Liver, Pancreas, and Biliary TractMalignant transformation of duct-like cells originating from acini in transforming growth factor α transgenic mice☆,☆☆
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).
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.
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Supported by a grant from Bausteinförderung P176 and the Bundesministerium für Bildung und Forschung (to R.M.S.).