Growth factors in liver development, regeneration and carcinogenesis.

Liver growth during regeneration is controlled by several growth factors which may be involved in the triggering, progression and termination of hepatocyte replication. It is likely that liver regeneration involves both circulating factors and those produced in hepatic tissue during the growth response. TGF alpha is an autocrine stimulator of hepatocyte proliferation which increases transiently in replicating hepatocytes both in vivo and in vitro. Constitutive TGF alpha overexpression in young transgenic mice causes liver hypertrophy and enhanced proliferation that progress to hepatic tumor development in the great majority of animals after 12 months of age. In contrast, HGF is present in normal blood in humans and animals and plasma concentrations increase after partial hepatectomy, liver injury and fulminant hepatic failure. In liver tissue, levels of HGF and its mRNA correlate better with the extent of injury than with the degree of proliferative activity. The factor is produced by nonparenchymal cells and presumably acts on hepatocytes through paracrine or endocrine mechanisms. A transient increase of TGF beta 1 in regenerating liver may promote the formation of extracellular matrix components and signal the end of hepatocyte proliferation. Prolonged overexpression of the factor in nonparenchymal cells causes liver fibrosis both in humans and experimental animals. The liver contains TGF beta 1,2 and 3, all of which inhibit hepatocyte DNA synthesis. Their mRNAs increase in the regenerating liver but with very different kinetics. Despite the enormous progress achieved in understanding the mechanisms that regulate liver regeneration, it is not known whether HGF, TGF alpha and TGF beta interact with each other or with other factors or hormones during the growth process. Further, it remains to be established how the effect of these factors may relate to the sequential changes in proto-oncogene expression that occur after partial hepatectomy.