Epithelial Mesenchymal Transition and Pancreatic Tumor Initiating CD44 -EpCAM Cells Are Inhibited by γ-Secretase Inhibitor IXReport as inadecuate




Epithelial Mesenchymal Transition and Pancreatic Tumor Initiating CD44 -EpCAM Cells Are Inhibited by γ-Secretase Inhibitor IX - Download this document for free, or read online. Document in PDF available to download.

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.



Author: Vindhya Palagani, Mona El Khatib, Uta Kossatz, Przemyslaw Bozko, Martin R. Müller, Michael P. Manns, Till Krech, Nisar P. Malek,

Source: http://plos.srce.hr/



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