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

被引：277

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

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