Mature acinar cells are refractory to carcinoma development by targeted activation of Ras oncogene in adult rats

Abstract

Pancreatic ductal adenocarcinoma (PDA) is one of the most debilitating malignancies in humans. A thorough understanding of the cytogenesis of this disease will aid in establishing successful treatments. We have developed an animal model which uses adult Hras G12V and Kras G12V transgenic rats in which oncogene expression is regulated by the Cre ⁄ loxP system and neoplastic lesions are induced by injection of adenovirus-expressing Cre recombinase. When adenovirus with Cre recombinase under the control of the CMV enhancer ⁄ chicken b-actin (CAG) promoter (Ad-CAG-Cre) is injected into the pancreatic duct of these animals, pancreatic neoplasias develop. Pathologically, the origin of these lesions is duct, intercalated duct, and centroacinar cells, but not acinar cells. The present study was undertaken to test the effect of acinar cell-specific oncogenic ras expression. Adult transgenic rats were injected with adenovirus with Cre recombinase under the control of the acinar cell-specific promoters amylase (Ad-Amy-Cre) and elastase-1 (Ad-Ela-Cre) or under the control of the non-specific CAG promoter. Injection of either Ad-Amy-Cre or Ad-Ela-Cre into the pancreatic ducts of transgenic animals in which oncogenic Kras is tagged with hemagglutinin (HA), HA-Kras G12V rats resulted in expression of oncogenic ras in acinar cells but not in duct, intercalated duct, or centroacinar cells. Notably, injected animals did not develop any observable proliferative or neoplastic lesions. In marked contrast, injection of Ad-CAG-Cre resulted in pancreatic cancer development within 4 weeks. These results indicate that adult acinar cells are refractory to Ras oncogene activation and do not develop neoplasia in this model. (Cancer Sci 2010; 101: 341-346) P ancreatic ductal adenocarcinoma (PDA) is a highly lethal disease, which is usually diagnosed in an advanced state. Most patients die within 1 year of diagnosis,(1) and the 5-year survival rate is <5%.(2) Understanding of the cytogenesis of PDA offers new directions for targeted therapeutic approaches to combat this disease.Previously, we reported on an animal model in which pancreatic neoplasia was induced in adult Hras G12V transgenic rats by injection of adenovirus with Cre recombinase under the control of the CMV enhancer ⁄ chicken b-actin (CAG) promoter into the pancreatic duct.(3) In these animals, it was shown that duct, intercalated duct, centroacinar, and acinar cells were all infected with the adenovirus, but induced pre-neoplastic and neoplastic lesions were shown to express only duct cell-specific characteristics and not acinar cell-specific characteristics. Moreover, proliferative lesions were not observed in acinar cells. Therefore, we hypothesized that PDA does not develop from adult pancreatic acinar cells in this model.The present study was undertaken to directly test the capability of mature acinar cells to develop into a neoplastic lesion.

A novel reporter rat strain that expresses LacZ upon Cre‐mediated recombination

“…Multiple grossly visible whitish nodules were observed throughout the pancreas in all of the Kras/LacZ and Hras/LacZ rats. Histological examination showed that these nodules were adenocarcinomas, as in our previous reports (Tanaka et al ., ; Ueda et al ., ). In Kras/LacZ rats, double immunofluorescence staining for LacZ and HA showed that the expression pattern of LacZ closely resembled that of HA‐K ras G12V (Fig.…”

Genetic Control of β-Cell Mass Homeostasis

“…Further indirect evidence for centroacinar and/or intercalated duct cells serving as adult pancreatic progenitor cells come from the cancer field. It has been suggested that malignant transformation in the pancreas originates from these cells and not from acinar or duct cells [43,44], consequently supporting a hypothesis where they serve as stem cells as well as cancer stem cells. Another study argues a similar conclusion [45].…”

Hepatitis B and C virus infections as possible risk factor for pancreatic adenocarcinoma

“…When mutant K-RasG12V is activated, during the phase of pancreatic development, acinoductal metaplasia, PanINs and invasive PAC arise. On the other hand, mature acinar cells are rather refractory to Ras oncogene activation and they are unable to originate preneoplastic lesions or invasive tumour [125]. Nevertheless, if adult mice harboring mutant K-RasG12V experience short episodic insults, such as limited bouts of non-acute pancreatitis caused by administration of caerulein for 3 months, chronic inflammation in parenchyma occurs and PanINs and PAC may develop [126].…”