Development Of Pancreatic Neoplasia Research Articles

Development of a non-functional pancreatic neuroendocrine tumor and a duodenal ulceration after cholecystoduodenostomy in a cat

A six-year-old Ragdoll with previous extrahepatic biliary tract obstruction due to cholangiohepatitis, treated with cholecystoduodenostomy, was presented for acute vomiting, hyporexia, and weight loss. Abdominal ultrasound examination revealed randomly distributed hepatic nodules and dilated biliary ducts. Gastroduodenoscopy showed a patent cholecystoduodenostoma but disclosed a perforated duodenal ulceration. Conversion to celiotomy revealed extensive liver pathology, a discrete pancreatic nodule, and a duodenal ulcer opposite to the cholecystoduodenostoma. The cat was euthanized intra-operatively and necropsy was performed. The intrahepatic biliary tract of the right liver lobes was obstructed and severely dilated, whereas bile from the left lobes drained through the cholecystoduodenostoma. Histopathologic diagnoses were a primary pancreatic tumor, positive for glucagon on immunohistochemistry, with liver metastases, chronic purulent cholecystitis, and duodenal ulceration. To the authors’ knowledge, this is the first report in which the development of pancreatic neoplasia is described in a cat with a history of biliary tract disease.

Alteration of strain background and a high omega‐6 fat diet induces earlier onset of pancreatic neoplasia in EL‐Kras transgenic mice

Diets containing omega-6 (ω-6) fat have been associated with increased tumor development in carcinogen-induced pancreatic cancer models. However, the effects of ω-6 fatty acids and background strain on the development of genetically-induced pancreatic neoplasia is unknown. We assessed the effects of a diet rich in ω-6 fat on the development of pancreatic neoplasia in elastase (EL)-Kras(G12D) (EL-Kras) mice in two different backgrounds. EL-Kras FVB mice were crossed to C57BL/6 (B6) mice to produce EL-Kras FVB6 F1 (or EL-Kras F1) and EL-Kras B6 congenic mice. Age-matched EL-Kras mice from each strain were compared to one another on a standard chow. Two cohorts of EL-Kras FVB and EL-Kras F1 mice were fed a 23% corn oil diet and compared to age-matched mice fed a standard chow. Pancreata were scored for incidence, frequency, and size of neoplastic lesions, and stained for the presence of mast cells to evaluate changes in the inflammatory milieu secondary to a high fat diet. EL-Kras F1 mice had increased incidence, frequency, and size of pancreatic neoplasia compared to EL-Kras FVB mice. The frequency and size of neoplastic lesions and the weight and pancreatic mast cell densities in EL-Kras F1 mice were increased in mice fed a high ω-6 fatty acid diet compared to mice fed a standard chow. We herein introduce the EL-Kras B6 mouse model which presents with increased frequency of pancreatic neoplasia compared to EL-Kras F1 mice. The phenotype in EL-Kras F1 and FVB mice is promoted by a diet rich in ω-6 fatty acid.

Transgenic expression of CCK2 receptors sensitizes murine pancreatic acinar cells to carcinogen‐induced preneoplastic lesions formation

In humans, initial events of pancreatic carcinogenesis remain unknown, and the question of whether this cancer, which has a ductal phenotype, exclusively arises from duct cells has been raised. Previous studies have demonstrated that transgenic expression of the CCK2 receptor in acinar cells of ElasCCK2 mice plays a role in the development of pancreatic neoplasia. The aim of our study was to examine initial steps of carcinogenesis in ElasCCK2 mice, adding a supplementary defect by using a chemical carcinogen, azaserine. Results of posttreatment sequential immunohistochemical examinations and quantifications demonstrate that mice responded to azaserine. Transition of acinar cells into duct-like cells expressing Pdx1 and gastrin, as well as proliferation of acinar cells, were transiently observed in both transgenic and control mice. The carcinogen also induced formation of preneoplastic lesions, adenomas, exhibiting properties of autonomous growth. Importantly, expression of the CCK2 receptor increased the susceptibility of pancreas to azaserine. Indeed, treated ElasCCK2 mice exhibited larger areas of pancreatic acinar-ductal transition, increased cellular proliferation as well as larger adenomas areas vs. control mice. These amplified responses may be related to auto/paracrine stimulation of CCK2 receptor by gastrin expressed in newly formed duct-like cells. Our results demonstrate that activation of CCK2 receptor and azaserine result in cumulative effects to favor the emergence of a risk situation that is a potential site for initiation of carcinogenesis.