Interruption of the HGF paracrine loop by NK4, an HGF antagonist, reduces VEGF expression of CT26 cells

Kubota,Takeshi; Matsumura,Atsushi; Taiyoh,Hiroaki; Izumiya,Yasuhito; Fujiwara,Hitoshi; Okamoto,Kazuma; Ichikawa,Daisuke; Shiozaki,Atsushi; Komatsu,Shuhei; Nakanishi,Masayoshi; Kuriu,Yoshiaki; Murayama,Yasutoshi; Ikoma,Hisashi; Ochiai,Toshiya; Nakamura,Takahiro; Matsumoto,Kunio; Nakamura,Toshikazu; Otsuji,Eigo

doi:10.3892/or.2013.2509

Interruption of the HGF paracrine loop by NK4, an HGF antagonist, reduces VEGF expression of CT26 cells

Authors:
- Takeshi Kubota
- Atsushi Matsumura
- Hiroaki Taiyoh
- Yasuhito Izumiya
- Hitoshi Fujiwara
- Kazuma Okamoto
- Daisuke Ichikawa
- Atsushi Shiozaki
- Shuhei Komatsu
- Masayoshi Nakanishi
- Yoshiaki Kuriu
- Yasutoshi Murayama
- Hisashi Ikoma
- Toshiya Ochiai
- Takahiro Nakamura
- Kunio Matsumoto
- Toshikazu Nakamura
- Eigo Otsuji
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Affiliations: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan, Division of Tumor Dynamics and Regulation, Kanazawa University Cancer Research Institute, Ishikawa, Japan, Kringle Pharma Joint Research Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, Osaka, Japan
Published online on: May 29, 2013 https://doi.org/10.3892/or.2013.2509
Pages: 567-572

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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.

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