Metformin targets gastric cancer stem cells

被引:68
作者
Courtois, Sarah [1 ]
Duran, Raul V. [2 ,3 ,4 ]
Giraud, Julie [1 ]
Sifre, Elodie [1 ]
Izotte, Julien [1 ,5 ]
Megraud, Francis [1 ,6 ]
Lehours, Philippe [1 ,6 ]
Varon, Christine [1 ]
Bessede, Emilie [1 ,6 ]
机构
[1] Univ Bordeaux, Bordeaux Res Translat Oncol UMR1053, INSERM, BaRITOn, F-33000 Bordeaux, France
[2] Inst Europeen Chim & Biol, 2 Rue Robert Escarpit, F-33607 Pessac, France
[3] INSERM, U1218, Inst Bergonie, 229 Cours Argonne, F-33076 Bordeaux, France
[4] Univ Bordeaux, 146 Rue Leo Saignat, F-33076 Bordeaux, France
[5] Univ Bordeaux, Anim Facil, 146 Rue Leo Saignat, F-33076 Bordeaux, France
[6] CHU Bordeaux, Lab Bacteriol, Pl Amelie Raba Leon, F-33076 Bordeaux, France
关键词
Gastric carcinoma; CD44; Primary tumour; Xenograft; Self-renewal; Tumourspheres; DIABETIC-PATIENTS; TUMOR-GROWTH; MARKER CD44; METAANALYSIS; EXPRESSION; CARCINOMA; PROLIFERATION; RISK; KLF4;
D O I
10.1016/j.ejca.2017.07.020
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Gastric cancer is the third leading cause of cancer-related deaths worldwide and has still a poor prognosis. Therefore, new therapeutic strategies are needed: among them, targeting cancer stem cells (CSCs) could offer new opportunities. The aim of our study was to evaluate the anti-tumoural effect of metformin on gastric cancer in vitro and in vivo and especially, to determine whether this molecule could target the gastric CSCs. Metformin effects were evaluated on the proliferation and tumourigenic properties of the gastric CSCs from patient-derived primary tumour xenografts (PDXs) and cancer cell lines (MKN45, AGS and MKN74) in vitro in conventional 2 dimensional (2D) and in 3 dimensional (3D) culture systems, in which only CSCs are able to form tumourspheres and in mouse xenograft models in vivo. Metformin induced a cell cycle arrest, which decreased cell proliferation in the 2D cultures. In a 3D culture system, metformin decreased the number of tumourspheres, revealing its capacity to target the CSCs. This effect was confirmed by the study of the expression of CSC markers (CD44 and Sox2) and differentiation markers (Kruppel-like factor 4 and MUC5AC), which were decreased or increased in response to metformin, respectively. Finally, in vivo treatment of PDXs with metformin led to a tumour growth delay and decreased the self-renewal ability of the CSCs. These results suggest that the use of metformin could represent an efficient strategy to inhibit tumour growth by targeting gastric CSCs. (C) 2017 Elsevier Ltd. All rights reserved.
引用
收藏
页码:193 / 201
页数:9
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