Z Gastroenterol 2012; 50 - K116
DOI: 10.1055/s-0032-1324051

Inhibition of Notch signaling attenuates epithelial mesenchymal transition and pancreatic tumor initiating CD44+/EpCAM+ cells

V Palagani 1, M El Khatib 1, U Kossatz 1, B Przemyslaw 1, M Müller 2, M Manns 3, T Krech 4, N Malek 1, R Plentz 1
  • 1Medizinische Universitätsklinik Tübingen, Gastroenterologie, Hepatologie und Infektiologie, Tübingen, Germany
  • 2Medizinische Universitätsklinik Tübingen, Hämatologie und Onkologie, Tübingen, Germany
  • 3Medizinische Hochschule Hannover, Gastroenterologie, Hepatologie und Endokrinologie, Hannover, Germany
  • 4Medizinische Hochschule Hannover, Pathologie, Hannover, Germany

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a high rate of metastasis and limited treatment options. The Notch pathway has recently emerged as a candidate drug target. Notch signalling is important in PDAC initiation and maintenance. A number of subpopulations within PDAC have been shown to have tumor initiating or cancer stem cells (CSC) properties. This provides a rationale for further analysis of Notch signalling in PDAC carcinogenesis and to treat pancreatic CSC.

Aims: Based on the known roles of Notch in development and stem cell biology, we investigated the effects of gamma-secretase-inhibitor (GSI IX) on epithelial mesenchymal transition (EMT) and on pancreatic tumor initiating CD44+/EpCAM+ cells.

Methods: 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. In addition, sorted CD44+/EpCAM+ cells were subcutaneously injected into nude mice (NMRI-nu/nu) and treated with vehicle or with GSI IX. The effect of GSI on Xenograft tumors, EMT markers, and cell proliferation was evaluated.

Results: GSI IX inhibited pancreatic cancer cell proliferation, migration and invasion in a dose-dependent manner. Apoptosis was induced after GSI IX treatment and EMT markers partially reversed. Finally, GSI IX significantly inhibited the growth of pancreatic tumor initiating CD44+/EpCAM+ cells in vitro and in a xenograft mouse model.

Conclusion: Our data support the central role of Notch signalling pathway in pancreatic cancer pathogenesis and identifies an effective approach to attenuate EMT and suppress tumorigenesis by eliminating pancreatic tumor initiating CD44+/EpCAM+ cells.