EVOLUTION OF NEOPLASTIC DEVELOPMENT IN THE LIVER OF TRANSGENIC MICE CO-EXPRESSING C-MYC AND TRANSFORMING GROWTH-FACTOR-ALPHA

We have previously shown that co-expression of c-myc and transforming growth factor (TGF)-alpha as transgenes in mouse liver results in majo r enhancement of neoplastic development in this organ as compared with expression of either of these transgenes alone. In this report we des cribe in detail the progression from liver cell dysplasia to hepatocel lular carcinomas (HCCs) occurring in the liver of c-myc/TGF-alpha and c-myc transgenic mice. Despite morphological similarities in the seque nce of events between the two transgenic lines, the dramatic accelerat ion, extent, and severity of hepatic lesions in c-myc/TGF-alpha mice c learly demonstrated the synergistic effects of this transgenic combina tion. Although c-myc/TGP-alpha and c-myc females displayed longer late ncy and lower tumor incidence, the pathological changes were the same as those seen in the male mice, including the formation of HCCs, which are absent in TGF-alpha single-transgenic females. Tumors in single- and double-transgenic mice showed induction of the endogenous c-myc an d TGF-alpha and, most frequently, unchanged or decreased epidermal gro wth factor receptor, further indicating the collaborative role of c-my c and TGF-alpha in providing a selective growth advantage to tumor cel ls independently of the epidermal growth factor receptor levels. To id entify Possible tumor precursors, we focused particularly on the dyspl astic changes Preceding and accompanying the appearance of preneoplast ic and neoplastic lesions in the double-transgenic mice. Early on, the se changes were characterized by the appearance of large dysplastic he patocytes, mostly pericentrally, expressing high levels of TGF-alpha a nd uPA, as wed as TGF-beta 1, particularly in apoptotic cells. After a short period of replication and expansion into the liver parenchyma, as well as penetration into the central veins, these cells underwent a poptotic cea death while preneoplastic and neoplastic lesions were for ming. The peritumorous tissues also contained small dysplastic hepatoc ytes and oval-like cells, similar to those found in the tumors. Transp lantation of the transgenic liver tissues harboring only dysplasia wit h or without vascular lesions onto nude mice was able to yield HCCs co mposed of small diploid cells, suggesting that initiated cells are gen erated during the early dysplastic phase and can progress to HCC. It i s therefore likely that large dysplastic hepatocytes undergo apoptosis , which may be closely associated with the up-regulation of TGF-beta 1 and uPA, whereas other cells evolve into the precursor population for HCC. Due to the simultaneous presence of c-myc, TGF-alpha, and dyspla sia in premalignant human liver diseases, our transgenic mouse system appears to be an appropriate model for studying human hepatocarcinogen esis.