Notch Signaling Pathway in Pancreatobiliary Tumors.

Francesca Borlak,Julia Gogolok,Ellen Von Hoerschelmann,Rosa B Schmuck,Anja Schirmeier,Johann Pratschke,Igor M Sauer,Marcus Bahra,Anja Reutzel-Selke

doi:10.3390/medicina57020105

Abstract

Background and Objectives: The Notch signaling pathway plays an important role both in the development of the ductal systems of the pancreas and the bile ducts as well as in cancer development and progression. The aim of this study was to examine the expression of central proteins of the Notch signaling pathway in pancreatobiliary tumors and its influence on patient survival. Materials and Methods: We compared the receptors (Notch1, Notch4), activating splicing factors (ADAM17), and target genes (HES1) of the Notch pathway and progenitor cell markers with relevance for the Notch signaling pathway (CD44, MSI1) between pancreatic adenocarcinomas (PDAC, n = 14), intrahepatic cholangiocarcinoma (iCC, n = 24), and extrahepatic cholangiocarcinoma (eCC, n = 22) cholangiocarcinomas via immunohistochemistry and ImageJ software-assisted analysis. An Immunohistochemistry (IHC)-score was determined by the percentage and intensity of stained (positive) cells (scale 0–7) and normal and malignant tissue was compared. In the IHC results, patients’ (gender, age) and tumor (TNM Classification of Malignant Tumors, Union Internationale contre le Cancer (UICC) stages, grading, and lymphangitic carcinomatosa) characteristics were correlated to patient survival. Results: For eCC, the expression of CD44 (p = 0.043, IHC-score 3.94 vs. 3.54) and for iCC, the expression of CD44 (p = 0.026, IHC-score 4.04 vs. 3.48) and Notch1 (p < 0.001, IHC-score 2.87 vs. 1.78) was significantly higher in the tumor compared to non-malignant tissue. For PDAC, the expression of ADAM17 (p = 0.008, IHC-score 3.43 vs. 1.73), CD44 (p = 0.012, IHC-score 3.64 vs. 2.27), Notch1 (p = 0.012, IHC-score 2.21 vs. 0.64), and Notch4 (p = 0.008, IHC-score 2.86 vs. 0.91) was significantly higher in the tumor tissue. However, none of the analyzed Notch-signaling related components showed an association to patient survival. Conclusion: A significant overexpression of almost all studied components of the Notch signaling pathway can be found in the tumor tissue, however, without a significant influence on patient survival. Therefore, further studies are warranted to draw conclusions on Notch pathway’s relevance for patient survival.

Highlights

CCs are subclassified into intrahepatic cholangiocarcinoma and extrahepatic cholangiocarcinoma, the latter comprising hilar and distal cholangiocarcinomas [2]
A total of 60 patients were included in the study: 14 suffering from Pancreatic ductal adenocarcinoma (PDAC), 22 from extrahepatic cholangiocarcinoma (eCC), and 24 from intrahepatic cholangiocarcinoma (iCC)
Patients were compared in terms of gender, age, survival, and Union Internationale contre le Cancer (UICC) stage

Summary

Introduction

PDAC and CC both share clinical and molecular features, especially tumors of the pancreatic head and dCCs are often difficult to distinguish [3,4] Both tumor entities reside in the ductal system of the pancreas or bile ducts respectively. Those ductal structures arise from the ventral foregut over the course of embryological development [5] During this development, as well as in adult tissue maintenance, the Notch signaling pathway plays a pivotal role [6]. Materials and Methods: We compared the receptors (Notch, Notch4), activating splicing factors (ADAM17), and target genes (HES1) of the Notch pathway and progenitor cell markers with relevance for the Notch signaling pathway (CD44, MSI1) between pancreatic adenocarcinomas (PDAC, n = 14), intrahepatic cholangiocarcinoma (iCC, n = 24), and extrahepatic cholangiocarcinoma (eCC, n = 22) cholangiocarcinomas via immunohistochemistry and ImageJ software-assisted analysis.

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Discussion

Conclusion