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Mechanisms of Hepatocyte Growth Factor Activation in Cancer Tissues

Section of Oncopathology and Regenerative Biology, Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan
Author to whom correspondence should be addressed.
Cancers 2014, 6(4), 1890-1904;
Received: 2 July 2014 / Revised: 2 September 2014 / Accepted: 3 September 2014 / Published: 29 September 2014
(This article belongs to the Special Issue MET in Cancer)
Hepatocyte growth factor/scatter factor (HGF/SF) plays critical roles in cancer progression through its specific receptor, MET. HGF/SF is usually synthesized and secreted as an inactive proform (pro-HGF/SF) by stromal cells, such as fibroblasts. Several serine proteases are reported to convert pro-HGF/SF to mature HGF/SF and among these, HGF activator (HGFA) and matriptase are the most potent activators. Increased activities of both proteases have been observed in various cancers. HGFA is synthesized mainly by the liver and secreted as an inactive pro-form. In cancer tissues, pro-HGFA is likely activated by thrombin and/or human kallikrein 1-related peptidase (KLK)-4 and KLK-5. Matriptase is a type II transmembrane serine protease that is expressed by most epithelial cells and is also synthesized as an inactive zymogen. Matriptase activation is likely to be mediated by autoactivation or by other trypsin-like proteases. Recent studies revealed that matriptase autoactivation is promoted by an acidic environment. Given the mildly acidic extracellular environment of solid tumors, matriptase activation may, thus, be accelerated in the tumor microenvironment. HGFA and matriptase activities are regulated by HGFA inhibitor (HAI)-1 (HAI-1) and/or HAI-2 in the pericellular microenvironment. HAIs may have an important role in cancer cell biology by regulating HGF/SF-activating proteases. View Full-Text
Keywords: hepatocyte growth factor; hepatocyte growth factor activator; matriptase; TTSP; HAI-1; HAI-2 hepatocyte growth factor; hepatocyte growth factor activator; matriptase; TTSP; HAI-1; HAI-2
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Kawaguchi, M.; Kataoka, H. Mechanisms of Hepatocyte Growth Factor Activation in Cancer Tissues. Cancers 2014, 6, 1890-1904.

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