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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy*
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Adenocarcinoma / genetics
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Adenocarcinoma / metabolism
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Adenocarcinoma / pathology
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Amyloid Precursor Protein Secretases / antagonists & inhibitors*
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Amyloid Precursor Protein Secretases / genetics
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Amyloid Precursor Protein Secretases / metabolism
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Animals
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Antigens, Neoplasm / genetics
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Antigens, Neoplasm / metabolism
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Apoptosis / drug effects
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Biological Assay
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Cell Adhesion Molecules / genetics
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Cell Adhesion Molecules / metabolism
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Cell Count
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Cell Line, Tumor
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Cell Movement / drug effects
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Dipeptides / pharmacology*
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Dipeptides / therapeutic use
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Dose-Response Relationship, Drug
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Epithelial Cell Adhesion Molecule
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Epithelial-Mesenchymal Transition / drug effects*
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Female
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Gene Expression
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Humans
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Hyaluronan Receptors / genetics
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Hyaluronan Receptors / metabolism
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Mice
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Mice, Nude
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Neoplasms, Experimental
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Neoplastic Stem Cells / drug effects*
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology
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Pancreatic Neoplasms / drug therapy*
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Pancreatic Neoplasms / genetics
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology
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Wound Healing / drug effects
Substances
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Antigens, Neoplasm
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Cell Adhesion Molecules
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Dipeptides
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EPCAM protein, human
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Epithelial Cell Adhesion Molecule
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Hyaluronan Receptors
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N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester
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Amyloid Precursor Protein Secretases
Grants and funding
The work was supported by Deutsche Forschungsgemeinschaft (DFG PL 468/4-1) and TUI Stiftung (TUI AZ68/09).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.