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COX/Mpges-1/PGE2 Pathway Depicts an Inflammatory- Dependent High-Risk Neuroblastoma Subset

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COX/Mpges-1/PGE2 Pathway Depicts an Inflammatory- Dependent High-Risk Neuroblastoma Subset COX/mPGES-1/PGE2 pathway depicts an inflammatory- dependent high-risk neuroblastoma subset Karin Larssona,1, Anna Kockb,1, Helena Idborga, Marie Arsenian Henrikssonc, Tommy Martinssond, John I. Johnsenb, Marina Korotkovaa, Per Kognerb,2,3, and Per-Johan Jakobssona,e,2,3 aRheumatology Unit, Department of Medicine, Karolinska Institutet, SE-171 76 Stockholm, Sweden; bChildhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Astrid Lindgren Children’s Hospital, SE-171 76 Stockholm, Sweden; cDepartment of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; dDepartment of Clinical Genetics, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, SE-405 30 Gothenburg, Sweden; and eRheumatology Clinic, Karolinska University Hospital, SE-171 76 Stockholm, Sweden Edited by Charles A. Dinarello, University of Colorado Denver, Aurora, CO, and approved May 27, 2015 (received for review January 16, 2015) The majority of solid tumors are presented with an inflammatory muscles contraction, and protection of the intestinal mucosa, and in microenvironment. Proinflammatory lipid mediators including pros- pathological conditions such as autoimmune diseases and cancer taglandin E2 (PGE2) contribute to the establishment of inflammation (6). Prostaglandins are formed by the conversion of arachidonic and have been linked to tumor growth and aggressiveness. Here we acid to prostaglandin H2 (PGH2) by the cyclooxygenases show that high-risk neuroblastoma with deletion of chromosome 11q COX-1 and COX-2, followed by further processing by terminal represents an inflammatory subset of neuroblastomas. Analysis of enzymes, the prostaglandin synthases. Prostaglandin E2 (PGE2) enzymes involved in the production of proinflammatory lipid media- is a proinflammatory and immunomodulatory lipid mediator tors showed that 11q-deleted neuroblastoma tumors express high formed from PGH2 by microsomal prostaglandin E synthase 1 levels of microsomal prostaglandin E synthase-1 (mPGES-1) and ele- (mPGES-1). Elevated levels of mPGES-1 and its enzymatic product PGE have been found in several different cancers, including colon vated levels of PGE . High mPGES-1 expression also corresponded to 2 2 cancer (7–9), nonsmall cell lung cancer (10), and prostate cancer (11, poor survival of neuroblastoma patients. Investigation of the tumor 12). PGE2 signaling contributes to increased proliferation (13, 14) microenvironment showed high infiltration of tumor-promoting mac- and invasiveness (15) of cancer cells, stimulates tumor angiogenesis rophages with high expression of the M2-polarization markers CD163 (16, 17), inhibit apoptosis (18), induces chemoresistance (19), and – and CD206. mPGES-1 expressing cells in tumors from different sub- mediates suppression of anti-tumor immunity (20, 21). Because tu- types of neuroblastoma showed differential expression of one or mor-promoting inflammation has been included as one of the several cancer-associated fibroblast markers such as vimentin, fibro- hallmarks of cancer (22), chronic inflammation and its impact on blast activation protein α, α smooth muscle actin, and PDGF receptor tumorigenesis in adult tumors have been immensely investigated. β . Importantly, inhibition of PGE2 production with diclofenac, a non- Less is known about the inflammatory component in child- selective COX inhibitor, resulted in reduced tumor growth in an in hood tumors; however, in a recent study, Asgharzadeh et al. (23) vivo model of 11q-deleted neuroblastoma. Collectively, these results showed that infiltration of immunosuppressive M2-polarized suggest that PGE2 is involved in the tumor microenvironment of spe- macrophages in metastatic MYCN-nonamplified neuroblastoma cific neuroblastoma subgroups and indicate that therapeutic strate- tumors contributed to the metastatic phenotype and worsened gies using existing anti-inflammatory drugs in combination with current treatment should be considered for certain neuroblastomas. Significance mPGES-1 | PGE2 | neuroblastoma | tumor microenvironment | Cancer-related inflammation promotes progression and therapy cancer-associated fibroblasts resistance in tumors of adulthood. Knowledge concerning the significance of inflammation in childhood malignancies has been euroblastoma is the most common and deadliest tumor limited. Neuroblastoma is an embryonal tumor of early childhood Nof childhood. Although the survival of children with neuro- with poor prognosis despite intensified therapy, and biological blastoma has improved during the last decade, patients with high- understanding is necessary to develop novel therapies. We found risk disease still have a poor prognosis, despite advanced and high-risk neuroblastoma, in particular the therapy-resistant subset intensive treatments, with overall survival rates less than 40% (1). with chromosome 11q-deletion, to be inflammatory driven and The International Neuroblastoma Risk Group (INRG) classifi- characterized by high expression of the COX/microsomal prosta- cation system defines neuroblastoma risk groups as low, in- glandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) pathway termediate, and high, based on age at diagnosis, histology, and that correlates with metastatic stage and poor clinical outcome. genetic aberrations (2). Among high-risk neuroblastomas, ampli- We further detected infiltrating cancer-associated fibroblasts fication of the neuroblastoma MYC (MYCN)oncogeneisthe expressing mPGES-1, the essential enzyme for synthesis of PGE2, most frequent genetic aberration, seen in 30–40% of the patients. promoting tumor growth, angiogenesis, and metastatic spread. Another common genetic change in the high-risk group is deletion Treatment targeting this inflammatory pathway provides a of the long arm of chromosome 11 (11q-deletion). Deletion of therapeutic option for neuroblastoma and other cancers. 11q occurs in tumors with multiple genetic aberrations and MYCN Author contributions: K.L., A.K., M.A.H., J.I.J., M.K., P.K., and P.-J.J. designed research; K.L., A.K., chromosome instability but commonly without -amplifi- and H.I. performed research; K.L., A.K., H.I., T.M., J.I.J., M.K., P.K., and P.-J.J. analyzed data; and cation and therefore is a useful prognostic marker in adverse- K.L., A.K., J.I.J., P.K., and P.-J.J. wrote the paper. stage tumors lacking MYCN-amplification (3). These patients The authors declare no conflict of interest. are often older at disease onset and have slow disease pro- This article is a PNAS Direct Submission. gression but often develop therapy resistance and have poor Freely available online through the PNAS open access option. clinical outcome. Among low- and intermediate-risk neuro- 1K.L. and A.K. contributed equally to this work. “ ” blastomas are the so-called special neuroblastomas (4S) that 2P.K. and P.-J.J. contributed equally to this work. show a metastatic phenotype but are associated with sponta- 3To whom correspondence may be addressed. Email: [email protected] or Per-Johan. neous regression and a survival rate of 90% (1, 4, 5). [email protected]. Prostaglandins are bioactive lipids involved in many biological This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. processes both in physiological processes e.g., blood pressure, smooth 1073/pnas.1424355112/-/DCSupplemental. 8070–8075 | PNAS | June 30, 2015 | vol. 112 | no. 26 www.pnas.org/cgi/doi/10.1073/pnas.1424355112 Downloaded by guest on September 24, 2021 extracted tissue homogenates from 29 primary neuroblastoma A mPGES-1 COX-1 COX-2 40 80 8 samples (four 11q-deleted, eight MYCN-amplified, and 17 low- 6 risk tumors; Table S1). There were significantly higher levels of 30 60 2 PGE2 in the 11q-deleted tumors than in the MYCN-amplified 20 40 tumors (P = 0.02) or in the low-risk tumors (P = 3.0e-04) (Fig. 1 1C). No significant differences were found in the levels of other 10 20 Fold change Fold Fold change Fold (COX-2/HPRT) (COX-1/HPRT) Fold change Fold prostanoids analyzed (Fig. S1 and Table S2). (mPGES-1/HPRT) 0 0 0 11q-NMA Low-risk 11q-NMA Low-risk 11q-NMA Low-risk Immunohistochemical Analysis of Prostaglandin Synthases. The BCexpression of enzymes involved in synthesis of prostaglandins in 100 Overall survival INSS 4 PGE2 neuroblastoma was analyzed using immunohistochemistry (IHC). Low mPGES-1 30 80 High mPGES-1 10 COX-1, COX-2, mPGES-1, lipocalin-type prostaglandin D synthase 0.3 (L-PGDS), hematopoietic-type prostaglandin D synthase (H-PGDS), 60 0.2 and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were an- 40 alyzed in tumors from 11 neuroblastoma patients (four 11q-deleted, 20 0.1 MYCN Percent survival Percent three -amplified, and four low-risk tumors; Fig. 2 and Fig. S2). 0 pmol/mg extracted 0.0 Expression of mPGES-1 was found in all tumors tested, with sig- 0 50 100 150 200 250 11q-NMA Low-risk nificantly higher levels in the 11q-deleted tumors than in the low-risk Follow up in month tumors alone (P = 0.02) or in the MYCN-amplified and low-risk tumors considered together (P = 0.004). mPGES-1 expression was Fig. 1. mPGES-1 expression and PGE2 levels are associated with 11q-deleted neuroblastoma. (A) Expression of mPGES-1, COX-1, and COX-2 mRNA in confirmed with IHC in additional 11q-deleted tumors (Fig. S3) neuroblastoma tissue samples was measured by the TaqMan Gene Expres- and with Western blot. Western blot analysis clearly showed sion Assay. Expression of mPGES-1 and COX-1 was significantly higher in 11q- higher levels of mPGES-1 in
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