Chronic Pancreatitis Is Essential for Induction of Pancreatic Ductal Adenocarcinoma by K-Ras Oncogenes in Adult Mice
2007; Cell Press; Volume: 11; Issue: 3 Linguagem: Inglês
10.1016/j.ccr.2007.01.012
ISSN1878-3686
AutoresCarmen Guerra, Alberto J. Schuhmacher, Marta Cañamero, Paul J. Grippo, Lena Verdaguer, Lucía Pérez-Gallego, Pierre Dubus, Eric P. Sandgren, Mariano Barbacid,
Tópico(s)Pancreatic function and diabetes
ResumoPancreatic ductal adenocarcinoma (PDA), one of the deadliest human cancers, often involves somatic activation of K-Ras oncogenes. We report that selective expression of an endogenous K-RasG12V oncogene in embryonic cells of acinar/centroacinar lineage results in pancreatic intraepithelial neoplasias (PanINs) and invasive PDA, suggesting that PDA originates by differentiation of acinar/centroacinar cells or their precursors into ductal-like cells. Surprisingly, adult mice become refractory to K-RasG12V-induced PanINs and PDA. However, if these mice are challenged with a mild form of chronic pancreatitis, they develop the full spectrum of PanINs and invasive PDA. These observations suggest that, during adulthood, PDA stems from a combination of genetic (e.g., somatic K-Ras mutations) and nongenetic (e.g., tissue damage) events.
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