The objective of this project is to develop transgenic mouse models to study the interaction of nuclear oncogenes and growth factors in tumorigenesis. Our initial model was aimed at defining the interaction, as well as the possible synergistic effect of c-myc and transforming growth factor-alpha (TGF-alpha) during hepatocarcinogenesis. Coexpression of c-myc and TGF-` as transgenes in the mouse liver resulted in a tremendous acceleration of neoplastic development in this organ as compared to expression of either of these transgenes alone. The two distinct cellular reactions that occurred in the liver of the double transgenic mice prior to the appearance of liver tumors were dysplastic and apoptotic changes in the existing hepatocytes followed by emergence of multiple focal lesions composed of both hyperplastic and dysplastic cell populations. We generated double-transgenic mice harboring both c- myc and hepatocyte growth factor (HGF) under the albumin promoter/enhancer. HGF was chosen because it is known to be an important regulator of liver regeneration in vivo and a potent mitogen for mature hepatocytes in vitro. The results of the current study demonstrate clearly that HGF and TGF-alpha act in a different way if co-expressed with c-myc in a transgenic mouse model. Whereas TGF-alpha/myc mice exhibited dysplastic and neoplastic changes in the liver at a very early age, the HGF/myc mice show no signs of neoplastic transformations at the same and even later time points. However, both double-transgenic models (HGF/myc and TGF-alpha/myc) exhibit morphological evidence for an increase in mitotic activity and apoptosis. This is of particular interest since it has been proposed that a balanced ratio between proliferating and apoptotic signals is critical to prevent a carcinogenic progression. We predict that these double-transgenic mouse models will be useful to analyze the factors acting throughout the multistep process of carcinogenesis.
