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Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated Fibroblasts Suppresses Neuroblastoma Tumor Growth.
EBioMedicine. 2018 Jun; 32:84-92.E

Abstract

Despite recent progress in diagnosis and treatment, survival for children with high-risk metastatic neuroblastoma is still poor. Prostaglandin E2 (PGE2)-driven inflammation promotes tumor growth, immune suppression, angiogenesis and resistance to established cancer therapies. In neuroblastoma, cancer-associated fibroblasts (CAFs) residing in the tumor microenvironment are the primary source of PGE2. However, clinical targeting of PGE2 with current non-steroidal anti-inflammatory drugs or cyclooxygenase inhibitors has been limited due to risk of adverse side effects. By specifically targeting microsomal prostaglandin E synthase-1 (mPGES-1) activity with a small molecule inhibitor we could block CAF-derived PGE2 production leading to reduced tumor growth, impaired angiogenesis, inhibited CAF migration and infiltration, reduced tumor cell proliferation and a favorable shift in the M1/M2 macrophage ratio. In this study, we provide proof-of-principle of the benefits of targeting mPGES-1 in neuroblastoma, applicable to a wide variety of tumors. This non-toxic single drug treatment targeting infiltrating stromal cells opens up for combination treatment options with established cancer therapies.

Authors+Show Affiliations

Childhood Cancer Research Unit, Dep. of Children's and Women's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.Rheumatology Unit, Dep. of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.Rheumatology Unit, Dep. of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.Childhood Cancer Research Unit, Dep. of Children's and Women's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.Childhood Cancer Research Unit, Dep. of Children's and Women's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.Rheumatology Unit, Dep. of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.Rheumatology Unit, Dep. of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.Childhood Cancer Research Unit, Dep. of Children's and Women's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.Rheumatology Unit, Dep. of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm SE-171 76, Sweden.Childhood Cancer Research Unit, Dep. of Children's and Women's Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden. Electronic address: Per.Kogner@ki.se.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29804818

Citation

Kock, Anna, et al. "Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated Fibroblasts Suppresses Neuroblastoma Tumor Growth." EBioMedicine, vol. 32, 2018, pp. 84-92.
Kock A, Larsson K, Bergqvist F, et al. Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated Fibroblasts Suppresses Neuroblastoma Tumor Growth. EBioMedicine. 2018;32:84-92.
Kock, A., Larsson, K., Bergqvist, F., Eissler, N., Elfman, L. H. M., Raouf, J., Korotkova, M., Johnsen, J. I., Jakobsson, P. J., & Kogner, P. (2018). Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated Fibroblasts Suppresses Neuroblastoma Tumor Growth. EBioMedicine, 32, 84-92. https://doi.org/10.1016/j.ebiom.2018.05.008
Kock A, et al. Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated Fibroblasts Suppresses Neuroblastoma Tumor Growth. EBioMedicine. 2018;32:84-92. PubMed PMID: 29804818.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated Fibroblasts Suppresses Neuroblastoma Tumor Growth. AU - Kock,Anna, AU - Larsson,Karin, AU - Bergqvist,Filip, AU - Eissler,Nina, AU - Elfman,Lotta H M, AU - Raouf,Joan, AU - Korotkova,Marina, AU - Johnsen,John Inge, AU - Jakobsson,Per-Johan, AU - Kogner,Per, Y1 - 2018/05/24/ PY - 2018/02/08/received PY - 2018/04/26/revised PY - 2018/05/04/accepted PY - 2018/5/29/pubmed PY - 2018/10/10/medline PY - 2018/5/29/entrez KW - Cancer-associated fibroblasts KW - PGE(2) KW - Tumor microenvironment KW - mPGES-1 SP - 84 EP - 92 JF - EBioMedicine JO - EBioMedicine VL - 32 N2 - Despite recent progress in diagnosis and treatment, survival for children with high-risk metastatic neuroblastoma is still poor. Prostaglandin E2 (PGE2)-driven inflammation promotes tumor growth, immune suppression, angiogenesis and resistance to established cancer therapies. In neuroblastoma, cancer-associated fibroblasts (CAFs) residing in the tumor microenvironment are the primary source of PGE2. However, clinical targeting of PGE2 with current non-steroidal anti-inflammatory drugs or cyclooxygenase inhibitors has been limited due to risk of adverse side effects. By specifically targeting microsomal prostaglandin E synthase-1 (mPGES-1) activity with a small molecule inhibitor we could block CAF-derived PGE2 production leading to reduced tumor growth, impaired angiogenesis, inhibited CAF migration and infiltration, reduced tumor cell proliferation and a favorable shift in the M1/M2 macrophage ratio. In this study, we provide proof-of-principle of the benefits of targeting mPGES-1 in neuroblastoma, applicable to a wide variety of tumors. This non-toxic single drug treatment targeting infiltrating stromal cells opens up for combination treatment options with established cancer therapies. SN - 2352-3964 UR - https://www.unboundmedicine.com/medline/citation/29804818/Inhibition_of_Microsomal_Prostaglandin_E_Synthase_1_in_Cancer_Associated_Fibroblasts_Suppresses_Neuroblastoma_Tumor_Growth_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2352-3964(18)30163-4 DB - PRIME DP - Unbound Medicine ER -