Genetically Engineered Mouse Models For Human Pancreatic Cancer: A Review Of The KC, KPC And iKRas*P53* Models
Abstract
Pancreatic cancer is almost always a ductal adenocarcinoma of the exocrine pancreas, called pancreatic ductal adenocarcinoma (PDAC). Over 80% of PDAC cases show oncogenic Kras activation, mostly co-occurring with p53 gene mutation. Pancreatic intraepithelial neoplasms (PanIN) are the precancerous lesions that usually precede PDAC. Desirable mouse models for PDAC must be able to reliably and predictably recapitulate the human disease. The choice of a mouse model for a particular research study requires careful evaluation of all the available models with respect to their characteristics and the research question.
The aim of this paper is to review and compare the characteristics of the conditional KC (Pdx1 Cre; LSL-KrasG12D), KPC (Pdx1 Cre; LSL-KrasG12D; LSL-P53R172H) mouse models and the newer inducible iKras*p53* (Ptf1a Cre; LSL-rtTa; LSL-P53R172H; tetO-Kras G12D) mouse model and to make an opinion about their suitability to use in oncogenic Kras-targeting translational research for PDAC.
The KC mouse model, developed in 2003, was the proof of principle. It shows a PanIN penetrance of 100% starting prenatally, PDAC penetrance of less than 10% in its first year of life and a transgene expression that is targeted to its usual Kras genomic locus. However, it lacks pancreas-specificity in its transgene expression. The KPC mouse model, developed in 2005, demonstrates 100% PanIN penetrance starting prenatally, 100% PDAC penetrance, a transgene that is targeted to its usual genomic locus and 5months mean survival. Like the KC mouse model, it lacks pancreas-specificity in its transgene expression. The iKras*p53* mouse model was developed in 2012. Unlike the other models above, its oncogenic KRas transgene expression is inducible and more pancreas-specific. It has about 7months mean survival, more rapid formation of PDAC and metastases with larger tumor masses than the KPC model. Its oncogenic Kras transgene expression, is however targeted to a different locus than the usual Ras locus of the mouse genome.
Our current opinion is that each of the above models has a unique place in pancreatic cancer research. The KC model (especially its Ptf1a-Cre analog) is more suited for preclinical evaluation of diagnostic agents and the others are useful for evaluating therapies. The iKras*p53* mouse is more suitable for studying oncogenic Kras pathway inhibitors but generally, the KPC mouse is still a reasonable choice since it has been studied for longer and researchers have had more years experience with it.
Key words: GEMMs, oncogenic Kras, pancreatic cancer
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