title: Epithelial mesenchymal transition and pancreatic tumor initiating CD44+/EpCAM+ cells are inhibited by γ-secretase inhibitor IX.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis. Recent studies have indicated that the Notch signalling pathway is important in PDAC initiation and maintenance, although the specific cell biological roles of the pathway remain to be established. Here we sought to examine this question in established pancreatic cancer cell lines using the γ-secretase inhibitor IX (GSI IX) to inactivate Notch. Based on the known roles of Notch in development and stem cell biology, we focused on effects on epithelial mesenchymal transition (EMT) and on pancreatic tumor initiating CD44+/EpCAM+ cells. We analyzed the effect of the GSI IX on growth and epithelial plasticity of human pancreatic cancer cell lines, and on the tumorigenicity of pancreatic tumor initiating CD44+/EpCAM+ cells. Notably, apoptosis was induced after GSI IX treatment and EMT markers were selectively targeted. Furthermore, under GSI IX treatment, decline in the growth of pancreatic tumor initiating CD44+/EpCAM+ cells was observed in vitro and in a xenograft mouse model. This study demonstrates a central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to inhibit selectively EMT and suppress tumorigenesis by eliminating pancreatic tumor initiating CD44+/EpCAM+ cells.
authors.affiliation: Department of Internal Medicine I, Medical University Hospital, Tuebingen, Germany.
authors.forename: Vindhya
authors.initials: V
authors.lastname: Palagani
authors.forename: Mona
authors.initials: M
authors.lastname: El Khatib
authors.forename: Uta
authors.initials: U
authors.lastname: Kossatz
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Bozko
authors.forename: Martin R
authors.initials: MR
authors.lastname: Müller
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Till
authors.initials: T
authors.lastname: Krech
authors.forename: Nisar P
authors.initials: NP
authors.lastname: Malek
authors.forename: Ruben R
authors.initials: RR
authors.lastname: Plentz
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001681:Biological Assay; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism; D002452:Cell Count; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D000071858:Epithelial Cell Adhesion Molecule; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D005260:Female; D015870:Gene Expression; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; D004151:Dipeptides; C499379:EPCAM protein, human; D000071858:Epithelial Cell Adhesion Molecule; D018960:Hyaluronan Receptors; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D053829:Amyloid Precursor Protein Secretases