Hepatocyte growth factor--pleiotropic cytokine produced by human leukemia cells.

Abstract

Hepatocyte growth factor (HGF) was identified, purified and molecularly cloned as a potent mitogen for mature rat hepatocytes in primary culture. It is one of the largest cytokines and is composed of disulfide-linked subunits of approximately 60 (heavy chain) and 35 kilodaltons (light chain). Recent observations revealed that HGF is mitogenic to various epithelial cells other than hepatocytes and to endothelial cells, and that it also acts as a motogen, morphogen and tumor-suppressor as well as a mitogen. These various biological activities of HGF are presumably transduced through the same receptor, c-Met, which is a member of the tyrosine kinase receptor family. Although it shows multiple biological activities on cells in culture, HGF is most likely the physiological hepatotrophic factor which triggers liver regeneration. It may also function as a renotrophic and pulmotrophic factor after tissue injury. HGF production in the liver, kidney and lung increases after injury to these organs. An elevated HGF level may act as an inducer of compensatory DNA synthesis. The regulation of HGF production is, therefore, important for the control of organ regeneration. HGF is produced mainly by mesenchymal cells such as fibroblasts and vascular smooth muscle cells. Various types of human leukemia cells also secrete HGF both in vitro and in vivo. Some biological activities of HGF on hematopoietic cells, including co-mitogenic activity on myeloid leukemia cell lines, were recently demonstrated. HGF gene expression and the protein production in leukemia and fibroblast cells are modulated by various cytokines and hormones. Those modulators may indirectly affect organ regeneration and other biological processes by controlling HGF production.