Modeling Pancreatic Cancer In Vivo

Abstract

In the last 10 years, there has been a relative explosion of new rodent systems that recapitulate both genetic and cellular lesions that lead to the development of pancreatic cancer. These models now need to be considered when selecting an appropriate in vivo system to study disease etiology, cell signaling, and drug development. The majority of these evaluations have used transplantation of cancer cells and the use of carcinogens, which still maintain their value when investigating human cancer and epigenetic contributors. Xenograft models utilize cultured or primary pancreatic cancer cells that are placed under the skin or implanted within the pancreas of immunocompromised mice. Carcinogen-induced systems rely on administration of certain chemicals to generate cellular changes that rapidly lead to pancreatic cancer. Genetically modified mice are more advanced in their design in that relevant genetic mutations can be inserted into mouse genomic DNA in both a conditional and inducible manner. Generation of mice that develop spontaneous pancreatic cancer from a targeted genetic mutation is a valuable research tool, considering the broad spectrum of genes and cell targets that can be used, producing a variety of neoplastic lesions and cancer that can reflect many aspects of human pancreatic ductal adenocarcinoma.

Pancreatic Cancer Chemoprevention Translational Workshop

“…Molecular pathobiology has provided a compendium of genetic lesions, often implicating aberrant molecular changes at genetic, transcriptomic, epigenetic, and proteomic levels that correlate with histological progression from normal to non-invasive precursor to invasive carcinoma 77–81 . This has led to the development of several complex genetically engineered mouse models (GEMMs) of pancreatic cancer that recapitulate key aspects of human pancreatic cancer development, including the development of precursor lesions in the pancreatic ducts.…”

“…Newer models such as the ELA-CreERT/CAG-lox- KRAS G12v , Mist1- KRAS , and LSL- KRAS G12D/p /DPC4 flox/p mice have been engineered that mimic human IPMN and MCN 85,86 . Thus, pancreatic GEMMs represent all the morphological spectrum of pancreatic cancer precursor lesions, as well as the histopathology of precursor lesion progression and its association with inflammation and desmoplasia 77,81,86,87 .…”

Relevance of Animal Models of Pancreatic Cancer and Pancreatitis to Human Disease

“…5 The generation of these models essentially involves targeting a variety of genes to a range of cell targets (including ductal cells and acinar cells) in the pancreas to produce an array of neoplastic changes. 6 Animals expressing mutant Kras in the pancreas develop a spectrum of preneoplastic changes in the form of pancreatic intraepithelial neoplasia. 7 Targeting additional somatic alterations including inactivation of p16/CDKN2A, 8 TP53, 9 and transforming growth factor- β pathway components such as DPC4/SMAD4 10 in the background of mutant Kras leads to the development of tumors that recapitulate the full spectrum of pancreatic tumor development including invasive cancer, locoregional spread, and metastatic disease.…”

Deploying Mouse Models of Pancreatic Cancer for Chemoprevention Studies

“…These models are now available to investigate the basic and translational aspects of this malignancy (4, 5). Models of neoplasms such as murine pancreatic intraepithelial neoplasia (mPanIN), intraductal papillary mucinous neoplasia (mIPMN), and mucinous cystic neoplasia (mMCN) have all been described (though mIPMN and mMCN should be further characterized for a more-complete validation).…”