title: Preinvasive duct-derived neoplasms in pancreas of keratin 5-promoter cyclooxygenase-2 transgenic mice.
abstract: OBJECTIVE
  Basic research aimed at a better understanding of pancreatic carcinogenesis and improving the treatment of this disease is crucial because the majority of pancreatic cancers are highly aggressive and therapeutically nonaccessible. Cyclooxygenase (COX)-2, which is a key enzyme of prostaglandin (PG) biosynthesis, is overexpressed in around 75% of human carcinomas including those of the pancreas.
  
  
  METHODS
  The pathologic changes of transgenic mouse pancreas with keratin 5-promoter-driven expression and activity of COX-2 were characterized.
  
  
  RESULTS
  Aberrant expression of COX-2 in a few ductal cells and COX-2-mediated PG synthesis in the transgenic mice resulted in keratin 19- and mucin-positive intraductal papillary mucinous neoplasm- and pancreatic intraepithelial neoplasia-like structures, characterized by an increased proliferation index and serous cystadenomas. Moreover, Ras activation was enhanced and the HER-2/Neu receptor was overexpressed. Loss of acini, fibrosis, and inflammation were pronounced. Feeding a COX-2-selective inhibitor to the transgenic mice suppressed the accumulation of PG and the phenotype. The changes resemble the human disease in which COX-2 was overexpressed consistently.
  
  
  CONCLUSIONS
  We present strong evidence for a causal relationship between aberrant COX-2 overexpression and COX-2-mediated PG synthesis and the development of serous cystadenoma, intraductal papillary mucinous, and pancreatic intraepithelial neoplasms. This model offers the unique possibility of identifying molecular pathways leading to the formation and malignant progression of the various types of preinvasive lesions of pancreatic adenocarcinomas that show different dismal outcomes.
authors.affiliation: Eicosanoids and Tumor Development Section, Deutsches Krebsforschungszentrum, Heidelberg, Germany. K.Mueller-Decker@DKFZ-Heidelberg.de
authors.forename: Karin
authors.initials: K
authors.lastname: Müller-Decker
authors.forename: Gerhard
authors.initials: G
authors.lastname: Fürstenberger
authors.forename: Nadine
authors.initials: N
authors.lastname: Annan
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kucher
authors.forename: Andrea
authors.initials: A
authors.lastname: Pohl-Arnold
authors.forename: Brigitte
authors.initials: B
authors.lastname: Steinbauer
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.forename: Sara
authors.initials: S
authors.lastname: Chiblak
authors.forename: Helmut
authors.initials: H
authors.lastname: Friess
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Irina
authors.initials: I
authors.lastname: Berger
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics* / Q000378:metabolism; D015237:Dinoprost / Q000032:analysis; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D011905:Genes, ras; D015151:Immunoblotting; D007150:Immunohistochemistry; D007633:Keratins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011336:Probability; D011401:Promoter Regions, Genetic / Q000235:genetics
chemical_list: D007633:Keratins; D015237:Dinoprost; D051546:Cyclooxygenase 2; D015232:Dinoprostone