title: Gamma-Secretase Inhibitor IX (GSI) Impairs Concomitant Activation of Notch and Wnt-Beta-Catenin Pathways in CD44+Gastric Cancer Stem Cells.
abstract: 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.
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Samarpita
authors.initials: S
authors.lastname: Barat
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Khac
authors.initials: K
authors.lastname: Cuong Bui
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Bozko
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Julian
authors.initials: J
authors.lastname: Götze
authors.affiliation: Institute of Pathology, Medical School Hannover, Hannover, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Christgen
authors.affiliation: Institute of Pathology, Universitötsklinik Hamburg Eppendorf, Hamburg, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Krech
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tübingen, Germany.
authors.forename: Ruben R
authors.initials: RR
authors.lastname: Plentz
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051880:Receptors, Notch / Q000378:metabolism*; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013274:Stomach Neoplasms / Q000473:pathology*; D016019:Survival Analysis; D000072056:Transcription Factor HES-1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C497483:CD44 protein, human; D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; C078493:HES1 protein, human; D053829:Amyloid Precursor Protein Secretases
keywords: CD44; Cancer stem cells; Gamma-secretase inhibitor IX; Gastric cancer; Notch; wnt-beta-catenin