Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice.
Pancreatic 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-Ras(G12V) 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-Ras(G12V)-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.
Guerra
Carmen
C
Molecular Oncology Program, Centro Nacional de Investigaciones Oncológicas, E-28029 Madrid, Spain. mcguerra@cnio.es
Schuhmacher
Alberto J
AJ
Cañamero
Marta
M
Grippo
Paul J
PJ
Verdaguer
Lena
L
Pérez-Gallego
Lucía
L
Dubus
Pierre
P
Sandgren
Eric P
EP
Barbacid
Mariano
M
D000818:Animals; D002278:Carcinoma in Situ / Q000378:metabolism / Q000473:pathology*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D002108:Ceruletide; D004318:Doxycycline / Q000494:pharmacology; D011905:Genes, ras; D008113:Liver Neoplasms / Q000556:secondary; D008175:Lung Neoplasms / Q000556:secondary; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009361:Neoplasm Invasiveness; D010179:Pancreas / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000473:pathology*; D015398:Signal Transduction
D002108:Ceruletide; D004318:Doxycycline