Abstract
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.
SUPPLEMENTAL MATERIAL
Supplemental material for this article may be found at http://mcb.asm.org/.
ACKNOWLEDGMENTS
We thank the MSKCC transgenic core for the generation of albumin-tv-a mice; Michelle Fluck for reagents; Mary Barrett, Jennifer Doherty, Ya-Wen Chen, Meena Tanwar, and Irina Linkov for technical assistance; Cornelia Matei and Mihaela Lupu for assistance with MRI; Agnes Viale, Juan Li and the MSKCC Genomics Core Lab for assistance with the microarray experiments; the MSKCC Molecular Cytology Core for assistance with in situ hybridization; and Kirsten Hubbard and members of the Varmus lab for discussion and critical reading of the manuscript.
This work was supported by NIH grants R24CA83084, CA08748, and CA94060 (J.A.K.). B.C.L. was supported by a Helen Hay Whitney Foundation postdoctoral fellowship and a Career Award in the Biomedical Sciences from the Burroughs Wellcome Fund.