title: Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids.
abstract: The development of resistance to chemotherapy is a major obstacle for lasting effective treatment of cancer. Here, we demonstrate that endogenous mesenchymal stem cells (MSCs) become activated during treatment with platinum analogs and secrete factors that protect tumor cells against a range of chemotherapeutics. Through a metabolomics approach, we identified two distinct platinum-induced polyunsaturated fatty acids (PIFAs), 12-oxo-5,8,10-heptadecatrienoic acid (KHT) and hexadeca-4,7,10,13-tetraenoic acid (16:4(n-3)), that in minute quantities induce resistance to a broad spectrum of chemotherapeutic agents. Interestingly, blocking central enzymes involved in the production of these PIFAs (cyclooxygenase-1 and thromboxane synthase) prevents MSC-induced resistance. Our findings show that MSCs are potent mediators of resistance to chemotherapy and reveal targets to enhance chemotherapy efficacy in patients.
authors: Department of Medical Oncology, University Medical Center Utrecht, The Netherlands.
authors: Jeanine M L
authors: JM
authors: Roodhart
authors: Laura G M
authors: LG
authors: Daenen
authors: Edwin C A
authors: EC
authors: Stigter
authors: Henk-Jan
authors: HJ
authors: Prins
authors: Johan
authors: J
authors: Gerrits
authors: Julia M
authors: JM
authors: Houthuijzen
authors: Marije G
authors: MG
authors: Gerritsen
authors: Henk S
authors: HS
authors: Schipper
authors: Marieke J G
authors: MJ
authors: Backer
authors: Miranda
authors: M
authors: van Amersfoort
authors: Joost S P
authors: JS
authors: Vermaat
authors: Petra
authors: P
authors: Moerer
authors: Kenji
authors: K
authors: Ishihara
authors: Eric
authors: E
authors: Kalkhoven
authors: Jos H
authors: JH
authors: Beijnen
authors: Patrick W B
authors: PW
authors: Derksen
authors: Rene H
authors: RH
authors: Medema
authors: Anton C
authors: AC
authors: Martens
authors: Arjan B
authors: AB
authors: Brenkman
authors: Emile E
authors: EE
authors: Voest
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage / Q000494:pharmacology; D002945:Cisplatin / Q000008:administration & dosage / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors; D019008:Drug Resistance, Neoplasm; D005227:Fatty Acids / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006801:Humans; D013058:Mass Spectrometry; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D055432:Metabolomics; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000494:pharmacology; D000077150:Oxaliplatin; D017671:Platinum Compounds / Q000494:pharmacology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D016861:Cyclooxygenase Inhibitors; D005227:Fatty Acids; D005231:Fatty Acids, Unsaturated; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; C562199:hexadeca-4,7,10,13-tetraenoic acid; D000077150:Oxaliplatin; C052515:12-keto-5,8,10-heptadecatrienoic acid; D016190:Carboplatin; D051545:Cyclooxygenase 1; D013930:Thromboxane-A Synthase; D002945:Cisplatin