Overview of the Pancreatic Toxicity and Carcinogenesis Session

Abstract

The theme of the Society of Toxicologic Pathology Annual Symposium 2013 was “Toxicologic Pathology of the Digestive Tract and Pancreas.” The last session focused on pancreatic toxicity and carcinogenesis. This overview highlights the various presentations in this session, focusing on pancreatic toxicologic pathology, responses of the pancreas to xenobiotics, and current understanding on pancreatic carcinogenesis. The objective of this symposium overview and the subsequent articles from this session is to enable the audience to develop a better appreciation for the pancreas as a target organ in toxicological studies.

The first presentation by Dr. Arun Pandiri from Experimental Pathology Laboratories, Inc. (Research Triangle Park, NC) introduced several topics that were discussed in greater detail by subsequent speakers. Dr. Pandiri provided an overview of the pancreatic anatomy, histology, and pathophysiology of exocrine pancreas. He highlighted the close proximity of the endocrine component (islets of Langerhans) with the exocrine component and the physiological basis of this unique anatomic arrangement (Wayland 1997). Compared with its size, the endocrine pancreas receives a significant proportion of the arterial blood supply that forms a glomeruloid vasculature within the islets that subsequently perfuses the surrounding exocrine tissue before draining into the venous circulation. This unique anatomic feature is responsible for the “perinuclear halos” that are characterized by the comparatively large size of the peri-insular exocrine acini compared with the small size of the teleinsular exocrine acini. This differential exocrine acinar cell size may be leveraged in toxicologic pathology for detecting at least some xenobiotics that affect either the islets (alloxan) or the acini (pilocarpine; Greaves 2007). The importance of several stimulating (insulin) and antagonistic (somatostatin) factors released by the islets on the exocrine pancreas was discussed. The neuroendocrine nature of cholecystokinin (CCK) stimulation of the exocrine pancreatic secretion in rodents and humans was presented. A brief overview of drug-induced pancreatitis, pathogenesis of pancreatitis, and chemical (DMBA)-induced pancreatic, cancer was also provided to introduce the topics for subsequent speakers.

The second presentation, by Dr. Charles Murtaugh from the University of Utah (Salt Lake City, UT), provided a thorough overview of the pathogenesis of pancreatic cancer. The American Cancer Society estimates that annually about 3% of American men and women are diagnosed with pancreatic cancer, and up to 7% succumb to the disease. Dr. Murtaugh indicated that KRAS (Kirsten rat sarcoma viral oncogene homolog) is frequently mutated in pancreatic intraepithelial neoplasia (PanIN) lesions that are precursors to pancreatic cancer (Hruban, Wilentz, and Kern 2000). The PanIN lesions accumulate with age, and in high-risk patients there is an earlier onset and greater incidence of PanINs (Andea, Sarkar, and Adsay 2003). In addition to the spontaneous KRAS mutations, several genetic and environmental factors determine the susceptibility of an individual to pancreatic cancer. The value and limitations of the various animal models of pancreatic cancer were discussed. In early studies, the Syrian hamster treated with N-nitrosobis(2-oxopropyl)amine (BOP) model served as an important animal model since it resulted in ductal adenocarcinomas (as seen in humans) and also harbored similar genetic mutations. However, this model was not tractable for genetic manipulation. Pancreatic tumors from conventional rodent models (rats and mice) do not have a ductal phenotype that is similar to human pancreatic cancer. The genetically altered mouse models of pancreatic carcinogenesis such as Elastase-Kras^G12D and Cytokeratin19-Kras^G12V replicate several aspects of the human disease and provide much insight into the pathogenesis of pancreatic cancer (Hingorani et al. 2003). The cell of origin of pancreatic cancer is not definitively determined since there is evidence that exocrine acinar cells are able to transdifferentiate and contribute to the ductal phenotype of pancreatic cancer (Wagner et al. 1998). Subsequent stimulating discussion was centered on the developmental biology of the pancreas and the importance of notch signaling, Kras signaling, and the loss of Ptf1a (pancreas specific transcription factor, 1a) in the pathogenesis of pancreatic cancer (De La et al. 2008). The field of pancreatic carcinogenesis is burgeoning with new information and still has to reveal the precise molecular pathogenesis of this deadly cancer.

The third presentation, by Dr. Karrie Brenneman from Pfizer (Groton, CT), highlighted a very interesting test article–related lesion that is characterized by islet and peri-islet inflammation and hemorrhage that occurred in rats but not in mice, dogs, or nonhuman primates. This lesion progressed from minimal to marked peri-islet inflammation to islet fibrosis and atrophy. Dr. Brenneman gave an overview of the de-risking activities in order to better understand this lesion’s species specificity and its translatability to humans. Similar lesions were noted in other animal models associated with aging, diabetes mellitus, hypertension, or microvascular injury (Onizuka et al. 1994; Imaoka, Satoh, and Furuhama 2007; Nugent, Smith, and Jones 2008; Miller et al. 2011). Dr. Brenneman presented data to rule out the roles played by aging, diabetes mellitus, and hypertension in the pathogenesis of these lesions. The subsequent focus of the presentation was on the microvascular injury at the exocrine–endocrine interface. Several lines of evidence including data from light microscopy, immunohistochemistry, electron microscopy, in vitro cytotoxicity on acinar and islet cells, and microsphere technique to monitor pancreatic blood flow were used to demonstrate that this rare lesion is indeed specific to rats and likely a result of unique injury to the microvasculature at the exocrine–endocrine interface.

The fourth presentation, by Dr. John Foster from Astra Zeneca (Alderly Park, UK), provided an overview of acute and chronic pancreatitis in humans and animal models to understand the pathogenesis of pancreatitis. Dr. Foster introduced the presentation by providing a review of the anatomy especially with regard to pancreatobiliary tree since it is often implicated in human pancreatitis and several animal models (like duodenal loop, duct ligation, bile acid injection into pancreatic duct, duct perfusion) that were used to reflect this mode of action. He also discussed the risk factors for pancreatitis, which included obesity, genetics, age, alcoholism, and drugs. Some of the cases of pancreatitis may be due to hyperstimulation of exocrine pancreas, resulting in increased enzyme synthesis as well as premature activation of the digestive enzymes resulting in pancreatitis. Several models that mimic this mode of action were used to study pancreatitis and the most common model is the use of CCK mimetics such as cerulein (Lampel and Kern 1977). Pancreatitis also results due to direct tissue damage from oxidative stress and metabolic poisons. The animal models that mimic these situations include ethanol and lipopolysaccharide, and l-arginine (Dawra et al. 2007). Several genes that are important in the development of pancreas and pancreatic physiology were leveraged to generate genetically modified rodent models to study the pathobiology of pancreatitis. The SPINK3 (serine peptidase inhibitor, Kazal type 3)-, PRSS1 (protease, serine, 1 (trypsin 1))-, and CFTR (cystic fibrosis transmembrane conductance regulator)-deficient mouse models provided important data to understand the pathogenesis of pancreatitis in populations that are genetically deficient in these genes (Schneider 2004; Dimagno et al. 2005; Romac et al. 2010). Combining the genetically modified rodent models with secretagogue models were also used to study the pathogenesis of pancreatitis. Examples of drug-induced pancreatitis and modes of action for testing the hypothesis, such as oxidative stress, ductal obstruction, toxic metabolite, and necrosis–fibrosis theory, were discussed.

The final presentation, by Dr. Chandikumar Elangbam from GlaxoSmithKline (Research Triangle Park, NC), provided a de-risking strategy of a novel CCK-1 receptor agonist indicated for treatment of obesity that resulted in pancreatitis in mice and rats. The occurrence of pancreatitis during preclinical stages of a compound development is a serious liability. The translatability of a lesion across species, especially humans, resulting from the compound exposure is usually the biggest question and hurdle in the further development of a compound. Dr. Elangbam presented data from a series of acute and repeat dose studies in several species such as rats, mice, and monkeys. In the mice and rats, the pancreatitis was dose and duration dependent, but, in contrast, no significant lesions were noted in monkeys. Likewise, there were no pancreatic liabilities in an obese patient population administered the compound during the clinical trial. The interspecies variation with regard to CCK-induced exocrine pancreatic stimulation was discussed in great detail (Wang and Cui 2007). In addition, the pathophysiology and molecular pathogenesis of secretagogue-induced pancreatitis was presented in a very elegant manner using diagrams and pathways. This presentation emphasized the importance of understanding the interspecies differences in basic physiology at the molecular level in order to better evaluate lesions during preclinical drug development.