Mechanisms of hepatocyte growth factor activation in cancer tissues.

Makiko Kawaguchi,Hiroaki Kataoka

doi:10.3390/cancers6041890

Abstract

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.

Highlights

The interactions between cancer cells and stromal cells in the tumor microenvironment play a pivotal role in establishing the aggressive characteristics of cancer, such as invasion and metastasis [1].the expression and activity of many growth factors involved in cancer progression are highly dependent on these interactions, with regulation of hepatocyte growth factor (HGF) activity being a typical example of the mutual interaction between cancer cells and stromal cells [2]
We have reported that in ApcMin/+ mice, targeted disruption of the Spint1 gene that encodes HGFA inhibitor (HAI)-1 resulted in significantly increased amounts of tumor formation, whereas activation of Hepatocyte growth factor/scatter factor (HGF/scatter factor (SF)) in the intestine was enhanced in HAI type-1 (HAI-1)-deficient tumors and non-tumor mucosa [19]
The HAI-2 (SPINT2) gene is a candidate for a novel tumor suppressor, further studies will be required to determine the regulatory roles of HAI-2 in pericellular activation of HGF/SF and induction of MET signaling, as well as to describe the effect of HAI-2 loss on MET signaling in cancer cells

Summary

Introduction

The interactions between cancer cells and stromal cells in the tumor microenvironment play a pivotal role in establishing the aggressive characteristics of cancer, such as invasion and metastasis [1].the expression and activity of many growth factors involved in cancer progression are highly dependent on these interactions, with regulation of hepatocyte growth factor (HGF) activity being a typical example of the mutual interaction between cancer cells and stromal cells [2]. This review summarizes the current knowledge regarding proteolytic activation of HGF/SF, its regulation by HAI in cancer tissues, and the possible roles of these proteins in carcinogenesis and cancer progression. In addition to pro-HGF/SF, matriptase has multiple other substrates, such as protease activated receptor 2, pro-prostasin and pro-MSP [48], which may be involved in cellular context- and environment-dependent effects of matriptase on cancer progression.

Results

Conclusion