Author/Authors :
Erik and Roodhart، نويسنده , , Jeanine M.L. and Daenen، نويسنده , , Laura G.M. and Stigter، نويسنده , , Edwin C.A. and Prins، نويسنده , , Henk-Jan and Gerrits، نويسنده , , Johan and Houthuijzen، نويسنده , , Julia M. and Gerritsen، نويسنده , , Marije G. and Schipper، نويسنده , , Henk S. and Backer، نويسنده , , Marieke J.G. and van Amersfoort، نويسنده , , Miranda and Vermaat، نويسنده , , Joost S.P. and Moerer، نويسنده , , Petra and Ishihara، نويسنده , , Kenji and Kalkhoven، نويسنده , , Eric and Beijnen، نويسنده , , Jos H. and Derksen، نويسنده , , Patrick W.B. and Medema، نويسنده , , Rene H. and Martens، نويسنده , , Anton C. and Brenkman، نويسنده , , Arjan B. and Voest، نويسنده , , Emile E.، نويسنده ,
Abstract :
Summary
velopment 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.
