title: Gene transfer of NK4, an angiogenesis inhibitor, induces CT26 tumor regression via tumor-specific T lymphocyte activation.
abstract: Hepatocyte growth factor (HGF) has been shown to be involved in malignant behaviors, such as invasion and metastasis, in different tumors. Hence, HGF could be a target molecule for control of the malignant potential of cancer. NK4 is a competitive antagonist for HGF and exerts an antitumor activity, not only by HGF antagonism but also by antiangiogenesis. Here, we studied the participation of cellular immunity in CT26 tumor regression by NK4 gene transfer. In vivo experiments showed that NK4-induced inhibition of subcutaneous tumor growth (as demonstrated in immunocompetent BALB/c mice) was weakened in T lymphocyte-deficient nude mice. In addition, the immunocompetent BALB/c mice that had shown complete regression of CT26-NK4 tumors generated an immune memory against repeated challenge with the same tumor antigen. Immunohistochemistry of tumor-infiltrating lymphocytes showed that the ratio of CD8/CD4 in CT26-NK4 tumors was significantly higher than that in control tumors. Also, the presence of tumor-specific cytotoxic T lymphocytes (CTL) was demonstrated by cytotoxicity assays. Depletion of CD8+ T lymphocytes markedly abrogated the antitumor activity of NK4. However, NK4 had no direct effect on the in vitro cellular immune system. Taken together, these data indicate that NK4 expression by gene transfer, at the tumor site, triggers tumor-specific CTL activation, resulting in complete CT26 tumor regression in vivo. This action was considered to be due to apoptosis induced by NK4's potent antiangiogenic and HGF antagonistic effects.
authors: Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan. tkubot@koto.kpu-m.ac.jp
authors: Takeshi
authors: T
authors: Kubota
authors: Hiroaki
authors: H
authors: Taiyoh
authors: Atsushi
authors: A
authors: Matsumura
authors: Yasutoshi
authors: Y
authors: Murayama
authors: Daisuke
authors: D
authors: Ichikawa
authors: Kazuma
authors: K
authors: Okamoto
authors: Hitoshi
authors: H
authors: Fujiwara
authors: Hisashi
authors: H
authors: Ikoma
authors: Masayoshi
authors: M
authors: Nakanishi
authors: Shojiro
authors: S
authors: Kikuchi
authors: Toshiya
authors: T
authors: Ochiai
authors: Chouhei
authors: C
authors: Sakakura
authors: Yukihito
authors: Y
authors: Kokuba
authors: Teruhisa
authors: T
authors: Sonoyama
authors: Yoshinori
authors: Y
authors: Suzuki
authors: Kunio
authors: K
authors: Matsumoto
authors: Toshikazu
authors: T
authors: Nakamura
authors: Eigo
authors: E
authors: Otsuji
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D002454:Cell Differentiation; D003110:Colonic Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D003713:Dendritic Cells; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics*; D006801:Humans; D007124:Immunoenzyme Techniques; D008213:Lymphocyte Activation; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
chemical_list: D020533:Angiogenesis Inhibitors; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor