Journal
STEM CELLS TRANSLATIONAL MEDICINE
Volume 6, Issue 3, Pages 819-829Publisher
OXFORD UNIV PRESS
DOI: 10.1002/sctm.16-0335
Keywords
Cancer stem cells; CD44; Gastric cancer; Gamma-secretase inhibitor IX; Notch; wnt-beta-catenin
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Funding
- Deutsche Krebshilfe [110870]
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Cancer stem cells (CSC) are associated with tumor resistance and are characterized in gastric cancer (GC). Studies have indicated that Notch and wnt-beta-catenin pathways are crucial for CSC development. Using CD44(+) CSCs, we investigated the role of these pathways in GC carcinogenesis. We performed cell proliferation, wound healing, invasion, tumorsphere, and apoptosis assays. Immunoblot analysis of downstream signaling targets of Notch and wnt-beta-catenin were tested after gammasecretase inhibitor IX (GSI) treatment. Immunohistochemistry, immunofluorescence, and Fluorescence activated cell sorting (FACS) were used to determine CD44 and Hairy enhancer of split-1 (Hes1) expression in human GC tissues. CD44(+) CSCs were subcutaneously injected into NMR-nu/nu mice and treated with vehicle or GSI. GC patients with expression of CD44 and Hes1 showed overall reduced survival. CD44(+) CSCs showed high expression of Hes1. GSI treatment showed effective inhibition of cell proliferation, migration, invasion, tumor sphere formation of CD44(+) CSCs, and induced apoptosis. Importanly, Notch1 was found to be important in mediating a crosstalk between Notch and wnt-betacatenin in CD44(+) CSCs. Our study highlights a crosstalk between Notch and wnt-beta-catenin in gastric CD44(+) CSCs. Expression of CD44 and Hes1 is associated with patient overall survival. GSI could be an alternative drug to treat GC. (C) STEM CELLS TRANSLATIONAL MEDICINE
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