Characterization of pancreatic adenocarcinomas arising in a COX2 transgenic mouse Free

3906

The importance of cyclooxygenase 2 (COX2) in tumor development and behavior has been demonstrated in numerous cancers, including pancreatic ductal adenocarcinoma. We noticed development of pancreatic tumors in hemizygous transgenics from a recently generated line of mice in which COX2 overexpression is driven by the bovine keratin 5 promoter. Histological examination reveals a range of lesions which appear to correspond well with the progression model proposed by Hruban et al., 2000. Histologic abnormalities in pancreata are apparent as early as 4 weeks of age, and all transgenics seem to be affected, with most succumbing to the disease around 5 to 6 months of age. Specifically, early lesions are characterized by over-proliferation of pancreatic ducts which otherwise retain relatively normal tissue architecture. During progression, a pronounced desmoplastic response, with large amounts of reactive stroma surrounding the aberrant ductal structures is observed. As lesions become still more advanced, nuclear atypia increases, with a concurrent shift to an overall more poorly differentiated state; the increasing mass of abnormal ducts appears to correlate with a reduction or compression of the stromal component of the tumors. We have demonstrated that the tumors show positive immunostaining for COX2, which appears to vary with the level of progression observed; COX2 staining is quite strong in otherwise normal acinar regions of the pancreas and is present in many ductal cells in earlier lesions, but tends to decrease in the ductal structures of more advanced tumors. We have also demonstrated positive immunostaining for mucin 4, erbB2, Ki67, s100, cytokeratins 5 and 8, b-catenin and E-cadherin. We are proposing that the BK5-COX2 mouse will prove to be an excellent model for studies of chemoprevention and chemotherapeutic intervention in pancreatic adenocarcinoma. Supported by CA 100140 and 5 T32 ES07247-14 from NIH.