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

Jeanine M.L. Roodhart; Laura G.M. Daenen; Edwin C.A. Stigter; Henk Jan Prins; Johan Gerrits; Julia M. Houthuijzen; Marije G. Gerritsen; Henk S. Schipper; Marieke J.G. Backer; Miranda van Amersfoort; Joost S.P. Vermaat; Petra Moerer; Kenji Ishihara; Eric Kalkhoven; Jos H. Beijnen; Patrick W.B. Derksen; Rene H. Medema; Anton C. Martens; Arjan B. Brenkman; Emile E. Voest

doi:10.1016/j.ccr.2011.08.010

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

Jeanine M.L. Roodhart, Laura G.M. Daenen, Edwin C.A. Stigter, Henk Jan Prins, Johan Gerrits, Julia M. Houthuijzen, Marije G. Gerritsen, Henk S. Schipper, Marieke J.G. Backer, Miranda van Amersfoort, Joost S.P. Vermaat, Petra Moerer, Kenji Ishihara, Eric Kalkhoven, Jos H. Beijnen, Patrick W.B. Derksen, Rene H. Medema, Anton C. Martens, Arjan B. Brenkman, Emile E. Voest^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-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 language	English
Pages (from-to)	370-383
Number of pages	14
Journal	Cancer Cell
Volume	20
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2011.08.010
Publication status	Published - 1 Sep 2011

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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. (2011). Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell, 20(3), 370-383. https://doi.org/10.1016/j.ccr.2011.08.010

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

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.",

author = "Roodhart, {Jeanine M.L.} and Daenen, {Laura G.M.} and Stigter, {Edwin C.A.} and Prins, {Henk Jan} and Johan Gerrits and Houthuijzen, {Julia M.} and Gerritsen, {Marije G.} and Schipper, {Henk S.} and Backer, {Marieke J.G.} and {van Amersfoort}, Miranda and Vermaat, {Joost S.P.} and Petra Moerer and Kenji Ishihara and Eric Kalkhoven and Beijnen, {Jos H.} and Derksen, {Patrick W.B.} and Medema, {Rene H.} and Martens, {Anton C.} and Brenkman, {Arjan B.} and Voest, {Emile E.}",

year = "2011",

month = sep,

day = "1",

doi = "10.1016/j.ccr.2011.08.010",

language = "English",

volume = "20",

pages = "370--383",

journal = "Cancer Cell",

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Roodhart, JML, Daenen, LGM, Stigter, ECA, Prins, HJ, 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 2011, 'Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids', Cancer Cell, vol. 20, no. 3, pp. 370-383. https://doi.org/10.1016/j.ccr.2011.08.010

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T1 - Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids

AU - Roodhart, Jeanine M.L.

AU - Daenen, Laura G.M.

AU - Stigter, Edwin C.A.

AU - Prins, Henk Jan

AU - Gerrits, Johan

AU - Houthuijzen, Julia M.

AU - Gerritsen, Marije G.

AU - Schipper, Henk S.

AU - Backer, Marieke J.G.

AU - van Amersfoort, Miranda

AU - Vermaat, Joost S.P.

AU - Moerer, Petra

AU - Ishihara, Kenji

AU - Kalkhoven, Eric

AU - Beijnen, Jos H.

AU - Derksen, Patrick W.B.

AU - Medema, Rene H.

AU - Martens, Anton C.

AU - Brenkman, Arjan B.

AU - Voest, Emile E.

PY - 2011/9/1

Y1 - 2011/9/1

N2 - 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.

AB - 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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AN - SCOPUS:80052592013

VL - 20

SP - 370

EP - 383

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 3

ER -

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

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