Animal models of pancreatic cancer and their application in clinical research

Abstract

Pancreatic cancer has one of the highest cancer-related mortality rates of all cancers, and despite worldwide efforts to identify new curative treatments, little improvement has been made toward disease-free survival rates. Due to the effect of a heterogeneous disease phenotype in an organ where desmoplastic effects modify tumor behavior and capacity to deliver chemotherapeutics, it is clear that accurate in vivo models are imperative for the understanding of this disease, to identify and test novel therapeutics, and to assist in identifying biomarkers. This review addresses the currently available mouse models of pancreatic ductal adenocarcinoma, in particular genetically engineered and patient-derived xenograft models, focusing on their utility in the drug discovery pipeline.

Pancreatic Cancer: Current Status and Challenges

“…Unlike cell culture, animal models provide the unique ability of studying cancer interactions with a diverse array of other cell types [61, 65]. Collectively, the various mouse models of PanCA fall into 5 categories: (1) genetically engineered mouse models (GEMMs), (2) Cell line xenografts, (3) patient-derived cell line xenografts (PDX), (4) patient derived tumor chip xenografts, and (5) humanized mouse models [61, 65].…”

“…Collectively, the various mouse models of PanCA fall into 5 categories: (1) genetically engineered mouse models (GEMMs), (2) Cell line xenografts, (3) patient-derived cell line xenografts (PDX), (4) patient derived tumor chip xenografts, and (5) humanized mouse models [61, 65]. Currently, there are over 30 types of GEMMs, which have been designed to study PanCA [65]. The overwhelming majority of these modified mice are variants of the KPC mouse.…”

“…The overwhelming majority of these modified mice are variants of the KPC mouse. These mice have pancreas specific mutations in KRAS and p53, which were introduced using a Cre/lox system [65]. Thus, the mice are KRAS G12D p53 mut/mut Cre mice or KPC mice.…”

“…The main benefits of using GEMM mice are normal disease progression in the pancreas, complete immune system, development of tumor stroma from the same species as the tumor, ability to study early stages of disease, ability to study effects of specific mutations on tumor development, ability to study invasive and metastatic tumor progression, and the ability to assess novel therapeutics [61, 65, 66]. The major disadvantages with GEMMs are that they are very expensive, labor intensive, and they lack tumor heterogeneity [61, 65]. The later point is particularly cumbersome as PanCA is known to be a heterogeneous disease owing to the wide array of genetic mutations, which can contribute to pancreatic tumorigenesis and therapeutic resistance [15].…”

“…Furthermore, and despite how closely their disease progression mimics human disease, these are still mice and because of inherent differences to humans the disease model will never completely recapitulate human disease [61]. Despite the issues associated with mouse models of PanCA, they are still the best models for studying PanCA [61, 65, 66]. …”