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Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids
Roodhart, J.M.L.; Daenen, L.G.M.; Stigter, E.C.A.; Prins, H.-J.; Gerrits, J.; Houthuijzen, J.M.; Gerritsen, M.G.; Schipper, H.S.; Backer, M.J.G.; van Amersfoort, M.; Vermaat, J.S.P.; Moerer, P.; Ishihara, K.; Kalkhoven, E.; Beijnen, J.H.; Derksen, P.W.B.; Medema, R.H.; Martens, A.C.; Brenkman, A.B.; Voest, E.E. (2011). Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 20(3): 370-383. http://dx.doi.org/10.1016/j.ccr.2011.08.010
In: Cancer Cell. Cell Press: Cambridge. ISSN 1535-6108; e-ISSN 1878-3686
Peer reviewed article  
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  • Roodhart, J.M.L.
  • Daenen, L.G.M.
  • Stigter, E.C.A.
  • Prins, H.-J.
  • Gerrits, J.
  • Houthuijzen, J.M.
  • Gerritsen, M.G.
  • Schipper, H.S.
  • Backer, M.J.G.
  • van Amersfoort, M.
  • Vermaat, J.S.P.
  • Moerer, P.
  • Ishihara, K.
  • Kalkhoven, E.
  • Beijnen, J.H.
  • Derksen, P.W.B.
  • Medema, R.H.
  • Martens, A.C.
  • Brenkman, A.B.
  • Voest, E.E.
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.
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