Gamma‐Secretase Inhibitor IX (GSI) Impairs Concomitant Activation of Notch and Wnt‐Beta‐Catenin Pathways in CD44(+) Gastric Cancer Stem Cells

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 gamma‐secretase 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‐beta‐catenin 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. Stem Cells Translational Medicine 2017;6:819–829