Abstract
Targeting of oncogenic Kras to the pancreatic Nestin-expressing embryonic progenitor cells and subsequently to the adult acinar compartment and Nestin-expressing cells is sufficient for the development of low grade pancreatic intraepithelial neoplasia (PanIN) between 2 and 4 months. The mice die around 6 month-old of unrelated causes, and it is therefore not possible to assess whether the lesions will progress to carcinoma. We now report that two brief episodes of caerulein-induced acute pancreatitis in 2 month-old mice causes rapid PanIN progression and pancreatic ductal adenocarcinoma (PDAC) development by 4 months of age. These events occur with similar frequency as observed in animals where the oncogene is targeted during embryogenesis to all pancreatic cell types. Thus, these data show that oncogenic Kras-driven PanIN originating in a non-ductal compartment can rapidly progress to PDAC when subjected to a brief inflammatory insult.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) accounts for over 95% of all exocrine pancreatic malignancies and is the fourth leading cause of cancer-related death in the United States, with a median survival of 6 months [1]
We show that N/K mice, when subjected to two episodes of caerulein-induced acute pancreatitis (AP), rapidly develop high-grade pancreatic intraepithelial neoplasia (PanIN) that have the capacity to progress to PDAC
We have previously shown that two episodes of acute pancreatitis (AP) induced by caerulein accelerated PanIN progression from low- to high-grade and increased PDAC frequency in the Pdx1-Cre; LSLKrasG12D (P/K) mouse model [14]
Summary
Pancreatic ductal adenocarcinoma (PDAC) accounts for over 95% of all exocrine pancreatic malignancies and is the fourth leading cause of cancer-related death in the United States, with a median survival of 6 months [1]. The first relevant mouse models of PDAC were generated by targeting a conditionally mutated Kras allele (KrasG12D) to early pancreatic progenitors (using Pdx and Ptf1a promoters) and subsequently to all pancreatic cell types [4,5]. These models recapitulated faithfully the full spectrum of human PanIN progression and pancreatic cancer development, demonstrating that oncogenic Kras expression is sufficient for PDAC initiation. We were not able to observe progression to PDAC in N/K mice, as they generally die around age 6 months from of central nervous system complications
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