Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids

J.M.L. Roodhart, L.G.M. Daenen, E.C.A. Stigter, H.J. Prins, J. Gerrits, J.M. Houthuijzen, M.G. Gerritsen, H.S. Schipper, M.J.G. Backer, M. van Amersfoort, J.S.P. Vermaat, P. Moerer, K. Ishihara, E. Kalkhoven, J.H. Beijnen, P.W.B. Derksen, R.H. Medema, A.C.M. Martens, A.B. Brenkman, E.E. Voest

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)370-383
Number of pages14
JournalCancer Cell
Volume20
Issue number3
DOIs
Publication statusPublished - 13 Sept 2011

Keywords

  • Animals
  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • Carboplatin/administration & dosage
  • Cisplatin/administration & dosage
  • Cyclooxygenase 1/metabolism
  • Cyclooxygenase Inhibitors
  • Drug Resistance, Neoplasm
  • Fatty Acids/metabolism
  • Fatty Acids, Unsaturated/metabolism
  • Humans
  • Mass Spectrometry
  • Mesenchymal Stem Cells/metabolism
  • Metabolomics
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Organoplatinum Compounds/administration & dosage
  • Oxaliplatin
  • Platinum Compounds/pharmacology
  • Thromboxane-A Synthase/antagonists & inhibitors
  • Tumor Cells, Cultured

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