INTERACTION OF C-MYC WITH TRANSFORMING-GROWTH-FACTOR-ALPHA AND HEPATOCYTE GROWTH-FACTOR IN HEPATOCARCINOGENESIS

Double transgenic mice bearing fusion genes consisting of mouse albumi n enhancer/promoter-mouse c-myc cDNA and mouse metallothionein 1 promo ter-human TGF-alpha cDNA were generated to investigate the interaction of these genes in hepatic oncogenesis and to provide a general paradi gm for characterizing the interaction of nuclear oncogenes and growth factors in tumorigenesis. Coexpression of c-myc and TGF-alpha as trans genes in the mouse liver resulted in a tremendous acceleration of neop lastic development in this organ as compared to expression of either o f these transgenes alone. The two distinct cellular reactions that occ urred in the liver of the double transgenic mice prior to the appearan ce of liver tumors were dysplastic and apoptotic changes in the existi ng hepatocytes followed by emergence of multiple focal lesions compose d of both hyperplastic and dysplastic cell populations. These observat ions suggest that the interaction of c-myc and TGF-alpha, during devel opment of hepatic neoplasia contributes to the selection and expansion of the preneoplastic cell populations which consequently increases th e probability of malignant conversion. These studies have now been ext ended to examine the interaction of hepatocyte growth factor (HGF) wit h c-myc during hepatocarcinogenesis in the transgenic mouse model. Whi le sustained overexpression of c-myc in the liver leads to cancer, coe xpression of HGF and c-myc in the Liver delayed the appearance of pren eoplastic lesions and prevented malignant conversion. Similarly, tumor promotion by phenobarbital was completely inhibited in the c-myc/HGF double transgenic mice whereas phenobarbital was an effective tumor pr omoter in the c-myc single transgenic mice. The results indicate that HGF may function as a tumor suppressor during early stages of Liver ca rcinogenesis, and suggest the possibility of therapeutic application f or this cytokine. Furthermore, we show for the first time that interac tion of c-myc with HGF or TGF-alpha results in profoundly different ou tcomes of the neoplastic process in the liver.