Abstract
Pancreatic ductal adenocarcinoma (PDA) is the most common cancer of the exocrine pancreas and probably the tumor that has benefited the least from clinical progress in the last three decades. A consensus has been reached regarding the histologic classification of the ductal preneoplastic lesions (pancreatic intra-epithelial neoplasia—PanIN) and the molecular alterations associated with them. Mutations in KRAS and inactivation of CDKN2A, SMAD4 and TP53 are among the most prevalent alterations. Next generation sequencing studies are providing a broad picture of the enormous heterogeneity in this tumor type, describing new mutations less prevalent. These studies have also allowed the characterization of different subtypes with prognostic value. However, all this knowledge has not been translated into a clinical progress. Effective preventive and early diagnostic strategies are essential to improve the survival rates. The main challenge is, indeed, to identify new effective drugs. Despite many years of research and its limited success, gemcitabine is still the first line treatment of PDA. New drug combinations and new concepts to improve drug delivery into the tumor, as well as the development of preclinical predictive assays, are being explored and provide optimism and prospects for better therapies.
Highlights
Pancreatic cancer development shows a strong association with the consumption of tobacco in cigarettes, which increases the risk of contracting the disease by two or three times
It is assumed that the cell origin of Pancreatic ductal adenocarcinoma (PDA) is the ductal cell, which progresses from limited forms of neoplasia, such as pancreatic intra-epithelial neoplasia (PanIN), intraductal papillary mucinous neoplasia (IPMN) and cystic mucinous neoplasia (MCN), to an infiltrating carcinoma
Oncogenes and tumor suppressors are altered in PDA, and recent next generation sequencing (NGS) studies have shown the enormous complexity in the number of molecular alterations present in the PDA that range from somatic mutations
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. Pancreatic cancer development shows a strong association with the consumption of tobacco in cigarettes, which increases the risk of contracting the disease by two or three times. It is assumed that the cell origin of PDA is the ductal cell, which progresses from limited forms of neoplasia, such as pancreatic intra-epithelial neoplasia (PanIN), intraductal papillary mucinous neoplasia (IPMN) and cystic mucinous neoplasia (MCN), to an infiltrating carcinoma. Experiments in mouse models have shown that the acinar cell can be a precursor for PDA development [5] In this regard, inflammatory processes, such as pancreatitis, induce acinar cell dedifferentiation and subsequently trans-differentiation into a “ductal-like” cell, through a process known acinar to ductal metaplasia (ADM). Intraductal papillary mucinous neoplasm (IPMN) maintains the majority of alterations associated with PDA except SMAD4 losses and differentially presents mutations in PIK3CA, GNAS and RNF43 [7]. This better classification will undoubtedly help the best management of this type of tumor, adjusting it to the needs of each patient
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