HEPATOCYTE GROWTH-FACTOR SCATTER FACTOR OVEREXPRESSION INDUCES GROWTH, ABNORMAL-DEVELOPMENT, AND TUMOR-FORMATION IN TRANSGENIC MOUSE LIVERS

To investigate the in vivo role of hepatocyte growth factor/scatter fa ctor (HGF/SF) in liver function, we generated transgenic mice using a mouse HGF/SF cDNA under the control of the mouse metallothionein gene promoter and 5'/3' flanking sequences. In adult HGF/SF transgenic mice , liver weight as a percentage of total body weight was at least twice that of wildtype mice. Comparison of transgenic and control liver mor phology revealed dramatic heterogeneity in the size and appearance of hepatocytes as a distinctive feature of HGF/SF overexpression. Transge nic livers exhibited a significant increase in the number of small hep atocytes with a 2N DNA content, accounting for the observed increase i n liver mass. The DNA labeling index of hepatocytes increased 11-fold at 4 weeks of age, when liver enlargement first became apparent, and w as still elevated about 5-fold in adult HGF/SF transgenic mice. Moreov er, hepatocytes isolated by perfusion of transgenic livers doubled eve ry 2 days in culture, whereas little or no growth was observed with is olated control hepatocytes. The mechanistic basis of hepatocyte prolif eration was elucidated as the chronic activation of the c-met proto-on cogene product. Met and substrates such as phosphatidylinositol 3-kina se. Src homology and collagen-like, pp60(c-src), focal adhesion kinase p125(FAK), and paxillin were associated with tyrosine-phosphorylated complexes in a hepatocyte cell line established from the transgenic li ver. This proliferative stimulus triggered the formation of hepatocell ular adenomas and/or carcinomas in most transgenic mice greater than o r equal to 1.5 years of age. Finally, the rate of transgenic mouse liv er regeneration was increased 3-fold over control livers following par tial hepatectomy.