Published online before print February 29, 2008

This Article Full Text Full Text (PDF) All Versions of this Article: ajpath.2008.070778v1 172/4/1081    most recent Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Morton, J. P. Articles by Lewis, B. C. Search for Related Content PubMed PubMed Citation Articles by Morton, J. P. Articles by Lewis, B. C.

(American Journal of Pathology. 2008;172:1081-1087.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.070778

Trp53 Deletion Stimulates the Formation of Metastatic Pancreatic Tumors

Jennifer P. Morton^*, David S. Klimstra, Michelle E. Mongeau^* and Brian C. Lewis^*

From the Programs in Gene Function and Expression,^* and Molecular Medicine, and the Memorial Cancer Center, University of Massachusetts Medical School, Worcester, Massachusetts; and the Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York

The presence of distant metastases is a common finding on diagnosis of pancreatic cancer; however, the mechanisms underlying the dissemination of this tumor type remain poorly understood. Loss of the p53 tumor suppressor protein has been associated with tumor progression and metastasis in several tumor types including pancreatic ductal adenocarcinoma. Here, we describe the generation of a progressive and metastatic pancreatic cancer mouse model after the somatic and sporadic delivery of avian retroviruses encoding the mouse polyoma virus middle T antigen to elastase-tv-a transgenic mice with a pancreas-specific deletion of the Trp53 tumor suppressor locus. In this model, the tumors metastasize most frequently to the liver, consistent with human pancreatic carcinomas. Analysis of metastatic lesions demonstrated that concomitant loss of the Ink4a/Arf locus was not required for metastasis; however, pancreas-specific deletion of a single Ink4a/Arf allele cooperated with Trp53 deletion in a haploinsufficient manner to accelerate tumor development. Thus, our findings illustrate the potential role of p53 loss of function in pancreatic tumor progression, demonstrate the feasibility of modeling pancreatic cancer metastasis after somatic and sporadic oncogene activation, and indicate that our model may provide a useful experimental system for investigation of the molecular mechanisms underlying pancreatic cancer progression and metastasis.