Gastroenterology

Gastroenterology

Volume 115, Issue 5, November 1998, Pages 1254-1262
Gastroenterology

Liver, Pancreas, and Biliary Tract
Malignant transformation of duct-like cells originating from acini in transforming growth factor α transgenic mice,☆☆

https://doi.org/10.1016/S0016-5085(98)70098-8Get rights and content

Abstract

Background & Aims: In transgenic mice overexpressing transforming growth factor (TGF)-α 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-α 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-α 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-α/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.

GASTROENTEROLOGY 1998;115:1254-1262

Section snippets

Animals

The transgenic mouse line EL-TGFα-hGH (#2261-3) was kindly provided by Sandgren et al. and has been described earlier.17 Mice were bred to C57BL/6 and kept as heterozygotes. Transgenic animals were identified by Southern blot analysis of mouse tail DNA using a 1.3–base pair (bp) EcoRI fragment of human growth hormone polyA as a probe.17

Light microscopy

For light microscopy, pancreatic tissue was fixed in 2% phosphate-buffered paraformaldehyde for 12 hours, embedded in paraffin, and sectioned (4 μm). Sections

Development of fibrosis and tubular complexes in TGF-α transgenic mice

TGF-α transgenic animals show no signs of altered behavior or growth abnormalities compared with littermate controls but develop a drastically enlarged and fibrotic pancreas. The characteristics of TGF-α transgenic mice and littermate controls are summarized in Table 1.

An increase in the interlobular fibroblast population was already detected at 14 days of age, which progressed to a massive fibrosis with extensive extracellular matrix accumulation at 180 days (Figure 1).

. Development of tubular

Discussion

In the present study, we show that transgenic mice overexpressing TGF-α in the pancreas show a differentiation of acinar cells toward duct-like cells. In addition, these mice developed malignant tumors with a duct-like phenotype. At 4 weeks of age, tubular complexes appeared that were intermingled with acini. The acini showed a dilatation of acinar lumen, which was lined by a monolayer epithelium mostly composed of flattened acinar cells and cells displaying an intermediate phenotype of acinar

Acknowledgements

The authors thank E. Sandgren (Laboratory of Reproductive Physiology, University of Pennsylvania, Philadelphia) for the generous gift of the transgenic mouse line EL-TGFα-hGH (#2261.3); R. D. Palmiter (Howard Hughes Medical Institute, University of Washington, Seattle) for the hGH polyA; H. Kemmler (Max Planck Institute for Immunobiology, Freiburg), for the antibodies TROMA1 and TROMA2; R. C. De Lisle (Department of Anatomy and Cell Biology, University of Kansas) for the acinar-1 and duct-1; W.

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    Address requests for reprints to: Roland M. Schmid, M.D., Department of Internal Medicine, University of Ulm, Robert-Koch-Strasse 8, 89081 Ulm, Germany. Fax: (49) 731-502-4302.

    ☆☆

    Supported by a grant from Bausteinförderung P176 and the Bundesministerium für Bildung und Forschung (to R.M.S.).

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