Trp53 deletion stimulates the formation of metastatic pancreatic tumors.
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.
Morton
Jennifer P
JP
University of Massachusetts Medical School, 364 Plantation Street, Worcester, MA 01605, USA. brian.lewis@umassmed.edu
Klimstra
David S
DS
Mongeau
Michelle E
ME
Lewis
Brian C
BC
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism; D002645:Chickens; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D017353:Gene Deletion; D007267:Injections; D051379:Mice; D009362:Neoplasm Metastasis / Q000473:pathology*; D010196:Pancreatic Elastase / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency* / Q000378:metabolism
D000952:Antigens, Polyomavirus Transforming; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016159:Tumor Suppressor Protein p53; D010196:Pancreatic Elastase