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**14**

*Japan* 

**Significance, Mechanisms, and Progress of** 

Because growth factors and their receptors play critical roles in cancer development and progression, they are potential target molecules in molecular-targeted cancer therapy. Hepatocyte growth factor (HGF) was discovered and cloned as a mitogenic protein for hepatocytes (Nakamura et al., 1984; Nakamura et al., 1989; Miyazawa et al., 1989). These early studies implicated an important role for HGF in regeneration of the liver. The receptor for HGF was identified as the Met transmembrane receptor tyrosine kinase in 1991 (Bottaro et al., 1991; Naldini et al., 1991). The Met oncogene was first isolated as a fused transforming gene from a human osteosarcoma-derived cell line, wherein sequences from the TPR (translocated promoter region) were fused to the Met sequence (Tpr-Met) (Cooper et al., 1984). In 1991, the scatter factor, originally identified as a fibroblast-derived cell motility factor for epithelial cells (Stoker et al., 1987), was shown to be an identical molecule to HGF (Weidner et al., 1990). These findings implicated further biological and pathophysiological roles for HGF in epithelial wound healing, epithelial-mesenchymal interaction, and cancer development and invasion. Based on its close involvement — not only in tumor development, invasion, and metastasis but also in resistance to anticancer therapies — the HGF-Met pathway has become a hot target in anticancer drug development (Comoglio et al., 2008; Sattler & Salgia, 2009; Hanahan & Weinberg, 2011). In most cases in the relationship between growth factors and their receptor tyrosine kinases, a single growth factor activates multiple receptors that have structural similarities, while a single growth factor receptor has multiple ligands with structural and functional similarities. By contrast, the sole receptor of HGF is Met, while the sole ligand of Met is HGF; the relationship between HGF and Met is a "one-to-one relationship." This unique biochemical characteristic in the HGF-Met pathway promotes drug development by targeting HGF-Met through either

Biologically active HGF, a protein composed of 697 or 692 amino acids, is a heterodimeric molecule composed of an -chain and a -chain (Fig. 1A). The -chain contains 4 kringle

the activation or the inhibition of the HGF-Met pathway.

**2. Biochemical and biological characteristics** 

**1. Introduction** 

**Anticancer Drugs Targeting HGF-Met** 

*Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa* 

Katsuya Sakai, Takahiro Nakamura, Yoshinori Suzuki and Kunio Matsumoto *Division of Tumor Dynamics and Regulation* 

breast cancer reoxygenation after neoadjuvant chemotherapy and hyperthermia treatment. *Int J Hyperther.*, Vol.19, pp. 498-506.

