Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras

Abstract

Chronic pancreatitis increases by 16-fold the risk of developing pancreatic ductal adenocarcinoma (PDAC), one of the deadliest human cancers. It also appears to accelerate cancer progression in genetically engineered mouse models. We now report that in a mouse model where oncogenic Kras is activated in all pancreatic cell types, two brief episodes of acute pancreatitis caused rapid PanIN progression and accelerated pancreatic cancer development. Thus, a brief inflammatory insult to the pancreas, when occurring in the context of oncogenic Kras(G12D), can initiate a cascade of events that dramatically enhances the risk for pancreatic malignant transformation.

Figure 1

PanIN progression 2 months following acute pancreatitis episodes. H&E staining of untreated (A) and caerulein treated NK pancreata (B–D). While untreated pancreata display rare lesions (A), treated pancreata show extensive ADM and high number of mPanIN-1 (B), as well as high-grade lesions mPanIN-2 (C) and -3 (D). Islets (dotted outlines), normal ducts (d), mPanIN-1 (empty arrowheads), and mPanIN-2 and -3 (solid arrowheads) are readily seen. Scale bar: 100μm for A–B, 20μm for C–D.

Figure 2

High grade PanIN characterization following acute pancreatitis. Ki67 staining shows a clear increase in proliferation in high-grade lesions (A) when compared to mPanIN-1 (*). High-grade PanINs express CK19 (B) and Muc5a (C). Markers of early progenitors Hes1, panel D) and Pdx1 (panel E) are reactivated; as expected, Pdx1 is also seen in the islet cells (dotted outline). ADM is observed as shown by coexpression of CK19 (green) and Amylase (red) in same cells (see inset). Scale bar: 20μm.

Figure 3

PK mice develop PDAC following acute pancreatitis. H&E staining of ductal adenocarcinoma (A) reveals the presence of many nuclei that are enlarged, pleomorphic and crowded, with the cancer cells exhibiting a ductal-like morphology. Adenocarcinoma cells are highly proliferative as shown by Ki67 expression (B). They are surrounded by fibroblasts characterized by SMA expression (C). Scale bar: 20μm.