Progressive Metaplastic and Dysplastic Changes in Mouse Pancreas Induced by Cyclooxygenase-2 Overexpression 1

Science Park-Research Division, University of Texas MD Anderson Cancer Center, Smithville, TX 78957, USA.
Neoplasia (New York, N.Y.) (Impact Factor: 4.25). 09/2008; 10(8):782-96. DOI: 10.1593/neo.08330
Source: PubMed


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.

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    • "Overexpression of COX-2 has been reported in a number of epithelial cancers, including pancreatic cancer [11-16]. Transgenic mouse models have suggested that COX-2 overexpression in pancreatic ductal cells contributes to pancreatic tumour development [17,18]. Upregulation of COX-2 leads to increased production of prostaglandins, in particular PGE2. "
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    ABSTRACT: Background Several studies have described an increased cyclooxygenase-2 (COX-2) expression in pancreatic cancer, but the role of COX-2 in tumour development and progression is not clear. The aim of the present study was to examine expression of COX-2 in cancer cells and stromal cells in pancreatic cancer specimens, and to explore the role of PGE2 in pancreatic stellate cell proliferation and collagen synthesis. Methods Immunohistochemistry and immunofluorescence was performed on slides from whole sections of tissue blocks using antibodies against COX-2 and α-smooth muscle actin (αSMA). Pancreatic stellate cells (PSC) were isolated from surgically resected tumour tissue by the outgrowth method. Cells were used between passages 4 and 8. Collagen synthesis was determined by [3H]-proline incorporation, or by enzyme immunoassay measurement of collagen C-peptide. DNA synthesis was measured by incorporation of [3H]-thymidine in DNA. Cyclic AMP (cAMP) was determined by radioimmunoassay. Collagen 1A1 mRNA was determined by RT-qPCR. Results Immunohistochemistry staining showed COX-2 in pancreatic carcinoma cells, but not in stromal cells. All tumours showed positive staining for αSMA in the fibrotic stroma. Cultured PSC expressed COX-2, which could be further induced by interleukin-1β (IL-1β), epidermal growth factor (EGF), thrombin, and PGE2, but not by transforming growth factor-β1 (TGFβ). Indirect coculture with the adenocarcinoma cell line BxPC-3, but not HPAFII or Panc-1, induced COX-2 expression in PSC. Treatment of PSC with PGE2 strongly stimulated cAMP accumulation, mediated by EP2 receptors, and also stimulated phosphorylation of extracellular signal-regulated kinase (ERK). Treatment of PSC with PGE2 or forskolin suppressed both TGFβ-stimulated collagen synthesis and PDGF-stimulated DNA synthesis. Conclusions The present results show that COX-2 is mainly produced in carcinoma cells and suggest that the cancer cells are the main source of PGE2 in pancreatic tumours. PGE2 exerts a suppressive effect on proliferation and fibrogenesis in pancreatic stellate cells. These effects of PGE2 are mediated by the cAMP pathway and suggest a role of EP2 receptors.
    Full-text · Article · Jun 2014 · BMC Cancer
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    • "COX-2 promotes cell proliferation (58), inhibits apoptosis (59) and facilitates angiogenesis by increasing vascular endothelial growth factor (VEGF) production (60). Previously, a mouse model (61) was generated, in which the overexpression of COX-2 was under the control of a bovine keratin 5 promoter driving pancreatic acinar-to-ductal metaplasia, which revealed that the elevation of COX-2 was significantly correlated with the metaplasia-dysplasia progressing in the exocrine pancreas. However, the precise mechanism by which COX-2 promotes PC growth is unclear. "
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    ABSTRACT: Inflammatory responses are known to be correlated with cancer initiation and progression, and exploration of the route from inflammation to cancer makes a great contribution in elucidating the mechanisms underlying cancer development. Pancreatic cancer (PC) is a lethal disease with a low radical-resection rate and a poor prognosis. As chronic pancreatitis is considered to be a significant etiological factor for PC development, the current review aims to describe the molecular pathways from inflammation to pancreatic carcinogenesis, in support of the strategies for the prevention, diagnosis and treatment of PC.
    Full-text · Article · Jun 2014 · Oncology letters
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    • "The strong inhibitory effect of a combination of atorvastatin, celecoxib and tipifarnib (relatively non-toxic drugs) on the growth of pancreas tumors provide a rationale for a clinical trial to determine the effectiveness of the simultaneous administration of atorvastatin, celecoxib and tipifarnib possibly in combination with gemcitabine on the growth of pancreas tumors in pancreas cancer patients or to determine whether the triple drug combination will prevent the recurrence of pancreas cancer in patients who have undergone surgery by the Whipple procedure to remove their pancreas cancer. It is well-known that patients who have had surgical removal of their pancreas tumor by the Whipple procedure have a high risk for recurrence of pancreas cancer (31,32). "
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    ABSTRACT: Because K-Ras mutation and cyclooxygenase-2 (COX-2) overexpression are hallmarks of majority of pancreatic cancer patients, an approach to inhibit the progression and growth of pancreatic cancer using the simultaneous administration of agents that inhibit the function of both targets, should be considered. In the present study, we assessed the effects of atorvastatin (Lipitor), celecoxib (Celebrex) and tipifarnib (Zarnestra) on the growth of human pancreatic cancer. In the in vitro studies, we found that treatment of human pancreatic tumor cells with a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on growth and a stronger stimulatory effect on apoptosis than each drug alone or for any combination of two drugs. We also found that treatment of Panc-1 cells with a combination of all three drugs strongly decreased the levels of phosphorylated Erk1/2 and Akt. In an animal model of xenograft tumors in severe combined immunodeficient (SCID) mice, we found that daily i.p. injections of a combination of atorvastatin, celecoxib and tipifarnib had a stronger inhibitory effect on the growth of the tumors in mice than each drug alone or for any combination of two drugs. The results of our study indicate that a combination of atorvastatin, celecoxib and tipifarnib may be an effective strategy for the treatment of pancreatic cancer.
    Full-text · Article · Mar 2014 · International Journal of Oncology
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