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Toxicologic Pathology
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Molecular Mechanisms of Hepatocarcinogenesis in Transgenic Mouse Models of Liver Cancer

Diego F. Calvisi and Snorri S. Thorgeirsson

Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA

Correspondence: Address correspondence to: Dr. Snorri S. Thorgeirsson, National Cancer Institute, NIH, 37 Convent Drive, MSC 4262, Building 37, Room 4146A, Bethesda, Maryland 20892-4262, USA; e-mail:snorri_thorgeirsson{at}nih.gov

Overexpression of c-myc and transforming growth factor-alpha (TGF-{alpha}) has been frequently observed in human hepatocellular carcinoma (HCC), suggesting a pivotal role played by these protooncogenes in liver oncogenesis. In order to investigate the molecular events underlying human hepatic malignant transformation, we have generated c-myc and c-myc/TGF-{alpha} transgenic mice that are prone to liver cancer. These transgenic mice develop HCCs with different incidence, kinetics and histopathological features. Indeed, co-expression of c-myc and TGF-{alpha} transgenes results in a dramatic synergistic effect on liver tumor development when compared with respective single transgenic lines, including a shorter latency period and a more aggressive phenotype. The more malignant histopathological features characteristic of c-myc/TGF-{alpha} HCCs are the result of the increased proliferation and reduced apoptosis in this model of liver cancer when compared with single parental lines. Accordingly, c-myc and c-myc/TGF-{alpha} transgenic mice display a different molecular pathogenesis of HCC. Importantly, the genetic and molecular mechanisms that are involved in c-myc and c-myc/TGF-{alpha} liver cancer development are major oncogenic events in human hepatocarcinogenesis, indicating that these mouse models represent a useful tool to dissect and elucidate the molecular basis of human HCC.

Key Words: c-myc • TGF-{alpha} • transgenic mice • HCC • genomic instability • β-catenin

Abbreviations: HCC, hepatocellular carcinoma • ROS, reactive oxygen species • TβR, transforming growth factor receptor II • TGF, transforming growth factor

Toxicologic Pathology, Vol. 33, No. 1, 181-184 (2005)
DOI: 10.1080/01926230590522095
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