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World J Gastroenterol. Jun 28, 2014; 20(24): 7830-7848
Published online Jun 28, 2014. doi: 10.3748/wjg.v20.i24.7830
Epigenetics and pancreatic cancer: Pathophysiology and novel treatment aspects
Daniel Neureiter, Tarkan Jäger, Matthias Ocker, Tobias Kiesslich
Daniel Neureiter, Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
Tarkan Jäger, Department of Surgery, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
Matthias Ocker, Experimental Medicine Oncology, Bayer Pharma AG, 13342 Berlin, Germany
Tobias Kiesslich, Department of Internal Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), 5020 Salzburg, Austria
Tobias Kiesslich, Institute of Physiology and Pathophysiology, Paracelsus Medical University, 5020 Salzburg, Austria
Author contributions: All authors contributed equally in literature retrieval and evaluation, design and drafting of the manuscript.
Correspondence to: Daniel Neureiter, MD, MA, Institute of Pathology, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Muellner Hauptstrasse 48, 5020 Salzburg, Austria. d.neureiter@salk.at
Telephone: +43-662-44824737 Fax: +43-662-4482882
Received: November 28, 2013
Revised: February 7, 2014
Accepted: March 12, 2014
Published online: June 28, 2014
Abstract

An improvement in pancreatic cancer treatment represents an urgent medical goal. Late diagnosis and high intrinsic resistance to conventional chemotherapy has led to a dismal overall prognosis that has remained unchanged during the past decades. Increasing knowledge about the molecular pathogenesis of the disease has shown that genetic alterations, such as mutations of K-ras, and especially epigenetic dysregulation of tumor-associated genes, such as silencing of the tumor suppressor p16ink4a, are hallmarks of pancreatic cancer. Here, we describe genes that are commonly affected by epigenetic dysregulation in pancreatic cancer via DNA methylation, histone acetylation or miRNA (microRNA) expression, and review the implications on pancreatic cancer biology such as epithelial-mesenchymal transition, morphological pattern formation, or cancer stem cell regulation during carcinogenesis from PanIN (pancreatic intraepithelial lesions) to invasive cancer and resistance development. Epigenetic drugs, such as DNA methyltransferases or histone deactylase inhibitors, have shown promising preclinical results in pancreatic cancer and are currently in early phases of clinical development. Combinations of epigenetic drugs with established cytotoxic drugs or targeted therapies are promising approaches to improve the poor response and survival rate of pancreatic cancer patients.

Keywords: Pancreatic cancer, Epigenetics, DNA methylation, Histone modification, microRNA, Targeted therapy, Epithelial-mesenchymal transition

Core tip: Pancreatic cancer represents a devastating disease with poor overall survival at advanced stages, and new and effective treatment options are required. Besides genetic mutations, epigenetic dysregulation of oncogenes and tumor suppressor genes is recognized as a novel therapeutic target. Mechanisms underlying DNA methylation, histone acetylation and microRNA regulation and their contribution to pancreatic cancer development and resistance to treatment are highlighted in this review. Potential therapeutic interventions are discussed.