With the advent of mouse models that recapitulate the cellular and molecular pathology of pancreatic neoplasia and cancer, it is now feasible to recruit and deploy these models for the evaluation of various chemopreventive and/or anticancer regimens. The highly lethal nature of pancreatic ductal adenocarcinoma (PDAC) makes multiple areas of research a priority, including assessment of compounds that prevent or suppress the development of early lesions that can transform into PDAC. Currently, there are over a dozen models available, which range from homogeneous preneoplastic lesions with remarkable similarity to human pancreatic intraepithelial neoplasms to models with a more heterogeneous population of lesions including cystic papillary and mucinous lesions. The molecular features of these models may also vary in a manner comparable with the differences observed in lesion morphology, and so, navigating the route of model selection is not trivial. Yet, arming the community of cancer investigators with a repertoire of models and the guidance to select relevant models that fit their research themes promises to produce findings that will have clinical relevance. Cancer Prev Res; 3(11); 1382–7. ©2010 AACR.
Pancreatic cancer develops insidiously, recurs quickly following surgical resection, and metastasizes widely, resulting in nearly uniform lethality. Although grim, these clinical characteristics nonetheless represent several opportunities to interrupt disease progression and improve the outcome for pancreatic cancer patients. Indeed, increased surveillance of individuals with a strong family history of pancreatic cancer has prompted the development of endoscopic, pathologic, and radiological methods that allow for highly beneficial prophylactic surgery (1). Furthermore, the limited but measurable benefit of adjuvant chemotherapy supports the premise that systemic treatments can also affect pancreatic cancer progression (2, 3); the challenge, though, is to identify the most effective systemic approaches for different stages of disease. The recent advent of genetically engineered mice that accurately develop early and advanced forms of the most common type of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), may provide preclinical model systems to address these issues.
Persistent research has culminated in the generation of genetically engineered mouse models that represent different stages of human PDAC. 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 (although mIPMN and mMCN should be further characterized for a more complete validation). These genetically engineered mouse models may be appropriate for assessing the role of genes, environmental conditions such as tobacco exposure and diet, comorbidities including pancreatitis, and the influence of immunologic and pharmacologic interventions on the development of invasive PDAC, as highlighted in Table 1. Models of localized PDAC have also been reported and could be used for neoadjuvant, adjuvant, and anti-metastatic approaches to prevent relapse and dissemination. Most of the genetically engineered models include Pdx1-Cre/Lox-Stop-Lox (LSL)-Kras or p48 Cre/LSL-Kras mice, which were further modified by conditional deletion or mutation of the p16/p19 (these mice also develop sarcomatoid lesions; ref. 6), p53 (7), smad4 (8, 9), or transforming growth factor β receptor II (TGFβ RII) loci (10). The results of these combined genotypes were a multiplicity of preinvasive lesions of all grades, invasive adenocarcinoma, and metastasis to other organs, ultimately leading to significantly reduced median survival. The most robust murine models of preneoplasms (earlier-stage lesions, as opposed to later-stage lesions such as PanIN3) display complete penetrance (all mice with a gene mutation have phenotypic manifestation of that disease) and express an endogenous or transgenic oncogenic Kras allele in pancreatic exocrine and/or progenitor cells. When combined with various tumor suppressor mutations, these models oftentimes yield invasive and metastatic PDAC and related epithelial histologies (see Table 2 in ref. 5). Models using inducible alleles of Cre recombinase, such as estrogen receptor–Cre fusion genes (Cre ER or Cre ERT) and tetracycline-responsive Cre expression alleles (TRE-Cre), are capable of being temporally controlled and thus initiated selectively in adult pancreata, better reflecting the somatic acquisition of genetic mutations thought to occur in humans (11–15).
