Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids.
Roodhart JML., Daenen LGM., Stigter ECA., Prins H-J., Gerrits J., Houthuijzen JM., Gerritsen MG., Schipper HS., Backer MJG., van Amersfoort M., Vermaat JSP., Moerer P., Ishihara K., Kalkhoven E., Beijnen JH., Derksen PWB., Medema RH., Martens AC., Brenkman AB., Voest EE.
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.