Preinvasive duct-derived neoplasms in pancreas of keratin 5-promoter cyclooxygenase-2 transgenic mice.
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.
Müller-Decker
Karin
K
Eicosanoids and Tumor Development Section, Deutsches Krebsforschungszentrum, Heidelberg, Germany. K.Mueller-Decker@DKFZ-Heidelberg.de
Fürstenberger
Gerhard
G
Annan
Nadine
N
Kucher
Dagmar
D
Pohl-Arnold
Andrea
A
Steinbauer
Brigitte
B
Esposito
Irene
I
Chiblak
Sara
S
Friess
Helmut
H
Schirmacher
Peter
P
Berger
Irina
I
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
D007633:Keratins; D015237:Dinoprost; D051546:Cyclooxygenase 2; D015232:Dinoprostone