Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids
Open accessAbstract
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.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Recent evidence points to tumor microenvironment components as potential participants in the generation of chemoresistance.
“Recent evidence points to tumor microenvironment components as potential participants in the generation of chemoresistance (Denardo et al., 2011; Gilbert and Hemann, 2010; Roodhart et al., 2011; Shaked et al., 2008; Shree et al., 2011).”
From A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis (2012) · cites this paper as Roodhart et al., 2011
Cites
Multilineage potential of adult human mesenchymal stem cells
Pittenger, M. F., Mackay, A. M., Beck, S. C., Jaiswal, R. K., Douglas, R., Mosca, J. D., Moorman, M. A., Simonetti, D. W., Craig, S., & Marshak, D. R. (1999) · Science · doi:10.1126/science.284.5411.143 · Cited by 21,052 · see citing works
The resurgence of platinum-based cancer chemotherapy
Kèlland, L. R. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2167 · Cited by 4,733 · see citing works
VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche
Kaplan, R. N., Riba, R. D., Zacharoulis, S., Bramley, A. H., Vincent, L., Costa, C., MacDonald, D. D., Jin, D. K., Shido, K., Kerns, S. A., et al. (2005) · Nature · doi:10.1038/nature04186 · Cited by 3,288 · see citing works
Mesenchymal stem cells within tumour stroma promote breast cancer metastasis
Karnoub, A. E., Dash, A. B., Vo, A. P., Sullivan, A., Brooks, M. W., Bell, G. W., Richardson, A. L., Polyak, K., Tubo, R., & Weinberg, R. A. (2007) · Nature · doi:10.1038/nature06188 · Cited by 3,206 · see citing works
Lyden, D., Hattori, K., Dias, S., Costa, C., Blaikie, P., Butros, L., Chadburn, A., Heissig, B., Marks, W., Witte, L., et al. (2001) · Nature Medicine · doi:10.1038/nm1101-1194 · Cited by 1,860 · see citing works
Wang, D., & DuBois, R. N. (2010) · Nature reviews. Cancer · doi:10.1038/nrc2809 · Cited by 1,794 · see citing works
Chen, L., Tredget, E. E., Wu, P. Y. G., & Wu, Y. (2008) · PLoS ONE · doi:10.1371/journal.pone.0001886 · Cited by 1,610 · see citing works
Tögel, F., Hu, Z.-M., Weiss, K., Isaac, J., Lange, C., & Westenfelder, C. (2005) · AJP - Renal Physiology · doi:10.1152/ajprenal.00007.2005 · Cited by 1,196 · see citing works
Environment-mediated drug resistance: A major contributor to minimal residual disease
Meads, M. B., Gatenby, R. A., & Dalton, W. S. (2009) · Nature Reviews Cancer · doi:10.1038/nrc2714 · Cited by 892 · see citing works
Weaver, V. M., Lelièvre, S. A., Lakins, J. N., Chrenek, M. A., Jones, J., Giancotti, F. G., Werb, Z., & Bissell, M. J. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00125-3 · Cited by 794 · see citing works
Sethi, T., Rintoul, R. C., Moore, S. M., MacKinnon, A. C., Salter, D. M., Choo, C., Chilvers, E. R., Dransfield, I., Donnelly, S. C., Strieter, R. M., et al. (1999) · Nature Medicine · doi:10.1038/9511 · Cited by 739 · see citing works
Kidd, S. M., Spaeth, E. L., Dembinski, J. L., Dietrich, M. F., Watson, K., Klopp, A. H., Battula, V. L., Weil, M., Andreeff, M., & Marini, F. C. (2009) · Stem Cells · doi:10.1002/stem.187 · Cited by 680 · see citing works
A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer
Farmer, P. J., Bonnefoi, H. R., Anderle, P., Cameron, D., Wirapati, P., Becette, V., André, S., Piccart, M. J., Campone, M., Brain, E. G. C., et al. (2009) · Nature Medicine · doi:10.1038/nm.1908 · Cited by 618 · see citing works
Young, W., Steele, T. A., Bray, R. A., Hudson, J. A., Floyd, J. A., Hawkins, K. C., Thomas, K. S. C., Austin, T., Edwards, C., Cuzzourt, J., et al. (2001) · The Anatomical Record · doi:10.1002/ar.1128 · Cited by 545 · see citing works
Toll-like receptors and their ligands control mesenchymal stem cell functions
Pevsner‐Fischer, M., Morad, V., Cohen-Sfady, M., Rousso-Noori, L., Zanin‐Zhorov, A., Cohen, S. J., Cohen, I. R., & Zipori, D. (2006) · Blood · doi:10.1182/blood-2006-06-028704 · Cited by 484 · see citing works
Shaked, Y., Henke, E., Roodhart, J. M. L., Mancuso, P., Langenberg, M. H. G., Colleoni, M. A., Daenen, L. G. M., Man, S., Xu, P., Emmenegger, U., et al. (2008) · Cancer Cell · doi:10.1016/j.ccr.2008.08.001 · Cited by 439 · see citing works
Self-citationVEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma
Beckermann, B. M., Kallifatidis, G., Groth, A., Frommhold, D., Apel, A., Mattern, J., Salnikov, A. V., Moldenhauer, G., Wagner, W., Diehlmann, A., et al. (2008) · British Journal of Cancer · doi:10.1038/sj.bjc.6604508 · Cited by 406 · see citing works
Morigi, M., Introna, M., Imberti, B., Corna, D., Abbate, M., Rota, C., Rottoli, D., Benigni, A., Perico, N., Zoja, C., et al. (2008) · Stem Cells · doi:10.1634/stemcells.2007-0795 · Cited by 381 · see citing works
Ringe, J., Strassburg, S., Neumann, K., Endres, M., Notter, M., Burmester, G. R., Kaps, C., & Sittinger, M. (2007) · Journal of Cellular Biochemistry · doi:10.1002/jcb.21172 · Cited by 371 · see citing works
Multi-targeted therapy of cancer by omega-3 fatty acids
Berquin, I. M., Edwards, I. J., & Chen, Y. Q. (2008) · Cancer Letters · doi:10.1016/j.canlet.2008.03.044 · Cited by 362 · see citing works
Bone marrow-derived mesenchymal stem cells and the tumor microenvironment
Bergfeld, S. A., & DeClerck, Y. A. (2010) · Cancer and Metastasis Reviews · doi:10.1007/s10555-010-9222-7 · Cited by 345 · see citing works
Mesenchymal stem cells: innovative therapeutic tools for rheumatic diseases
Djouad, F., Bouffi, C., Ghannam, S., Noël, D., & Jørgensen, C. (2009) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2009.104 · Cited by 315 · see citing works
Concise Review: Mesenchymal Stromal Cells: Potential for Cardiovascular Repair
Psaltis, P. J., Zannettino, A. C. W., Worthley, S. G., & Gronthos, S. (2008) · Stem Cells · doi:10.1634/stemcells.2008-0428 · Cited by 303 · see citing works
Müerköster, S. S., Wegehenkel, K., Arlt, A., Witt, M., Sipos, B., Kruse, M., Sebens, T., Klöppel, G., Kalthoff, H., Fölsch, U. R., et al. (2004) · Cancer Research · doi:10.1158/0008-5472.can-03-1860 · Cited by 254 · see citing works
Basic Fibroblast Growth Factor Controls Migration in Human Mesenchymal Stem Cells
Schmidt, A., Ladage, D., Schinköthe, T., Klausmann, U., Ulrichs, C., Klinz, F., Brixius, K., Arnhold, S., Desai, B., Mehlhorn, U., et al. (2006) · Stem Cells · doi:10.1634/stemcells.2005-0191 · Cited by 237 · see citing works
Siddappa, R., Martens, A. C., Doorn, J., Mentink-Leusink, A., Olivo, C., Licht, R., van Rijn, L., Gaspar, C., Fodde, R., Janssen, F., et al. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0711190105 · Cited by 219 · see citing works
Self-citationLoebinger, M. R., Kyrtatos, P. G., Turmaine, M., Price, A. N., Pankhurst, Q. A., Lythgoe, M. F., & Janes, S. M. (2009) · Cancer Research · doi:10.1158/0008-5472.can-09-1912 · Cited by 212 · see citing works
Hazlehurst, L. A., Landowski, T. H., & Dalton, W. S. (2003) · Oncogene · doi:10.1038/sj.onc.1206943 · Cited by 203 · cited 1× · see citing works
“The surrounding stroma is believed to modulate the response to chemotherapy by either direct cell-cell interactions with tumor cells, or by the local release of soluble factors such as interleukin-6, promoting survival and tumor growth (Weaver et al., 2002; Shekhar et al., 2007; Hazlehurst et al., 2003; Sethi et al.,…”
Backgroundvan der Meij, B. S., Langius, J. A. E., Smit, E. F., Spreeuwenberg, M. D., Blomberg, B. M. E. V., Heijboer, A. C., Paul, M. A., & van Leeuwen, P. A. M. (2010) · Journal of Nutrition · doi:10.3945/jn.110.121202 · Cited by 199 · see citing works
12(S)-hydroxyheptadeca-5Z, 8E, 10E–trienoic acid is a natural ligand for leukotriene B4 receptor 2
Okuno, T., Iizuka, Y., Okazaki, H., Yokomizo, T., Taguchi, R., & Shimizu, T. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20072329 · Cited by 194 · see citing works
Naraba, H., Murakami, M., Matsumoto, H., Shimbara, S., Ueno, A., Kudo, I., & Oh‐ishi, S. (1998) · The Journal of Immunology · doi:10.4049/jimmunol.160.6.2974 · Cited by 178 · see citing works
Köhne, C.-H., Grève, J. D., Hartmann, J. T., Láng, I., Vergauwe, P. L., Becker, K., Braumann, D., Joosens, E. J., Müller, L., Janssens, J., et al. (2007) · Annals of Oncology · doi:10.1093/annonc/mdm544 · Cited by 162 · see citing works
Adult human mesenchymal stem cells enhance breast tumorigenesis and promote hormone independence
Rhodes, L. V., Muir, S. E., Elliott, S. G., Guillot, L. M., Antoon, J. W., Penfornis, P., Tilghman, S. L., Salvo, V. A., Fonseca, J. P., Lacey, M. R., et al. (2009) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0458-2 · Cited by 110 · see citing works
Pierga, J., Delaloge, S., Espié, M., Brain, E. G. C., Sigal‐Zafrani, B., Mathieu, M., Bertheau, P., Jm, G., Spielmann, M., Savignoni, A., et al. (2010) · Breast Cancer Research and Treatment · doi:10.1007/s10549-010-0939-3 · Cited by 105 · see citing works
Direct Involvement of Breast Tumor Fibroblasts in the Modulation of Tamoxifen Sensitivity
Shekhar, M. P. V., Santner, S. J., Carolin, K. A., & Tait, L. R. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.061004 · Cited by 105 · see citing works
Prins, H., Rozemuller, H., Vonk-Griffioen, S., Verweij, V. G. M., Dhert, W. J. A., Slaper‐Cortenbach, I., & Martens, A. C. (2009) · Tissue Engineering Part A · doi:10.1089/ten.tea.2008.0666 · Cited by 97 · see citing works
Self-citationJiang, Z., Wilmore, D. W., Wang, X., Wei, J., Zhang, Z. T., Gu, Z. Y., Wang, S., Han, S., Jiang, H., & Yu, K. (2010) · British journal of surgery · doi:10.1002/bjs.6999 · Cited by 80 · see citing works
Role of bone marrow-derived cells in tumor angiogenesis and treatment
Jain, R. K., & Duda, D. G. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00138-7 · Cited by 67 · see citing works
Li, Y., Shi, C., Yuan, J., Yang, Y., Li, J., Ma, J., Wu, X., Freund, M., Pollok, K. E., Hanenberg, H., et al. (2009) · Blood · doi:10.1182/blood-2008-07-168138 · Cited by 66 · see citing works
Enhancing Cytotoxic Therapies for Breast and Prostate Cancers With Polyunsaturated Fatty Acids
Shaikh, I., Brown, I. M., Wahle, K. W. J., et al. (2010) · Nutrition and Cancer · doi:10.1080/01635580903407189 · Cited by 43 · see citing works
ISHIHARA, K., Murata, M., Kaneniwa, M., et al. (2000) · Bioscience Biotechnology and Biochemistry · doi:10.1271/bbb.64.2454 · Cited by 42 · see citing works
Self-citationWilliard, D. E., Kaduce, T. L., Harmon, S. D., & Spector, A. A. (1998) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)33865-7 · Cited by 29 · see citing works
Agins, A. P., Thomas, M. J., Edmonds, C. G., et al. (1987) · Biochemical Pharmacology · doi:10.1016/0006-2952(87)90241-3 · Cited by 15 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Microenvironmental regulation of tumor progression and metastasis
Quail, D. F., & Joyce, J. A. (2013) · Nature Medicine · doi:10.1038/nm.3394 · Cited by 7,994 · see citing works
A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis
Acharyya, S., Oskarsson, T., Vanharanta, S., Malladi, S., Kim, J., Morris, P. G., Manova-Todorova, K., Leversha, M., Hogg, N., Seshan, V. E., et al. (2012) · Cell · doi:10.1016/j.cell.2012.04.042 · Cited by 1,085 · see citing works
Systems biology of cisplatin resistance: past, present and future
Galluzzi, L., Vitale, I., Michels, J., Brenner, C., Szabadkai, G., Harel-Bellan, A., Castedo, M., & Kroemer, G. (2014) · Cell Death & Disease · doi:10.1038/cddis.2013.428 · Cited by 782 · see citing works
New horizons in tumor microenvironment biology: challenges and opportunities
Chen, F., Zhuang, X., Lin, L., Yu, P., Wang, Y., Shi, Y., Hu, G., & Sun, Y. (2015) · BMC Medicine · doi:10.1186/s12916-015-0278-7 · Cited by 704 · see citing works
Understanding metabolic regulation and its influence on cell physiology
Metallo, C. M., & Vander Heiden, M. G. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.018 · Cited by 367 · see citing works
Role of the tumor microenvironment in tumor progression and the clinical applications (Review)
YUAN, Y., JIANG, Y.-C., SUN, C.-K., & CHEN, Q.-M. (2016) · Oncology Reports · doi:10.3892/or.2016.4660 · Cited by 320 · see citing works
3D Bioprinting of Breast Cancer Models for Drug Resistance Study
Wang, Y., Shi, W., Kuss, M., Mirza, S., Qi, D., Krasnoslobodtsev, A., Zeng, J., Band, H., Band, V., & Duan, B. (2018) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.8b01277 · Cited by 157 · see citing works
Recent discoveries concerning the tumor - mesenchymal stem cell interactions
Lazennec, G., & Lam, P. Y. (2016) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2016.10.004 · Cited by 117 · see citing works
Tu, B., Zhu, J., Liu, S., Wang, L., Fan, Q., Hao, Y., Fan, C., & Tang, T.-T. (2016) · Oncotarget · doi:10.18632/oncotarget.10219 · Cited by 95 · see citing works
Mesenchymal Stem Cells and Extracellular Vesicles in Osteosarcoma Pathogenesis and Therapy
Sarhadi, V. K., Daddali, R., & Seppänen-Kaijansinkko, R. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222011035 · Cited by 63 · see citing works
Bosco, D. B., Kenworthy, R., Zorio, D. A. R., & Sang, Q.-X. A. (2015) · PLOS ONE · doi:10.1371/journal.pone.0128511 · Cited by 50 · see citing works
Ma, Y., Wang, J., Li, Q., & Cao, B. (2021) · Nutrition and Cancer · doi:10.1080/01635581.2020.1743873 · Cited by 27 · see citing works
- Authors
- 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.
- Affiliations
- University Medical Center Utrecht (NL)
- Netherlands Metabolomics Centre (NL)
- Japan Fisheries Research and Education Agency (JP)
- Slotervaartziekenhuis (NL)
- Corresponding author
- Voest, Emile E.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 20
- Issue
- 3
- Pages
- 370-383
- ISSN
- 1535-6108 (ISSN-L)
- OpenAlex
- W2145742835
- Cited by
- 305
- References
- 43
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 6 · 2023: 21 · 2022: 7 · 2021: 31 · 2020: 29 · 2019: 26 · 2018: 17 · 2017: 25 · 2016: 26 · 2015: 27 · 2014: 23 · 2013: 30 · 2012: 23
- FWCI
- 12.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 685 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Health Sciences › Medicine › Genetics › Mesenchymal stem cell research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- mesenchymal stem cells, chemoresistance, platinum analogues, polyunsaturated fatty acids, cyclooxygenase-1, thromboxane synthase, tumor microenvironment, cancer metabolism, metabolomics
- MeSH terms
- Oxaliplatin, Animals, Antineoplastic Agents, Cisplatin, Fatty Acids, Fatty Acids, Unsaturated, Humans, Mice, Inbred BALB C, Mice, Inbred C57BL, Organoplatinum Compounds, Mass Spectrometry, Thromboxane-A Synthase, Tumor Cells, Cultured, Carboplatin, Cyclooxygenase Inhibitors, Apoptosis, Platinum Compounds, Drug Resistance, Neoplasm, Mice, Cyclooxygenase 1, Metabolomics, Mesenchymal Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
