Abstract
Hepatocyte growth factor (HGF) is composed of an α-chain and a β-chain, and these chains contain four kringle domains and a serine protease-like structure, respectively. Activation of the HGF–Met pathway evokes dynamic biological responses that support morphogenesis (e.g., epithelial tubulogenesis), regeneration, and the survival of cells and tissues. Characterizations of conditional Met knockout mice have indicated that the HGF–Met pathway plays important roles in regeneration, protection, and homeostasis in various cells and tissues, which includes hepatocytes, renal tubular cells, and neurons. Preclinical studies designed to address the therapeutic significance of HGF have been performed on injury/disease models, including acute tissue injury, chronic fibrosis, and cardiovascular and neurodegenerative diseases. The promotion of cell growth, survival, migration, and morphogenesis that is associated with extracellular matrix proteolysis are the biological activities that underlie the therapeutic actions of HGF. Recombinant HGF protein and the expression vectors for HGF are biological drug candidates for the treatment of patients with diseases and injuries that are associated with impaired tissue function. The intravenous/systemic administration of recombinant HGF protein has been well tolerated in phase I/II clinical trials. The phase-I and phase-I/II clinical trials of the intrathecal administration of HGF protein for the treatment of patients with amyotrophic lateral sclerosis and spinal cord injury, respectively, are ongoing.
Highlights
Background of Hepatocyte GrowthFactor (HGF)–Met Pathway Leading to Drug DiscoveryHepatocyte growth factor (HGF) was molecularly cloned as a growth factor for hepatocytes [1,2]
Based on the close involvement of HGF and its receptor Met— in tumor development, invasion, and metastasis and in resistance to anticancer therapies—drug discovery targeting the HGF–Met pathway has become a hot target in anticancer drug development [156,157,158,159,160]
On the other hand, based on studies using cell/tissue-specific disruption of functional Met and preclinical disease models in experimental animals, recombinant HGF proteins and HGF genes have become biological drug candidates for the treatment of patients with diseases marked by impaired tissue function [43,141]
Summary
Tissue-specific disruption of the functional Met in mice indicated that HGF plays a promoting role in the regeneration, protection, and homeostasis of tissues, and an inhibitory role in the progression of chronic inflammation and fibrosis. Enhancement of Met-mediated signaling and biological responses is likely to become therapeutic for the treatment of different types of diseases. The prevention of cell death against various types of stress and injury explains the protective action of HGF, and this seems to be associated with a subsequent suppression of inflammation. The biological actions of HGF on immune cells are likely to underlie the mechanisms by which HGF exerts its therapeutic effect on diseases associated with allergies, inflammation, and fibrosis, at least in part. It should be emphasized that there has been no effective medicine for the treatment of chronic fibrotic diseases, whereas HGF-treatment has been effective in reducing fibrosis and improving tissue function in disease models, including liver cirrhosis, chronic kidney disease, dilated cardiomyopathy, lung fibrosis, and vocal fold scarring
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