Transgenic mouse models in carcinogenesis: interaction of c-myc with transforming growth factor α and hepatocyte growth factor in hepatocarcinogenesis

Abstract

1Overexpression of the c-myc oncogene is associated with a variety of both human and experimental tumours, and cooperation of other oncogenes and growth factors with the myc family are critical in the evolution of the malignant phenotype.

2Double transgenic mice bearing fusion genes consisting of mouse albumin enhancer/promoter-mouse c-myc cDNA and mouse metallothionein 1 promoter-human transforming growth factor (TGF-α) cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradigm for characterizing the interaction of nuclear oncogenes and growth factors in tumourigenesis.

3Coexpression of c-myc and TGF-α 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 tumours were dysplastic and apoptotic changes in the existing hepatocytes followed by emergence of multiple focal lesions composed of both hyperplastic and dysplastic cell populations.

4These observations suggest that the interaction of c-myc and TGF-α, during development of hepatic neoplasia contributes to the selection and expansion of the preneoplastic cell populations which consequently increases the probability of malignant conversion.

5We have now extended these studies and examined the interaction of hepatocyte growth factor (HGF) with c-myc during hepatocarcinogenesis in the transgenic mouse model. While sustained overexpression of c-myc in the liver leads to cancer, coexpression of HGF and c-myc in the liver delayed the appearance of preneoplastic lesions and prevented malignant conversion. Similarly, tumour promotion by phenobarbitone was completely inhibited in the c-myc/HGF double transgenic mice whereas phenobarbitone was an effective tumour promoter in the c-myc single transgenic mice.

6The results indicate that HGF may function as a tumour suppressor during early stages of liver carcinogenesis, and suggest the possibility of therapeutic application for this cytokine. Furthermore, we show for the first time that interaction of c-myc with HGF or TGF-α results in profoundly different outcomes of the neoplastic process in the liver.

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