Progressive Metaplastic and Dysplastic Changes in Mouse Pancreas Induced by Cyclooxygenase-2 Overexpression

Abstract

Cyclooxygenase-2 (COX-2) overexpression is an established factor linking chronic inflammation with metaplastic and neoplastic change in various tissues. We generated transgenic mice (BK5.COX-2) in which elevation of COX-2 and its effectors trigger a metaplasia-dysplasia sequence in exocrine pancreas. Histologic evaluation revealed a chronic pancreatitis-like state characterized by acinar-to-ductal metaplasia and a well-vascularized fibroinflammatory stroma that develops by 3 months. By 6 to 8 months, strongly dysplastic features suggestive of pancreatic ductal adenocarcinoma emerge in the metaplastic ducts. Increased proliferation, cellular atypia, and loss of normal cell/tissue organization are typical features in transgenic pancreata. Alterations in biomarkers associated with human inflammatory and neoplastic pancreatic disease were detected using immunohistochemistry. The abnormal pancreatic phenotype can be completely prevented by maintaining mice on a diet containing celecoxib, a well-characterized COX-2 inhibitor. Despite the high degree of atypia, only limited evidence of invasion to adjacent tissues was observed, with no evidence of distant metastases. However, cell lines derived from spontaneous lesions are aggressively tumorigenic when injected into syngeneic or nude mice. The progressive nature of the metaplastic/dysplastic changes observed in this model make it a valuable tool for examining the transition from chronic inflammation to neoplasia.

Chemopreventive effect of saikosaponin-d on diethylinitrosamine-induced hepatocarcinogenesis: Involvement of CCAAT/enhancer binding protein�β and cyclooxygenase-2

“…Additionally, HCC is known to be an inflammation-related malignancy, which is attributed to the above-mentioned risk factors. Cyclooxygenase-2 (COX-2), a rate-limiting enzyme in the production of prostaglandins, is usually induced by stimuli involved in inflammatory responses and has been shown to be associated with carcinogenesis and tumor progression (4,5). Various HCC-related molecules such as hepatitis B virus X protein (6), hepatitis C virus (7) and diethylinitrosamine (DEN) (8), have been reported to induce the expression of COX-2, which finally facilitates hepatocarcinogenesis and cancer progression.…”

PGE2 regulates pancreatic stellate cell activity via the EP4 receptor

“…Traditional NSAIDs can inhibit both COX-1 and COX-2, to varying degrees. Selective inhibition of COX-2 by celecoxib was found to effectively suppress the growth of pancreatic cancer cells in vitro (17) and to inhibit PDAC tumor growth and angiogenesis in orthotopic implantation tumor models (33). More recently it was shown that Celecoxib could slow or prevent the progression of early PanIn lesions in mouse models to metastatic disease (32).…”

“…The expression of COX-2 in chronic pancreatitis is primarily localized in the cytoplasm of pancreatic acinar cells, islet cells, and ductal cells (6), while in pancreatic adenocarcinoma it is localized primarily to cancer cells (7). Transgenic over-expression of COX-2 in the pancreas led to the development of pancreatic fibrosis and even cellular transformation (17). However, despite the strong correlation between COX-2 and pancreatic fibrosis, the mechanisms involved in COX-2 mediated effects on the stroma are unclear.…”

Risk Factors for Pancreatic Cancer: Underlying Mechanisms and Potential Targets

“…Chemotherapeutic agents like gemcitabine have been approved for pancreatic cancer not amenable to surgery, but have not shown clear therapeutic effects (Lohr and Jesenofsky, 2009). In order to understand the complexities of molecular mechanisms and drug interactions various mouse models have been developed (Lee et al, 1995;Colby et al, 2008;Jung et al, 2011). In the following sections, common cellular pathways in pancreatitis and pancreatic cancer will be considered, and their role in the transformation of acute to chronic disease, and ultimately cancer, will be discussed.…”

“…COX-2 has been linked to development of pancreatic dysplasia and PDAC and may form a potential link between CP and subsequent development of pancreatic cancer. Elevated COX-2 has been associated with pancreatic cancer cell proliferation (Sun et al, 2009) and tumor growth (Colby et al, 2008;Mukherjee et al, 2009;Hill et al, 2012). Moreover, a recent study has shown that a combination therapy, involving pharmacologic inhibitors of COX-2 and histone deacetylases (HDAC), a family of enzymes that regulate paramount cellular activities, results in a complete inhibition of tumor growth.…”