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Gastrointestinal Unit [F. H. B., F. S. S., T. B. D., B. R., G. S., D. G. S., A. K. R.], Department of Genetics [A. K. R.], Abramson Cancer Center and Family Cancer Research Institute [F. H. B., F. S. S., T. B. D., B. R., A. K. R.], and Division of Endocrinology, Diabetes and Metabolism [D. A. S.], University of Pennsylvania, Philadelphia, Pennsylvania 19014; University of Tennessee College of Veterinary Medicine, Tennessee [L. C.]; and Department of Surgery, Northwestern University, Chicago, IL 60611 [P. G.]
A frequent genetic alteration found in premalignant stages of pancreatic adenocarcinoma is K-ras oncogene point mutation. The mechanistic basis for the inability of K-ras mutation to transform pancreatic ductal cells is unclear, although cooperating events with p16 inactivation, p53 mutation, and SMAD 4 mutation are recognized to be necessary. We have generated a novel mouse model in which the cytokeratin 19 promoter, specifically active in pancreatic ductal cells but not other cell types of the pancreas, is fused to mutant K-ras. This is of direct relevance to human pancreatic cancer because premalignant lesions are found specifically in ductal cells. There is dramatic periductal lymphocytic infiltration in the pancreata of transgenic mice, predominantly CD4+ T lymphocytes, which may act as an adaptive immune response to activated ras-mediated signaling. In addition, gene array analysis reveals an induction of N-cadherin in transgenic mice pancreatic ductal cells, the significance of which relates to promotion of cell adhesion and deterrence of cell migration. Apart from these important biological considerations, there is parallel activity of the cytokeratin 19 promoter in the stem cell region of the gastric epithelium, namely in mucous neck cells. Activated K-ras in this context causes mucous neck cell hyperplasia, a precursor to gastric adenocarcinoma. There is concomitant parietal cell decrease, which is a key step toward gastric adenocarcinoma. Taken together, we have defined how mutant K-ras signaling modulates important molecular events in the initiating events of pancreatic and gastric carcinogenesis.
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