Malignant transformation of duct-like cells originating from acini in transforming growth factor transgenic mice

Gastroenterology. 1998 Nov;115(5):1254-62. doi: 10.1016/s0016-5085(98)70098-8.


Background & aims: In transgenic mice overexpressing transforming growth factor (TGF)-alpha in the exocrine pancreas, progressive pancreatic fibrosis and a transdifferentiation of acinar cells to duct-like cells occurs. The present study was undertaken to analyze this transdifferentiation process.

Methods: Pancreatic specimens were characterized using light microscopy and immunohistochemistry. Expression of the epidermal growth factor receptor (EGFR) and TGF-alpha was evaluated with slot blot and Western analysis. To identify other generic events, K-ras mutations were screened with an enriched polymerase chain reaction approach and p53 expression was detected with immunohistochemistry.

Results: Morphological examination revealed an aggregation of interlobular fibroblasts and a decrease in acinar cell height starting at day 14 after birth. In older animals, these acinar cells change to duct-like cells, which form tubular structures and express ductal markers. Evidence for dysplastic changes was found in 12 of 21 TGF-alpha transgenic mice older than 1 year. We also observed four malignant pancreatic tumors, which were multicentric and originated from dysplastic tubular complexes. They displayed a mixed cystic-papillary phenotype strongly positive for carbonic anhydrase activity. EGFR expression progressively increased in the transition from acinar to duct-like and transformed cells. 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 pancreatic tumor development. Furthermore, these observations are in favor of an acinar-ductal carcinoma sequence. Thus, these transgenic animals will be useful to define genetic alterations associated with a transition from acinar cells to a neoplastic ductal phenotype.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / analysis
  • Cell Nucleus / metabolism
  • Cell Transformation, Neoplastic / pathology*
  • Fibrosis
  • Kidney Tubules / pathology
  • Mice
  • Mice, Transgenic / genetics
  • Pancreatic Ducts / metabolism
  • Pancreatic Ducts / pathology*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Reference Values
  • Transforming Growth Factor alpha / genetics*
  • Tumor Cells, Cultured
  • Tumor Suppressor Protein p53 / metabolism


  • Biomarkers
  • Transforming Growth Factor alpha
  • Tumor Suppressor Protein p53