Published online before print April 26, 2007

This Article Full Text (Rapid PDF) All Versions of this Article: ajpath.2007.061176v1 171/1/263    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhu, L. Articles by Konieczny, S. F. Search for Related Content PubMed Articles by Zhu, L. Articles by Konieczny, S. F.

Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.061176

Accepted for publication March 22, 2007.

Article

Acinar Cells Contribute to the Molecular Heterogeneity of Pancreatic Intraepithelial Neoplasia

Liqin Zhu^*, Guanglu Shi^*, C. Max. Schmidt, Ralph H. Hruban, and Stephen F. Konieczny^*@

From the Department of Biological Sciences and the Purdue Cancer Center,* Purdue University, West Lafayette, Indiana; the Departments of Surgery and Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana; and the Departments of Pathology and Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland

^@ To whom correspondence should be addressed. E-mail: sfk{at}bio.purdue.edu.

	Abstract

A number of studies have shown that pancreatic ductal adenocarcinoma develops through precursor lesions termed pancreatic intraepithelial neoplasia (PanIN). PanINs are thought to initiate in the small ducts of the pancreas through activating mutations in the KRAS proto-oncogene. What remains unanswered is the identification of the individual cell type(s) that contributes to pancreatic ductal adenocarcinoma formation. To follow the cellular and molecular changes that occur in acinar and duct cell properties on Kras^G12D expression, we took advantage of LSL-Kras^G12D/+/p48^Cre/+ mice, which faithfully mimic the human disease. In young animals (4 weeks), the predominant cellular alteration in the exocrine pancreas was acinar metaplasia in which individual acini consisted of acinar cells and duct-like cells. Metaplastic acinar structures were highly proliferative, expressed Notch target genes, and exhibited mosaic expression patterns for epidermal growth factor receptor, ErbB2, and pErk. This expression pattern paralleled the expression pattern detected in mouse PanINs, suggesting that mouse PanINs and acinar-ductal metaplasia follow similar molecular pathways. Indeed, immunofluorescence studies confirmed the presence of acinar cells within mPanIN lesions, raising the possibility that Kras^G12D-induced mPanINs develop from acinar cells that undergo acinar-ductal metaplasia. Identification of an acinar contribution to PanIN formation offers new directions for successful targeted therapeutic approaches to combat this disease.

This article has been cited by other articles:

				M Mimeault and S K Batra Recent progress on normal and malignant pancreatic stem/progenitor cell research: therapeutic implications for the treatment of type 1 or 2 diabetes mellitus and aggressive pancreatic cancer Gut, October 1, 2008; 57(10): 1456 - 1468. [Abstract] [Full Text] [PDF]

				A. F. Hezel, S. Gurumurthy, Z. Granot, A. Swisa, G. C. Chu, G. Bailey, Y. Dor, N. Bardeesy, and R. A. DePinho Pancreatic Lkb1 Deletion Leads to Acinar Polarity Defects and Cystic Neoplasms Mol. Cell. Biol., April 1, 2008; 28(7): 2414 - 2425. [Abstract] [Full Text] [PDF]