Einfluss des Transkriptionsfaktors Snail in der Initiation und Progression von PanINs beim invasiven duktalen Pankreaskarzinom im transgenen Tumormausmodell

Das duktale Adenokarzinom des Pankreas rangiert in Deutschland an vierter Stelle der Krebstodesursachen. Die relative Fünf-Jahres-Überlebensrate liegt bei nur 8%. Ursächlich für die schlechte Prognose sind zum einen die späte Diagnosestellung aufgrund fehlender Früherkennungsmaßnahme und die aggress...

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Bibliographic Details
Main Author: Jendryschek, Frederike Sophia
Contributors: Fendrich, Volker (Prof. Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2016
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Adenocarcinoma of the pancreas is the fourth leading cause of cancer related deaths in Germany. The five-year survival is still less than 8% and the number of annual incidence and mortality are almost identical. Studies have shown that the EMT regulatory protein Snail is overexpressed in pancreatic cancer cells which correlates with invasiveness and metastatic ability. Snail is a transcription factor which works as a direct repressor of E-Cadherin. Aim of this study was to compare homozygous and heterozygous Snaildel1;Pdx-1-Cre;LSL-KrasG12D/+-mice with Pdx-1-Cre;LSL-KrasG12D/+-mice in order to draw conclusions about the influence of Snail in initiation and progression of PanINs. Mouse strains of Pdx-1-Cre;LSL-KrasG12D/+- and Snail-/- were crossed to generate homozygous and heterozygous Snaildel1;Pdx-1-Cre;LSL-KrasG12D/+-Mice. Groups of those mice were observed and sacrificed at a defined age. The pancreas was harvested for further histopathological analyses, immunostaining and real-time PCR. Quantification of PanINs showed delayed initiation and progression of PanIN lesions at all ages in both homozygous and heterozygous Snaildel1;Pdx-1-Cre;LSL-KrasG12D/+-Mice. Invasive carcinoma was not observed. Using real-time PCR we found a significant downregulation of Sox9, Snail1 and Twist1. E-Cadherin expression was also analysed using qRT-PCR and immunostaining. Immunostaining showed higher expression of E-Cadherin in Snaildel1;Pdx-1-Cre;LSL-KrasG12D/+-mice. In qRT-PCR we found heterogenic results, presenting a lower expression in 5 of 6 Snail-Knock-Out mice. This study provides in vivo evidence that progression of pancreatic intraepithelial neoplasias is dramatically delayed under genetic abrogation of snail. Further studies will need to examine the clinical relevance of those results. Especially Snail1 as a biomarker or therapeutic target should be analysed.