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

J.M.L. Roodhart; L.G.M. Daenen; E.C.A. Stigter; H.J. Prins; J. Gerrits; J.M. Houthuijzen; M.G. Gerritsen; H.S. Schipper; M.J.G. Backer; M. van Amersfoort; J.S.P. Vermaat; P. Moerer; K. Ishihara; E. Kalkhoven; J.H. Beijnen; P.W.B. Derksen; R.H. Medema; A.C.M. Martens; A.B. Brenkman; E.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

J.M.L. Roodhart
, L.G.M. Daenen
, E.C.A. Stigter
, H.J. Prins
, J. Gerrits
, J.M. Houthuijzen
, M.G. Gerritsen
, H.S. Schipper
, M.J.G. Backer
, M. van Amersfoort
, J.S.P. Vermaat
, P. Moerer
, K. Ishihara
, E. Kalkhoven
, J.H. Beijnen
, P.W.B. Derksen
, R.H. Medema
, A.C.M. Martens
, A.B. Brenkman
, E.E. Voest

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 - 13 Sept 2011

Keywords

Animals
Antineoplastic Agents/pharmacology
Apoptosis/drug effects
Carboplatin/administration & dosage
Cisplatin/administration & dosage
Cyclooxygenase 1/metabolism
Cyclooxygenase Inhibitors
Drug Resistance, Neoplasm
Fatty Acids/metabolism
Fatty Acids, Unsaturated/metabolism
Humans
Mass Spectrometry
Mesenchymal Stem Cells/metabolism
Metabolomics
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Organoplatinum Compounds/administration & dosage
Oxaliplatin
Platinum Compounds/pharmacology
Thromboxane-A Synthase/antagonists & inhibitors
Tumor Cells, Cultured

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10.1016/j.ccr.2011.08.010

http://www.ncbi.nlm.nih.gov/pubmed/21907927

Cite this

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. M., 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

@article{9300b84da4ba4280962311e0fe1ec49c,

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.",

keywords = "Animals, Antineoplastic Agents/pharmacology, Apoptosis/drug effects, Carboplatin/administration \& dosage, Cisplatin/administration \& dosage, Cyclooxygenase 1/metabolism, Cyclooxygenase Inhibitors, Drug Resistance, Neoplasm, Fatty Acids/metabolism, Fatty Acids, Unsaturated/metabolism, Humans, Mass Spectrometry, Mesenchymal Stem Cells/metabolism, Metabolomics, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Organoplatinum Compounds/administration \& dosage, Oxaliplatin, Platinum Compounds/pharmacology, Thromboxane-A Synthase/antagonists \& inhibitors, Tumor Cells, Cultured",

author = "J.M.L. Roodhart and L.G.M. Daenen and E.C.A. Stigter and H.J. Prins and J. Gerrits and J.M. Houthuijzen and M.G. Gerritsen and H.S. Schipper and M.J.G. Backer and \{van Amersfoort\}, M. and J.S.P. Vermaat and P. Moerer and K. Ishihara and E. Kalkhoven and J.H. Beijnen and P.W.B. Derksen and R.H. Medema and A.C.M. Martens and A.B. Brenkman and E.E. Voest",

year = "2011",

month = sep,

day = "13",

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

language = "English",

volume = "20",

pages = "370--383",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

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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, ACM, 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

TY - JOUR

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

AU - Roodhart, J.M.L.

AU - Daenen, L.G.M.

AU - Stigter, E.C.A.

AU - Prins, H.J.

AU - Gerrits, J.

AU - Houthuijzen, J.M.

AU - Gerritsen, M.G.

AU - Schipper, H.S.

AU - Backer, M.J.G.

AU - van Amersfoort, M.

AU - Vermaat, J.S.P.

AU - Moerer, P.

AU - Ishihara, K.

AU - Kalkhoven, E.

AU - Beijnen, J.H.

AU - Derksen, P.W.B.

AU - Medema, R.H.

AU - Martens, A.C.M.

AU - Brenkman, A.B.

AU - Voest, E.E.

PY - 2011/9/13

Y1 - 2011/9/13

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.

KW - Animals

KW - Antineoplastic Agents/pharmacology

KW - Apoptosis/drug effects

KW - Carboplatin/administration & dosage

KW - Cisplatin/administration & dosage

KW - Cyclooxygenase 1/metabolism

KW - Cyclooxygenase Inhibitors

KW - Drug Resistance, Neoplasm

KW - Fatty Acids/metabolism

KW - Fatty Acids, Unsaturated/metabolism

KW - Humans

KW - Mass Spectrometry

KW - Mesenchymal Stem Cells/metabolism

KW - Metabolomics

KW - Mice

KW - Mice, Inbred BALB C

KW - Mice, Inbred C57BL

KW - Organoplatinum Compounds/administration & dosage

KW - Oxaliplatin

KW - Platinum Compounds/pharmacology

KW - Thromboxane-A Synthase/antagonists & inhibitors

KW - Tumor Cells, Cultured

U2 - 10.1016/j.ccr.2011.08.010

DO - 10.1016/j.ccr.2011.08.010

M3 - Article

C2 - 21907927

SN - 1535-6108

VL - 20

SP - 370

EP - 383

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

Abstract

Keywords

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