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Hepatocyte growth factor (HGF) was purified as a potent mitogen for rat hepatocytes in primary culture and is believed to be the most physiological hepatotrophic factor that triggers liver regeneration. HGF is one of the largest disulfide-linked cytokines, consisting of a 60-kDa heavy chain and a 35-kDa light chain. Human HGF is synthesized as a single polypeptide chain precursor of 728 amino acid residues that has an appreciable homology with plasminogen, and it is processed proteolytically to release an N-terminal signal peptide of 31 amino acids and to generate an active heterodimer after secretion. The novel serine protease HGF activator and urokinase-type plasminogen activator (u-PA) are responsible for the latter extracellular processing. HGF stimulates the proliferation of rat hepatocytes in primary culture at concentrations as low as 10 pM. It also stimulates the growth of various epithelial cells, endothelial cells, and some kinds of mesenchymal cells. HGF inhibits the proliferation of several tumor cell lines and induces apoptosis of some of them. It also has motogenic, morphogenic, anti-apoptotic, angiogenic, and immunoregulatory activities. The receptor of HGF is the product of c-met proto-oncogene with tyrosine kinase activity that mediates the transduction of multiple biological signals of HGF. During liver regeneration, HGF gene expression in the liver, spleen, and lung and HGF levels in the blood and liver increase prior to the induction of liver DNA synthesis. Liver regeneration is markedly inhibited by continuous administration of a neutralizing anti-HGF antibody. HGF production in cultured cells is induced by PKC-activating agents, cAMP-elevating agents, PKA-activating agents, growth factors, and inflammatory cytokines; and it is inhibited by TGF-beta, glucocorticoids, 1,25-dihydroxyvitamin D3, and retinoic acid. There are many reports on potential application of HGF as a therapeutic agent for organ diseases that are difficult to cure such as liver cirrhosis, chronic renal failure, pulmonary fibrosis, myocardial infarction, and arteriosclerosis obliterans utilizing its potent growth-stimulating activity for a wide variety of cells. ELISA kits for assays of serum and plasma HGF levels are clinically used to prognosticate the development of fulminant hepatic failure.

Antitumor activity of cisplatin, carboplatin, etoposide, or human hepatocyte growth factor (hHGF), was compared by examining the colony formation ability of four liver cancer cell lines (PLC/PRF/5 and HuH-7, hepatocellular carcinoma; HuH-6 and HepG2, hepatoblastoma). Antitumor activity was evaluated from the drug concentration causing 50% cell death by a colony assay. PLC/PRF/5 cells were most effectively killed by cisplatin and etoposide, HuH-7 cells by cisplatin and carboplatin, HuH-6 cells by etoposide, and Hep G2 cells by cisplatin. These results indicate that among four liver cancer cell lines, the three were the most sensitive to cisplatin, the two were to etoposide and the only one cell line was to carboplatin. There was no significant relationship between each drug and types of liver cancer. Combined treatment with cisplatin (0.01-1.0 microgram/ml) and etoposide (0.1 microgram/ml) showed synergistic cytotoxic effects on the colony formation of PLC/PRF/5 cells, while combination of carboplatin (0.01-0.1 microgram/ml) and etoposide (0.1 microgram/ml) caused subadditive cytotoxic effects. hHGF stimulated the colony formation of HuH-6 cells, while it inhibited that of Hep G2 cells. The treatment of HuH-6 with cisplatin and hHGF showed a higher cell survival percentage compared with the treatment with cisplatin alone. On the other hand, cell survival of Hep G2 cells was remarkably decreased by the combined treatment with cisplatin and hHGF.