Pharmaceutical Sciences Faculty Publications

Preinvasive and Invasive Ductal Pancreatic Cancer and its Early Detection in the Mouse

Document Type

Article

Publication Date

12-1-2003

Journal Title

Cancer Cell

ISSN

1535-6108

Volume

4

Issue

6

First Page

437

Last Page

450

Abstract

To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.

Keywords

Basic helix-loop-helix transcription factors, carcinoma, pancreatic ductal, homeodomain proteins, immunohistochemistry, isoenzymes, membrane proteins, mice, mutation, neoplasms, pancreas, pancreatic neoplasms, prostaglandin-endoperoxide synthases

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