Ras Activity Levels Control the Development of Pancreatic Diseases

Overview

Journal Gastroenterology

Specialty Gastroenterology

Date 2009 Jun 9

PMID 19501586

Citations 120

Authors

Baoan Ji

Lilian Tsou

Huamin Wang

Sebastian Gaiser

David Z Chang

Jaroslaw Daniluk

Yan Bi

Tobias Grote

Daniel S Longnecker

Craig D Logsdon

Affiliations

Soon will be listed here.

Abstract

Background & Aims: Differentiated pancreatic acinar cells expressing endogenous levels of mutant K-Ras do not spontaneously develop pancreatic ductal adenocarcinoma (PDAC). However, we hypothesized that acinar cells would develop PDAC in the presence of Ras activity levels mimicking those of human tumor cells.

Methods: We measured Ras activity in PDAC cells from mice and humans using a Raf pull-down assay. We compared the effects of acinar cell expression of mutant K-Ras at endogenous and elevated levels on Ras activity and on the development of PDAC.

Results: Ras activity was greatly elevated in PDAC cells compared with nontransformed cells expressing endogenous levels of mutant K-Ras. Expression of endogenous levels of mutant K-Ras in differentiated acinar cells resulted in moderately elevated Ras activity and in sparse murine pancreatic intraepithelial neoplasias (mPanINs) that did not spontaneously advance to PDAC unless the tumor suppressor p53 was simultaneously deleted. In contrast, expression of mutant K-Ras at higher levels generated Ras activity equal to that in PDAC. High Ras activity mimicking levels in PDAC led to acinar cell senescence and generated inflammation and fibrosis resembling the histologic features of chronic pancreatitis. With higher Ras activity in acinar cells, abundant mPanINs formed and spontaneously progressed to both cystic papillary carcinoma and metastatic PDAC.

Conclusions: There is an important relationship between Ras activity levels and the progression of PDAC. Sufficient Ras activity in pancreatic acinar induces several important pancreatic disease manifestations not previously reported and supports a potential direct linkage between chronic pancreatitis, cystic papillary carcinoma, and PDAC.

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