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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 publication

DOI

10.1016/j.ccr.2011.08.010

Type

Journal article

Journal

Cancer cell

Publication Date

13/09/2011

Volume

20

Pages

370 - 383

Keywords

Animals, Antineoplastic Agents, Apoptosis, Carboplatin, Cisplatin, Cyclooxygenase 1, Cyclooxygenase Inhibitors, Drug Resistance, Neoplasm, Fatty Acids, Fatty Acids, Unsaturated, Humans, Mass Spectrometry, Mesenchymal Stem Cells, Metabolomics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Organoplatinum Compounds, Oxaliplatin, Platinum Compounds, Thromboxane-A Synthase, Tumor Cells, Cultured