Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids

被引：281

作者：

Roodhart, Jeanine M. L. ^{[1
]}

Daenen, Laura G. M. ^{[1
]}

Stigter, Edwin C. A. ^{[2
,3
]}

Prins, Henk-Jan ^{[4
]}

Gerrits, Johan ^{[2
,3
]}

Houthuijzen, Julia M. ^{[1
]}

Gerritsen, Marije G. ^{[1
]}

Schipper, Henk S. ^{[3
,5
]}

Backer, Marieke J. G. ^{[4
]}

van Amersfoort, Miranda ^{[1
]}

Vermaat, Joost S. P. ^{[1
]}

Moerer, Petra ^{[4
]}

Ishihara, Kenji ^{[6
]}

Kalkhoven, Eric ^{[2
,3
,5
]}

Beijnen, Jos H. ^{[7
]}

Derksen, Patrick W. B. ^{[8
]}

Medema, Rene H. ^{[1
]}

Martens, Anton C. ^{[4
,9
]}

Brenkman, Arjan B. ^{[2
,3
]}

Voest, Emile E. ^{[1
]}

机构：

[1] Univ Med Ctr Utrecht, Dept Med Oncol F02 126, NL-3508 GA Utrecht, Netherlands

[2] Netherlands Metabol Ctr, NL-2333 CC Leiden, Netherlands

[3] Dept Metab & Endocrine Dis, NL-3584 EA Utrecht, Netherlands

[4] Dept Immunol, NL-3584 EA Utrecht, Netherlands

[5] Dept Pediat Immunol, NL-3584 EA Utrecht, Netherlands

[6] Natl Res Inst Fisheries Sci Kanazawaku, Yokohama, Kanagawa 2368648, Japan

[7] Netherlands Canc Inst Slotervaart Hosp, Dept Pharm & Pharmacol, NL-1066 EC Amsterdam, Netherlands

[8] Univ Med Ctr Utrecht, Dept Pathol, NL-3508 GA Utrecht, Netherlands

[9] Univ Med Ctr Utrecht, Dept Cell Biol, NL-3508 GA Utrecht, Netherlands

来源：

CANCER CELL | 2011年 / 20卷 / 03期

关键词：

IN-VIVO; TUMOR ANGIOGENESIS; DRUG-RESISTANCE; BREAST-CANCER; LUNG-CANCER; GROWTH; MACROPHAGES; RECEPTORS; CARCINOMA; APOPTOSIS;

D O I：

10.1016/j.ccr.2011.08.010

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：370 / 383

页数：14

共 43 条

[1] IDENTIFICATION OF 12-KETO-5,8,10-HEPTADECATRIENOIC ACID AS AN ARACHIDONIC-ACID METABOLITE PRODUCED BY HUMAN HL-60 LEUKEMIA-CELLS [J].

AGINS, AP ;

THOMAS, MJ ;

EDMONDS, CG ;

MCCLOSKEY, JA .

BIOCHEMICAL PHARMACOLOGY, 1987, 36 (11) :1799-1805

[2] VEGF expression by mesenchymal stem cells contributes to angiogenesis in pancreatic carcinoma [J].

Beckermann, B. M. ;

Kallifatidis, G. ;

Groth, A. ;

Frommhold, D. ;

Apel, A. ;

Mattern, J. ;

Salnikov, A. V. ;

Moldenhauer, G. ;

Wagner, W. ;

Diehlmann, A. ;

Saffrich, R. ;

Schubert, M. ;

Ho, A. D. ;

Giese, N. ;

Buechler, M. W. ;

Friess, H. ;

Buechler, P. ;

Herr, I. .

BRITISH JOURNAL OF CANCER, 2008, 99 (04) :622-631

[3] Bone marrow-derived mesenchymal stem cells and the tumor microenvironment [J].

Bergfeld, Scott A. ;

DeClerck, Yves A. .

CANCER AND METASTASIS REVIEWS, 2010, 29 (02) :249-261

[4] Multi-targeted therapy of cancer by omega-3 fatty acids [J].

Berquin, Isabelle M. ;

Edwards, Iris J. ;

Chen, Yong Q. .

CANCER LETTERS, 2008, 269 (02) :363-377

[5] Paracrine Factors of Mesenchymal Stem Cells Recruit Macrophages and Endothelial Lineage Cells and Enhance Wound Healing [J].

Chen, Liwen ;

Tredget, Edward E. ;

Wu, Philip Y. G. ;

Wu, Yaojiong .

PLOS ONE, 2008, 3 (04)

[6] Mesenchymal stem cells: innovative therapeutic tools for rheumatic diseases [J].

Djouad, Farida ;

Bouffi, Carine ;

Ghannam, Soufiane ;

Noel, Daniele ;

Jorgensen, Christian .

NATURE REVIEWS RHEUMATOLOGY, 2009, 5 (07) :392-399

[7] A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer [J].

Farmer, Pierre ;

Bonnefoi, Herve ;

Anderle, Pascale ;

Cameron, David ;

Wirapati, Pratyakasha ;

Becette, Veronique ;

Andre, Sylvie ;

Piccart, Martine ;

Campone, Mario ;

Brain, Etienne ;

MacGrogan, Gaetan ;

Petit, Thierry ;

Jassem, Jacek ;

Bibeau, Frederic ;

Blot, Emmanuel ;

Bogaerts, Jan ;

Aguet, Michel ;

Bergh, Jonas ;

Iggo, Richard ;

Delorenzi, Mauro .

NATURE MEDICINE, 2009, 15 (01) :68-74

[8] Role of the tumor microenvironment in mediating de novo resistance to drugs and physiological mediators of cell death [J].

Hazlehurst, LA ;

Landowski, TH ;

Dalton, WS .

ONCOGENE, 2003, 22 (47) :7396-7402

[9] Purification of stearidonic acid (18:4(n-3)) and hexadecatetraenoic acid (16:4(n-3)) from algal fatty acid with lipase and medium pressure liquid chromatography [J].

Ishihara, K ;

Murata, M ;

Kaneniwa, M ;

Saito, H ;

Komatsu, W ;

Shinohara, K .

BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 2000, 64 (11) :2454-2457

[10] Role of bone marrow-derived cells in tumor angiogenesis and treatment [J].

Jain, RK ;

Duda, DG .

CANCER CELL, 2003, 3 (06) :515-516

← 1 2 3 4 5 →