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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., Pan, F.C., Kim, J.N., Washington, M.K., Padmanabhan, C., Meyer, C.T., Kopp, J.L., Sander, M., Gannon, M., Beauchamp, R.D., 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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