriksson, M., Martinsson, T., Johnsen, J. I., Korotkova, M., Kogner, P., & Jakobsson, P. J. (2015). COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset. Proceedings of the National Academy of Sciences of the United States of America, 112(26), 8070-5. https://doi.org/10.1073/pnas.1424355112
Larsson K, et al. COX/mPGES-1/PGE2 Pathway Depicts an Inflammatory-dependent High-risk Neuroblastoma Subset. Proc Natl Acad Sci USA. 2015 Jun 30;112(26):8070-5. PubMed PMID: 26080408.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset. AU - Larsson,Karin, AU - Kock,Anna, AU - Idborg,Helena, AU - Arsenian Henriksson,Marie, AU - Martinsson,Tommy, AU - Johnsen,John I, AU - Korotkova,Marina, AU - Kogner,Per, AU - Jakobsson,Per-Johan, Y1 - 2015/06/15/ PY - 2015/6/17/entrez PY - 2015/6/17/pubmed PY - 2015/11/18/medline KW - PGE2 KW - cancer-associated fibroblasts KW - mPGES-1 KW - neuroblastoma KW - tumor microenvironment SP - 8070 EP - 5 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc. Natl. Acad. Sci. U.S.A. VL - 112 IS - 26 N2 - 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/26080408/COX/mPGES_1/PGE2_pathway_depicts_an_inflammatory_dependent_high_risk_neuroblastoma_subset_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=26080408 DB - PRIME DP - Unbound Medicine ER -