title: Interruption of the HGF paracrine loop by NK4, an HGF antagonist, reduces VEGF expression of CT26 cells.
abstract: Hepatocyte growth factor (HGF), acting through the c‑Met receptor, plays an important role in solid tumors. Various malignant cells utilize the biological actions of the HGF/c‑Met pathway for their dissociative, invasive and metastatic behaviors. HGF also binds to the receptor expressed on endothelial cells that stimulates angiogenesis, a process critical to continued growth of solid tumors. It is known that HGF induces in vitro expression of vascular endothelial growth factor (VEGF), a key agonist of tumor angiogenesis. In the present study, we showed using in vitro co-culture system with fibroblasts that VEGF expression of CT26 cells was amplified through tumor-stromal interaction, i.e., the HGF paracrine loop. This action was inhibited by interruption of the HGF paracrine loop by gene transfer of NK4, an HGF antagonist. In in vivo experiments, CT26 tumor growth and angiogenesis were markedly enhanced by fibroblast co-inoculation, while the effect of fibroblasts was not observed in NK4‑expressing CT26 cells. These findings suggest that NK4 exerted potent anti‑angiogenic action via indirectly inhibiting VEGF expression of tumor cells in addition to direct effects on endothelial cells. Thus, the HGF/c‑Met pathway may be a considerable candidate for molecular targeting strategy against tumor angiogenesis.
authors.affiliation: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. tkubot@koto.kpu-m.ac.jp
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kubota
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsumura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Taiyoh
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Izumiya
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Fujiwara
authors.forename: Kazuma
authors.initials: K
authors.lastname: Okamoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ichikawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shiozaki
authors.forename: Shuhei
authors.initials: S
authors.lastname: Komatsu
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kuriu
authors.forename: Yasutoshi
authors.initials: Y
authors.lastname: Murayama
authors.forename: Hisashi
authors.initials: H
authors.lastname: Ikoma
authors.forename: Toshiya
authors.initials: T
authors.lastname: Ochiai
authors.forename: Takahiro
authors.initials: T
authors.lastname: Nakamura
authors.forename: Kunio
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Toshikazu
authors.initials: T
authors.lastname: Nakamura
authors.forename: Eigo
authors.initials: E
authors.lastname: Otsuji
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques / Q000379:methods; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019899:Paracrine Communication / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics* / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; C553307:HGF protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D017228:Hepatocyte Growth Factor