Pancreatic Cancer: Translating Lessons from Mouse Models and Hereditary Syndromes

Abstract

Pancreatic ductal adenocarcinoma is the overwhelmingly predominant form of pancreatic cancer and the second most common type of gastrointestinal cancer (behind colorectal cancer) in the United States. Recent exciting advances in two areas of pancreatic ductal adenocarcinoma (i.e., the development and characterization of genetically engineered mouse models and the dissection of the genetic basis of hereditary forms in families) have been illuminating. These preclinical models and clinical syndromes provide the first tangible basis for progress in screening and prevention in high-risk populations and in the development of molecular diagnostics and experimental therapeutics.Gastrointestinal cancers comprise a wide spectrum of tumors. Their diversity is highlighted further by their variable incidences and mortality rates. Historically, colorectal cancer has served as the paradigm for our understanding of the genetics of cancers. This has proven extremely helpful in the development and characterization of mouse models, dissecting hereditary syndromes, identifying novel diagnostic strategies, implementation of chemopreventive strategies, and integrating biologics into conventional therapy. Only in recent years has increased attention been applied to pancreatic cancer, the second most common type of gastrointestinal cancer in the United States. Yet, a typical discussion surrounding pancreatic cancer turns to one of pessimism; however, we would advocate that biomedical research and clinical medicine underlying pancreatic cancer emulate the pathways of historic progress in colorectal cancer. The purpose of this commentary is to provide an overview of the very exciting developments in hereditary syndromes and in preclinical models, and that we are at the cusp of translating this knowledge into better strategies for screening, diagnosis, and therapy of pancreatic cancer. We cannot be exhaustive in each of these strategies but will highlight how knowledge about hereditary pancreatic cancer can be used to screen for this disease in high-risk patients and how preclinical models can be interrogated for the development of new diagnostics and therapeutics. These approaches have the opportunity to improve our understanding and management of patients with sporadic pancreatic cancer.Pancreatic cancers comprise a variety of malignancies, including the preponderant form, pancreatic ductal adenocarcinoma (PDAC), and islet cell tumors (part of a class of neuroendocrine tumors), rare acinar cell tumors, mucinous neoplasms (divided further into mucinous cystic neoplasms and intraductal papillary mucinous neoplasms), lymphoma, and sarcoma. There are approximately 37,000 new cases of PDAC each year in the United States, with an increasing annual incidence in African-Americans. Median survival for PDAC is 6 months, and 5-year survival is <5%. When PDAC is identified in its early stage, 5-year survival approaches 20%. Yet, most PDAC cases present at late stages, when therapies are limited. These staggering data spawned attention on P...

Effects of a Non Thermal Plasma Treatment Alone or in Combination with Gemcitabine in a MIA PaCa2-luc Orthotopic Pancreatic Carcinoma Model

“…Tumor of the exocrine pancreas mainly ductal adenocarcinoma, the most common form of pancreatic cancer [7], is rarely curable and has an overall survival rate of less than 5%. Moreover, chemotherapy and radiotherapy are ineffective in most cases, so new therapeutic approaches and in vivo models offering high predictivity for translational research are necessary.…”

“…In human, the most common pancreatic cancer is ductal adenocarcinoma [7], developing within the exocrine part of the pancreas and characterized by a severe tumor hypoxia [8] inducing a resistance against chemo- and radiation therapies [9]. In this goal, among other pancreatic tumor cell lines, the MIA PaCa2 cell line appeared quite relevant for a preclinical approach.…”

KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma

“…Although some (~2–10%) PDACs seem to be associated with hereditary factors 5,6 , most are associated with high-frequency somatic mutations in a subset of genes, including those that encode the small GTPase protein KRAS 7 , and the tumour suppressors INK4A 8 , p53 (REFS 9,10) and SMAD4 (REF. 11).…”

Binding of pro-prion to filamin A: by design or an unfortunate blunder

“…On the other hand, about half of the PDAC cases have mutations in TP53 or DPC4 (Hezel et al ., 2006; Shi et al ., 2008). The contribution of these genes to human PDAC development is supported by transgenic animal studies, which show that involvement by more than one of these genes is essential for the initiation and progression of PDAC (Hezel et al ., 2006; Hruban et al ., 2006; Wescott and Rustgi, 2008; Ottenhof et al ., 2009). In addition, other growth factor genes, signal transducing molecules, transcription factors, as well as cell adhesion molecules are also implicated in the progression of human PDAC.…”