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Introduction
Hepatocyte growth factor/scatter factor (HGF/SF), which is mainly secreted by Kuppfer cells, endothelial cells, fibroblasts and hepatic stellate cells in the liver, has been shown to have a role in embryonic organ development, adult organ regeneration and wound healing (1). HGF regulates cell growth, cell motility and morphogenesis by binding to its unique receptor c-Met and by activating a tyrosine kinase-signaling cascade (2–4). Owing to its functions, including stimulating mitogenesis, cell motility and matrix invasion, HGF has a central role in angiogenesis, tumorigenesis and tissue regeneration.
Hepatocellular carcinoma (HCC) is one of most common malignant tumors; the incidence rate and mortality of HCC is the fifth- and third-highest in the world, respectively (5). Although several advanced treatments are now available, including surgical resection, liver transplantation and ablation therapies (6), and in spite of the development of molecular-target drugs such as sorafenib (7), the five-year overall survival rate of patients with advanced HCC remains poor (8). The main reason for the poor survival rate of advanced HCC is the high rate of recurrence and metastasis after local treatment (9).
The tumor microenvironment is composed of various stromal cells, including myofibroblasts, vascular cells and immune cells, and it has an important role in not only supporting the growth and survival of tumor cells but also in triggering tumor recurrence and metastasis (10). Within the tumor microenvironment, several of the growth factors secreted by stromal or tumor cells, including HGF, insulin-like growth factor 1 (IGF1), epidermal growth factor (EGF), vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), may induce a similar signaling cascade downstream of receptor tyrosine kinase (RTK) and trigger synergistic tumor recurrence and metastasis (11). The important role of the HGF/c-Met signaling pathway in carcinogenesis and development has been well established. For example, this pathway activates mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathways as well as enables cross-talk with epidermal growth factor and transforming growth factor (TGF)-β ligands. Overactivation of these pathways promotes proliferation, survival, migration, invasiveness and angiogenesis of certain tumors (11,12). In general, the HGF expression levels in the liver cancer microenvironment after surgery show marked increases, implicating HGF as one of the main causes of HCC recurrence and metastasis (13).
In addition to...