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The Absence of p53 Promotes Metastasis in a Novel Somatic Mouse Model for Hepatocellular Carcinoma

Cancer Biology and Genetics Program,¹ Department of Pathology,² Computational Biology Program,³ Department of Medical Physics, Memorial Sloan-Kettering Cancer Center, New York,⁵ Department of Pathology, Albert Einstein College of Medicine, Bronx, New York⁴

Received 11 June 2004/ Returned for modification 30 July 2004/ Accepted 18 November 2004

We have generated a mouse model for hepatocellular carcinoma using somatic delivery of oncogene-bearing avian retroviral vectors to the liver cells of mice expressing the viral receptor TVA under the control of the albumin gene promoter (Alb-TVA mice). Viruses encoding mouse polyoma virus middle T antigen (PyMT) induced tumors, which can be visualized with magnetic resonance imaging, in 65% of TVA-positive animals. While these tumors can exceed 10 mm in diameter, they do not invade locally or metastasize to the lungs. Delivery of PyMT-expressing viruses to Alb-TVA mice lacking an intact p53 gene does not increase tumor incidence. However, the resulting tumors are poorly differentiated, invasive, and metastatic to the lungs. Gene expression microarrays identified over 100 genes that are differentially expressed between tumors found in p53 wild-type and p53 null mice. Some of these genes, such as cathepsin E and Igf2, have been previously implicated in tumor cell migration and invasion. Tumors induced in p53 null, TVA transgenic mice by PyMT mutants with changes in specific tyrosine residues fail to form metastases, indicating that metastasis is dependent on both the oncogene and the absence of p53.

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