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| Item Type: | Article |
|---|---|
| Title: | Differential cell susceptibilities to kras(G12D) in the setting of obstructive chronic pancreatitis |
| Creators Name: | Shi, C. and Pan, F.C. and Kim, J.N. and Washington, M.K. and Padmanabhan, C. and Meyer, C.T. and Kopp, J.L. and Sander, M. and Gannon, M. and Beauchamp, R.D. and Wright, C.V. and Means, A.L. |
| Abstract: | BACKGROUND & AIMS: Activating mutation of the KRAS gene is common in some cancers, such as pancreatic cancer, but rare in other cancers. Chronic pancreatitis is a predisposing condition for pancreatic ductal adenocarcinoma (PDAC), but how it synergizes with KRAS mutation is not known. METHODS: We used a mouse model to express an activating mutation of Kras in conjunction with obstruction of the main pancreatic duct to recapitulate a common etiology of human chronic pancreatitis. Because the cell of origin of PDAC is not clear, Kras mutation was introduced into either duct cells or acinar cells. RESULTS: Although Kras(G12D) expression in both cell types was protective against damage-associated cell death, chronic pancreatitis induced p53, p21, and growth arrest only in acinar-derived cells. Mutant duct cells did not elevate p53 or p21 expression and exhibited increased proliferation driving the appearance of PDAC over time. CONCLUSIONS: One mechanism by which tissues may be susceptible or resistant to KRAS(G12D)-initiated tumorigenesis is whether they undergo a p53-mediated damage response. In summary, we have uncovered a mechanism by which inflammation and intrinsic cellular programming synergize for the development of PDAC. |
| Keywords: | Cdkn1a, Cell of Origin, Acinar-to-Ductal Metaplasia, Pancreatic Duct Ligation, Animals, Mice |
| Source: | Cellular and molecular gastroenterology and hepatology |
| ISSN: | 2352-345X |
| Publisher: | Elsevier |
| Volume: | 8 |
| Number: | 4 |
| Page Range: | 579-594 |
| Date: | 31 October 2019 |
| Official Publication: | https://doi.org/10.1016/j.jcmgh.2019.07.001 |
| PubMed: | View item in PubMed |
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