LIVER-REGENERATION AND HEPATOCARCINOGENESIS IN TRANSFORMING GROWTH FACTOR-ALPHA-TARGETED MICE

Transforming growth factor-alpha (TGF alpha), a member of the epiderma l growth factor receptor ligand family, has been implicated in the reg eneration and transformation of liver. Our recent development of mice that are homozygous for a disrupted TGF alpha gene allowed us to asses s the requirement for this growth factor in these complex processes. W e report here that although a 70% hepatectomy produced a significant i ncrease in hepatic TGF alpha protein levels in wild-type mice, liver r egeneration nevertheless proceeded normally in the absence of the grow th factor. The hepatocyte labeling indices determined for homozygous t argeted and wild-type mice at 36 and 48 h after hepatectomy were compa rable, and the total liver DNA to body weight ratios 8 d after hepatec tomy were essentially identical for the two genotypes. These results i ndicate that TGF alpha is not necessary for liver regeneration. To tes t its requirement in liver carcinogenesis, young mice were administere d single doses of diethylnitrosamine (DEN) with or without subsequent chronic treatment with the promoting agent phenobarbital (PB). Both wi ld-type and homozygous mutant male mice treated with DEN or DEN plus P B developed multiple preneoplastic foci or tumors by 9 mo of age with relatively high incidence. However, while five of 88 tumors in wild-ty pe mice attained a diameter greater than 5 mm and were classified as h epatocellular carcinomas, none of 132 tumors in livers of targeted mic e reached this size. Furthermore, three of these large wild-type tumor s expressed significantly elevated levels of TGF alpha protein compare d with normal liver. These results indicate that TGF alpha is not requ ired for early events in chemically induced hepatocarcinogenesis but s uggest that it could be important in the progression from small preneo plastic foci to large tumors. (C) 1996 Wiley-Liss, Inc.