Su1251 Overexpression of EGFR in the Exocrine Pancreas Induces a Chronic Pancreatitis

Abstract

Background and Aim: Chronic pancreatitis and pancreatic ductal adenocarcinoma (PDA) frequently overexpress epidermal growth factor receptor (EGFR) and EGF-family ligands. Although chronic pancreatitis is a risk factor for PDA, the relationship between chronic pancreatitis and PDA remains obscure. A critical obstacle to understanding the role of chronic pancreatitis in development of PDA is the lack of appropriate animal models for chronic pancreatitis with similar clinical courses as in human patients. Serine protease inhibitor Kazal type 1 (SPINK1: mouse homolog Spink3), which is also known as tumor associated trypsin inhibitor (TATI), is mainly produced in the pancreatic acinar cells. Recently, we showed that SPINK1 binds to EGFR to activate its downstream signaling. The present study aims to generate chronic pancreatitis model mice and assess the molecular events from chronic pancreatitis to PDA. Methods: 1) C57BL/6 female mice were repeatedly induced acute pancreatitis by using choline-deficient with ethionine (CDE) diet for 54 weeks. 2) To assess the molecular events caused by long term CDE diet treatment using Western blotting. 3) To further analyze the clinical importance of EGFR and SPINK1 in the chronic pancreatitis and PDA, we examined the expression of SPINK1 and EGFR. Immunohistochemical analyses were performed using human chronic pancreatitis and PDA samples. Results: 1) Histological evaluation revealed that chronic pancreatitis, characterized by acinar atrophy, fibrosis and well-developed tubular complexes (TCs), was observed after 24 wk of CDE-diet treatment. In spite of the severe pancreatic degeneration, neoplastic changes were not observed. 2) Expression of EGFR and its ligands (Spink3 and TGF α) and activation of K-Ras (GTP-Ras formation), which are frequently observed in human PDA, were indeed observed in parallel with TCs formation. In addition, cyclooxygenase-2 which induced by stimuli involved in inflammatory responses was also overexpressed. 3) In the human chronic pancreatitis samples, TCs were positive EGFR immunostaining. Furthermore, PDA cases were positive for both SPINK1 and EGFR immunoreactivity. Conclusion: We have successfully developed a chronic pancreatitis model with CDE diet. We also showed expression of EGFR and its potent ligands, phosphorylation of EGFR, and activation of K-Ras as the step of chronic inflammation. It was suggested that EGFR signaling cascades were important for the development from chronic pancreatitis to PDA. Howevere, chronic pancreatitis itself is not sufficient for the development of PDA. Further combinations of CDE-diet treatment with the administration of other promotion insults or genetic alterations may result in PDA development.