Highlights
- •Metformin reduces self-renewal gastric cancer stem cells (CSCs) capacities.
- •Metformin decreases the pool of gastric CSCs.
- •Metformin is able to induce differentiation of gastric CSCs.
Abstract
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.
Keywords
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Article info
Publication history
Published online: August 17, 2017
Accepted:
July 18,
2017
Received in revised form:
July 14,
2017
Received:
April 26,
2017
Identification
Copyright
© 2017 Elsevier Ltd. All rights reserved.
