Gastroenterology

Gastroenterology

Volume 142, Issue 5, May 2012, Pages 1079-1092
Gastroenterology

Reviews and Perspectives
Reviews in Basic and Clinical Gastroenterology and Hepatology
What We Have Learned About Pancreatic Cancer From Mouse Models

https://doi.org/10.1053/j.gastro.2012.03.002Get rights and content

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Conditional Kras Models of Pancreatic Cancer

Although approaches to generate mouse models of pancreatic cancer started in the late 1980s,2, 3 the GEMM that most closely resembles human disease was established in 2003.4 This model is based on the LSL-KrasG12D strain of mice, which has an endogenous, conditional KrasG12D mutant allele silenced by a floxed transcriptional STOP cassette (Lox-Stop-Lox or LSL) inserted upstream of the targeted Exon1. Removal of this LSL by directing expression of Cre recombinase with adenoviral-Cre allows

Cancer-Initiating Cells in PDA

The ductal-like properties of cells in PanIN lesions indicated that PDAs might derive from normal ductal cells or their precursors.6, 7 However, attempts to induce PanINs from ductal cells, by regulating expression of Kras oncogenes with the cytokeratin-19 promoter, did not generate PanINs or PDA.26 These observations raised doubts that PanINs, despite their ductal-like properties, arise from the ductal cell lineage. In fact, the development of another GEMM similar to the original strain

Pancreatitis and PDA

Adult mice that express endogenous Kras oncogenes in the acinar cell compartment develop PanINs and PDAs with high penetrance when subjected to acute or chronic cerulein-induced pancreatitis. Sporadic bouts of pancreatitis that last as little as 1 month are sufficient to induce PDAs in these mice (Figure 1). Longer bouts (3 months) or chronic pancreatitis increase the tumor incidence and reduce latency.27, 36 Expression of KrasG12V does not have to precede or coincide with pancreatitis,

Inflammation and PDA Development

GEMMs have been used to study how the inflammatory response contributes to the progression of PanINs to yield PDA. In a recent study, Guerra et al showed that the inflammatory response inhibited senescence in low-grade PanINs.36 Interestingly, expression of oncogenic Kras did not induce senescence in normal pancreatic cells; markers of senescence could be detected only in Kras oncogene-expressing cells that were undergoing the transition from acinar to ductal metaplasia or in low-grade PanINs.36

The Ras Effector Pathway in PDA

Activating mutations at codons 12, 13, and 61 in the Kras gene are present in ∼90% of PDAs.49 Oncogenic forms of Kras show impaired intrinsic and extrinsic guanosine triphosphatase function and thereby remain bound to guanosine triphosphate to enable constitutive interactions with downstream effectors (more than 20 are known) that regulate cell responses such as proliferation migration, differentiation, adhesion, survival, and apoptosis.50, 51 The most well-studied Ras effectors include

Using Mouse Models to Identify and Validate Human PDA Genes

During the past decade, many new genes and biochemical pathways have been associated with the progression of pancreatic cancer. The whole exome sequencing and copy number analyses of 24 human tumors have identified more than 1000 somatic mutations, with an average of 63 per tumor.86 These mutant alleles have been assigned to 12 proposed core pathways of PDA.86 Determining the role of such genes in PDA initiation and progression is important and could uncover new therapeutic approaches.

Development of Diagnostic and Therapeutic Strategies for PDA

GEMMs might be used to identify markers of early-stage pancreatic cancer because no good markers are currently available for early detection of patients. The PanIN models are ideal for development of tissue biomarkers of pancreatic preneoplasia; a low-resolution serum proteomic analyses provided initial evidence that such an approach could succeed.4 A more quantitative approach revealed multiple potential plasma biomarkers of pancreatic preneoplasia in GEMMs.99 Additional work by Kelly et al

Conclusions

Over the past decade, GEMMs of PDA have increased our understanding of this disease and allowed initial exploration of therapeutic and diagnostic strategies. Refinements of these first-generation models will continue to provide new insights into the genes, pathways, and cell types involved in the pathogenesis of PDA. Nonetheless, these freely available models should be expeditiously used by our community to identify better diagnostic and therapeutic options for patients. GEMMs could also be

Acknowledgments

The authors thank Dr A. Neesse and Dr F. Connor for critically reviewing the manuscript; Dr C. Feig for providing images of mouse pancreatitis; Dr N. Cook, Dr K. Freese, and Dr D. Lewis for providing the FDG-PET/CT image; and Paul Mackin for providing the high-resolution ultrasonography image.

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    Conflicts of interest The authors disclose no conflicts.

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    Copyright © 2012 AGA Institute. Published by Elsevier Inc. All rights reserved.