Article
The role of epithelial-mesenchymal transition in tumorigenesis of neuroendocrine pancreatic tumors
Search Medline for
Authors
-
Volker Fendrich
- Universitätsklinik Marburg, Klinik für Viszeral-, Thorax- und Gefäßchirurgie, Marburg
-
Jens Waldmann
- Universitätsklinik Marburg, Visceral-, Thorax- und Gefaesschirurgie, Marburg
-
Katja Maschuw
- Universitätsklinik Marburg, Visceral-Thorax- und Gefäßchirurgie, Marburg
-
Detlef Bartsch
- Universitätsklinik Marburg, Visceral-Thorax- und Gefäßchirurgie, Marburg
| Published: | May 20, 2011 |
|---|
Outline
Text
Introduction: The transcription factors Snail, Slug and Twist repress E-cadherin and induce epithelial-mesenchymal transition (EMT), a process also exploited by invasive cancer cells. In this study, we evaluated the role of EMT in the tumorgenesis of neuroendocrine tumors of the pancreas (NPTs) in vitro, in vivo and in resected human tumor specimen.
Materials and methods: Expression of Snail, Twist and E-Cadherin was analyzed using immunohistochemistry and real-time PCR.
For in vitro studies, pancreatic carcinoid BON-1 cells were analyzed regarding expression of EMT markers before and after transfection with siRNA against Slug or Snail. To determine the cell-cell adhesion capacity, cell aggregation assays were performed. Finally for luciferase reporter assay BON-1 cells were cotransfected with constructs containing fragments of the E-cadherin promoter, siRNA against Slug or control siRNA.
To asses in vivo effects, trasngenic Rip1Tag2 mice who develop islet cell tumors were treated with vehicle or the snail-inhibitor polythlylenglykol from week 5-10 of age. The resected pancreata were evaluated by weight, tumor surface, tumor cell proliferation and apoptosis.
Results: Using immunohistochemistry, we found expression of Snail in 58/95 (61 %) and of Twist in 61/95 (64%) human NPT samples, but not in adjacent normal tissues. This expression was associated with a reduced expression of E-cadherin. In BON-1 cells RT-PCR also revealed conservation of the EMT markers Slug and Snail. Transfection with siRNA against Slug was associated with an upregulation of E-cadherin, an enhanced cell-cell adhesion and inhibition of cell proliferation and migration. Snail-inhibition in vivo was confirmed by downregulation in RT-PCR and was associated with increased apoptosis, decreased tumor cell proliferation and reduced tumor volume in transgenic Rip1Tag2 mice.
Conclusion: This is the first study to show that EMT plays a significant role in tumorgenesis of NPTs. Activation of EMT markers in human NPT samples and inhibition of Snail in vivo may lead to a new therapeutic approach.
