Role of Epithelial-Mesenchymal Transition in Pancreatic Ductal Adenocarcinoma: Is Tumor Budding the Missing Link?

Eva Karamitopoulou

doi:10.3389/fonc.2013.00221

Abstract

Pancreatic ductal adenocarcinoma (PDAC) ranks as the fourth commonest cause of cancer death while its incidence is increasing worldwide. For all stages, survival at 5 years is<5%. The lethal nature of pancreatic cancer is attributed to its high metastatic potential to the lymphatic system and distant organs. Lack of effective therapeutic options contributes to the high mortality rates of PDAC. Recent evidence suggests that epithelial-mesenchymal transition (EMT) plays an important role to the disease progression and development of drug resistance in PDAC. Tumor budding is thought to reflect the process of EMT which allows neoplastic epithelial cells to acquire a mesenchymal phenotype thus increasing their capacity for migration and invasion and help them become resistant to apoptotic signals. In a recent study by our own group the presence and prognostic significance of tumor budding in PDAC were investigated and an association between high-grade budding and aggressive clinicopathological features of the tumors as well as worse outcome of the patients was found. The identification of EMT phenotypic targets may help identifying new molecules so that future therapeutic strategies directed specifically against them could potentially have an impact on drug resistance and invasiveness and hence improve the prognosis of PDAC patients. The aim of this short review is to present an insight on the morphological and molecular aspects of EMT and on the factors that are involved in the induction of EMT in PDAC.

Highlights

PANCREATIC CANCER Pancreatic ductal adenocarcinoma (PDAC) is a common cancer with dismal prognosis [1] that escapes early detection and resists treatment [2]
Many molecular processes are involved in the initiation of epithelial-mesenchymal transition (EMT) including activation of transcription factors, expression of specific cell-surface proteins, reorganization and expression of cytoskeletal proteins, production of extracellular matrix (ECM)-degrading enzymes, and changes in the expression of specific microRNAs
Zeb1 expression in PDAC correlated with advanced tumor grade and worse outcomes [14,15,16] and was shown to be primarily responsible for the acquisition of an EMT phenotype, along with increased migration and invasion in response to NF-κB signaling in pancreatic cancer cells [16]

Summary

Introduction

PANCREATIC CANCER Pancreatic ductal adenocarcinoma (PDAC) is a common cancer with dismal prognosis [1] that escapes early detection and resists treatment [2]. The zinc finger transcription factors Snail, Slug, Zeb1, and Twist repress genes responsible for the epithelial phenotype and represent important regulators of EMT [6, 7, 12].

Results

Conclusion