MALIGNANT TRANSFORMATION OF DUCT-LIKE CELLS ORIGINATING FROM ACINI INTRANSFORMING-GROWTH-FACTOR A TRANSGENIC MICE

Background & Aims: In transgenic mice overexpressing transforming grow th factor (TGF)-alpha in the exocrine pancreas, progressive pancreatic fibrosis and a transdifferentiation of acinar cells to duct-like cell s occurs. The present study was undertaken to analyze this transdiffer entiation process. Methods: Pancreatic specimens were characterized us ing light microscopy and immunohistochemistry. Expression of the epide rmal growth factor receptor (EGFR) and TGF-alpha was evaluated with sl ot blot and Western analysis. To identify other generic events, K-ras mutations were screened with an enriched polymerase chain reaction app roach and p53 expression was detected with immunohistochemistry. Resul ts: Morphological examination revealed an aggregation of interlobular fibroblasts and a decrease in acinar cell height starting at day 14 af ter birth. In older animals, these acinar cells change to duct-like ce lls, which form tubular structures and express ductal markers. Evidenc e for dysplastic changes was found in 12 of 21 TGF-alpha transgenic mi ce older than 1 year. We also observed four malignant pancreatic tumor s, which were multicentric and originated from dysplastic tubular comp lexes. They displayed a mixed cystic-papillary phenotype strongly posi tive for carbonic anhydrase activity. EGFR expression progressively in creased in the transition from acinar to duct-like and transformed cel ls. Activating K-ras mutations could not be detected; however, tubular complexes and tumors displayed increased immunoreactivity for nuclear p53. Conclusions: These data suggest an involvement of the TGF-alpha/ EGFR pathway in conjunction with other yet unknown events in pancreati c tumor development. Furthermore, these observations are in favor of a n acinar-ductal carcinoma sequence. Thus, these transgenic animals wil l be useful to define genetic alterations associated with a transition from acinar cells to a neoplastic ductal phenotype.