Characterization of the Stem Cell Fraction in Pancreatobiliary Carcinomas: The Notch Signaling Pathway as a Potential Therapeutic Target

Elisabeth Seidel,Christopher Neumann,Joseph Gassner,Johann Pratschke,Julia Gogolok,Igor M Sauer,Andreas Andreou,Anja Schirmeier,Cynthia De Carvalho Fischer,Anja Reutzel-Selke,Marcus Bahra,Rosa B Schmuck,Fritz Klein,Peter Tang

doi:10.4236/jct.2018.96040

Abstract

Pancreatic adenocarcinoma (PDAC) and extrahepatic cholangiocarcinoma (ECC) are highly lethal malignancies with limited treatment options. Both a small subpopulation of cancer stem cells (CSC) and the deregulation of the notch pathway have been considered potential sources of tumor formation. In this study, flow cytometry (FCM) was conducted to identify the CSC population and Notch-associated proteins in ECC and PDAC cell lines. Additionally, the treatment effect of Gemcitabine and the specific notch-inhibitor DAPT on ECC and PDAC cell lines was evaluated. Our results show that the amount of SP cells in ECC cell lines is significantly higher than in PDAC cell lines, and that SP-ECC cells show a higher sensitivity to therapy. In conclusion, inhibition of Notch signaling with DAPT may be of therapeutic value in ECC, but seems to show no effect on more aggressive PDAC. As it could be essential for the improvement in outcomes of the ECC patients, other trials are needed to determine the role of further Notch components.

Highlights

Our results show that the amount of Side Population (SP) cells in extrahepatic cholangiocarcinoma (ECC) cell lines is significantly higher than in Pancreatic adenocarcinoma (PDAC) cell lines, and that SP-ECC cells show a higher sensitivity to therapy
To investigate whether cancer stem cells (CSC) are present in PDAC and ECC cell lines, side population (SP) sorting via flow cytometry was performed
Based on the observation that SP cells do exist in ECC and PDAC cell lines, we investigated the activation of the Notch pathway in this subpopulation

Summary

Introduction

Distal cholangiocarcinoma (dCC) is a subtype of extrahepatic cholangiocarcinoma, which develops from the distal bile duct. The differentiation of this neoplastic entity from ductal adenocarcinomas arising from the head of pancreas is complex, due to their anatomical proximity and their overlapping histopathological and morphological appearance [5]. For both entities, the only curative therapy remains radical surgical resection [2] [3]. Life expectancy could be improved with those therapeutic approaches, in light of the poor prognosis of these cancer types, as well as the lack of curative success that has been achieved through the use of conventional chemotherapeutics, it is necessary to focus on the development of new treatment targets and regimens for these neoplasms

Objectives

Results

Conclusion