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Blood, 1 April 2007, Vol. 109, No. 7, pp. 3042-3049. Prepublished online as a Blood First Edition Paper on December 19, 2006; DOI 10.1182/blood-2006-02-003103. This Article Full Text (PDF) All Versions of this Article: blood-2006-02-003103v1 109/7/3042    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Du, W. Articles by Ikeda, Y. Search for Related Content PubMed PubMed Citation Articles by Du, W. Articles by Ikeda, Y. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted February 22, 2006 Accepted November 12, 2006 NK4, an antagonist of hepatocyte growth factor (HGF), inhibits growth of multiple myeloma cells in vivo; molecular targeting of angiogenic growth factor Wenlin Du, Yutaka Hattori*, Taketo Yamada, Kunio Matsumoto, Toshikazu Nakamura, Morihiko Sagawa, Takemi Otsuki, Takako Niikura, Toshihiro Nukiwa, and Yasuo Ikeda Dept of Pathology, Keio University School of Medicine, Japan Division of Hematology, Keio University School of Medicine, Japan Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, Japan Dept of Hygiene, Kawasaki Medical School, Japan Dept of Pharmacology, Keio University School of Medicine, Japan Institute of Development, Aging and Cancer, Tohoku University, Japan * Corresponding author; email: yhattori{at}sc.itc.keio.ac.jp. Hepatocyte growth factor (HGF) promotes cell growth and motility and also increases neovascularization. Multiple myeloma (MM) cells produce HGF, and the plasma concentration of HGF is significantly elevated in clinically active MM patients, suggesting that HGF might play a role in the pathogenesis of MM. NK4, an antagonist of HGF, is structurally homologous to angiostatin, and our previous report showed that NK4 inhibited the proliferation of vascular endothelial cells induced by HGF stimulation. The purposes of this study were to elucidate the contribution of HGF to the growth of MM cells, as well as to investigate the possibility of the therapeutic use of NK4. In vitro study showed that NK4 protein stabilized the growth of MM cell lines and regulated the activation of c-Met, ERK1/2, STAT3, and AKT-1. Recombinant adenovirus containing NK4 cDNA (AdCMV.NK4) was intramuscularly injected into lcr/scid-mice bearing tumors derived from HGF-producing MM cells. AdCMV.NK4 significantly inhibited the growth of these tumors in vivo. Histological examination revealed that AdCMV.NK4 induced apoptosis of MM cells, accompanied by a reduction in neovascularization in the tumors. Thus, NK4 inhibited the growth of MM cells via anti-angiogenic as well as direct anti-tumor mechanisms. The molecular targeting of HGF by NK4 could be applied as a novel therapeutic approach to MM. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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