HGF-Antagonists: Structure, Activities, and Anti-cancer Approach

Katsuya      Sakai; Takahiro      Nakamura; Takayoshi      Kinoshita; Toshikazu      Nakamura; Kunio      Matsumoto

Abstract

Hepatocyte growth factor (HGF) and Met receptor participate in the malignant progression of cancer, particularly in invasive growth, metastasis, and drug resistance. Recent studies indicate that the HGF-Met pathway participates in the spreading and maintenance of cancer stem cells, at least in some types of cancers. HGF and Met have become molecular targets of much attention in anticancer therapy. Based on the functional assignment of each domain in HGF, and in the structures of the HGF-Met interface, polypeptide HGF-Met inhibitors have been identified, including NK4, NK1 mutants, and HB10. NK4 is composed of the N-terminal (N) and four kringle domains (K4) of HGF. NK4 binds to the Met without its activation, thereby competitively inhibiting HGF-dependent Met activation. Moreover, independent of the HGF-antagonist action, NK4 inhibits angiogenesis, and this action is mediated by NK4-perlecan interaction. In a variety of tumor models, NK4 inhibited the HGF-Met pathway and angiogenesis, and these actions were associated with inhibition of invasive growth and metastasis. Thus, therapeutic approaches using NK4, the first discovered inhibitor against HGF-Met, revealed the significance of HGF-Met inhibition in cancer treatment. In addition to NK4, different types of HGF-Met inhibitors have been developed, including small molecule inhibitors for Met tyrosine kinase and neutralizing monoclonal antibodies against HGF or Met. During the past few decades, the success of drug development targeting growth factors and their receptor tyrosine kinases in human cancer has triggered a new therapeutic strategy for treating cancer. Preclinical and clinical development of HGF-Met inhibitors will provide further advances in molecular-targeted therapy of cancer.

Keywords: Angiogenesis, cancer stem cell, gefitinib, hepatocyte growth factor, invasion, Met, metastasis, NK4, tyrosine kinase, vascular endothelial growth factor, epithelial growth factor receptor, gene therapy, peripheral artery disease (PAD), c-Met, SHIP-2, plasmid DNA transfer, Phase III clinical trial, EPCs, Cbl, ROS, VSMC, CLI, Ang II, fibroblast growth factor, epithelial growth factor, senescence, GTP binding rac1, Rutherford 5, ERK, Akt, ankle-brachial pressure index, QOL