REGULATION OF TUMOR VESSEL FORMATION BY THE IMMUNE SYSTEM

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 16390120
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: JUNTENDO UNIVERSITY
• Principal Investigator: OKUMURA Ko Juntendo University, Immunology, Professor, 医学部, 教授 (50009700)
• Co-Investigator(Kenkyū-buntansha): YAGITA Hideo Juntendo University, Immunology, Associate Professor, 医学部, 助教授 (30182306) ; TAKEDA Kazuyoshi Juntendo University, Immunology, Assistant Professor, 医学部, 講師 (80272821) ; NAKANO Hiroyasu Juntendo University, Immunology, Assistant Professor, 医学部, 講師 (70276476) ; EBATA Tomohiko Juntendo University, Immunology, Research associate, 医学部, 助手 (30343487)
• Project Period (FY): 2004 – 2005
• Keywords: TWEAK / Fn14 / tumor / apoptosis / cytokine / angiogenesis / tumor rejection

Research Abstract

TWEAK and its receptor, Fn14 belong to the tumor necrosis factor (TNF) superfamily and the TNF receptor superfamily, respectively. We have previously shown that TWEAK induces production of pro-inflammatory chemokine, cell migration, proliferation, and cell death through Fn14. To investigate roles for TWEAK/Fn14 interaction in tumor-associated angiogenesis and tumor rejection by macrophages, we generated anti-murine TWEAK monoclonal antibody (mAb), and transfectants expressing TWEAK or Fn14. We examined the effect of TWEAK or Fn14 expression in tumor cells on tumor outgrowth in vivo. Administration of neutralizing anti-TWEAK mAb significantly reduced the frequency of tumor rejection and shortened the survival of mice intraperitoneally inoculated with TWEAK-sensitive Fn14-expressing tumor cells. Moreover, anti-TWEAK mAb treatment promoted the subcutaneous growth of TWEAK-sensitive Fn14-expressing tumor cells, and this promotion was abolished by the inhibition of macrophage infiltration but not NK cell depletion. In contrast, administration of anti-TWEAK mAb had no apparent effect on the growth of TWEAK-resistant tumor cells, even if tumor cells expressed Fn14. These results indicate that TWEAK mediates anti-tumor effect of macrophages in vivo. Taken that TWEAK expression in tumor cells had no significant effect on subcutaneous tumor growth, TWEAK/Fn14 interaction does not appear to promote tumor growth through enhancing angiogenesis.

Research Products

• [Journal Article] Reactive oxygen species mediate crosstalk between NF-κB and JNK. (2006)
  • Author(s): Nakano, H. et al.
  • Journal Title: Cell Death Differ 13 Pages: 730-737
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Reactive oxygen species mediate crosstalk between NF-kappaB and JNK. (2006)
  • Author(s): Nakano, H., A Nakajima, S.Sakon-Komazawa, J.H.Pino, X.Xue, K.Okumura
  • Journal Title: Cell Death Differ 13 Pages: 730-737
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TWEAK mediates anti-tumor effect of tumor-infiltrating macrophage (2005)
  • Author(s): Kaduka, Y. et al.
  • Journal Title: Biochem Biophys Res Commun 331 Pages: 384-390
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo (2005)
  • Author(s): Akiba, H. et al.
  • Journal Title: J Immunol 175 Pages: 2340-2348
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Renal allograft rejection is prevented by adoptive transfer of anergic T cells in nonhuman primates. (2005)
  • Author(s): Bashuda, H. et al.
  • Journal Title: J Clin Invest 115 Pages: 1896-1902
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] ICOS costimulates invariant NKT cell activation. (2005)
  • Author(s): Kaneda, H. et al.
  • Journal Title: Biochem Biophys Res Commun 327 Pages: 201-207
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Amelioration of acute graft-versus-host disease by NKG2A engagement on donor T cells. (2005)
  • Author(s): Kawamura, H. et al.
  • Journal Title: Eur J Immunol 35 Pages: 2358-2366
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Immune responses against a single CD8+-T-cell epitope induced by virus vector vaccination can successfully control Trypanosoma cruzi infection. (2005)
  • Author(s): Miyahira, Y. et al.
  • Journal Title: Infect Immun 73 Pages: 7356-7365
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] IFN-γ-mediated negative feedback regulation of NKT-cell function by CD94/NKG2. (2005)
  • Author(s): Ota, T.et al.
  • Journal Title: Blood 106 Pages: 184-192
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. (2005)
  • Author(s): Takeda, K. et al.
  • Journal Title: Blood 105 Pages: 2082-2089
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Beta2-microglobulin required for cell surface expression of blastocyst MHC. (2005)
  • Author(s): Takeda, K. et al.
  • Journal Title: Biochem Biophys Res Commun 332 Pages: 311-317
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Regulation of murine chronic colitis by CD4+CD25-programmed death-1+T cells. (2005)
  • Author(s): Totsuka, T. et al.
  • Journal Title: Eur J Immunol 35 Pages: 1773-1785
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Critical contribution of CD80 and CD86 to induction of anterior chamber-associated immune deviation. (2005)
  • Author(s): Tsukahara, R. et al.
  • Journal Title: Int Immunol 17 Pages: 523-530
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Tumor necrosis factor alpha (TNFα) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFα. (2005)
  • Author(s): Xue, X.et al.
  • Journal Title: J Biol Chem 280 Pages: 33917-33925
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Blockade of B7-H1 on macrophages suppressed CD4+ T cell proliferation by augmenting IFN-γ-induced nitric oxide production. (2005)
  • Author(s): Yamazaki, T. et al.
  • Journal Title: I Immunol 175 Pages: 1586-1592
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of ICOS in the CXCR5+ follicular B helper T cell maintenance in vivo. (2005)
  • Author(s): Akiba, H., K.Takeda, Y.Kojima, Y.Usui, N.Harada, T.Yamazaki, J.Ma, K.Tezuka, H.Yagita, K.Okumura
  • Journal Title: J Immunol 175 Pages: 2340-2348
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Renal allograft rejection is prevented by adoptive transfer of anergic T cells in nonhuman primates. (2005)
  • Author(s): Bashuda, H., M.Kimikawa, K.Seino, Y.Kato, F.Ono, A.Shimizu, H.Yagita, S.Teraoka, K.Okumura
  • Journal Title: J Clin Invest 115 Pages: 1896-1902
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 2005.TWEAK mediates anti-tumor effect of tumor-infiltrating macrophage. (2005)
  • Author(s): Kaduka, Y., K.Takeda, M.Nakayama, K.Kinoshita, H.Yagita, K.Okumura
  • Journal Title: Biochem Biophys Res Commun 331 Pages: 384-390
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] ICOS costimulates invariant NKT cell activation. (2005)
  • Author(s): Kaneda, H., K.Takeda, T.Ota, Y.Kaduka, H.Akiba, Y.Ikarashi, H.Wakasugi, M.Kronenberg, K.Kinoshita, H.Yagita, K.Okumura
  • Journal Title: Biochem Biophys Res Commun 327 Pages: 201-207
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Amelioration of acute graft-versus-host disease by NKG2A engagement on donor T cells. (2005)
  • Author(s): Kawamura, H., H.Yagita, T.Nisizawa, N.Izumi, C.Miyaji, R.E.Vance, D.H.Raulet, K.Okumura, T.Abo
  • Journal Title: Eur J Immunol 35 Pages: 2358-2366
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Immune responses against a single CD8+-T-cell epitope induced by virus vector vaccination can successfully control Trypanosoma cruzi infection. (2005)
  • Author(s): Miyahira, Y., Y.Takashima, S.Kobayashi, Y.Matsumoto, T.Takeuchi, M.Ohyanagi-Hara, A.Yoshida, A.Ohwada, H.Akiba, H.Yagita, K.Okumura, H.Ogawa
  • Journal Title: Infect Immun 73 Pages: 7356-7365
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] IFN-gamma-mediated negative feedback regulation of NKT-cell function by CD94/NKG2. (2005)
  • Author(s): Ota, T., K.Takeda, H.Akiba, Y.Hayakawa, K.Ogasawara, Y.Ikarashi, S.Miyake, H.Wakasugi, T.Yamamura, M.Kronenberg, D.H.Raulet, K.Kinoshita, H.Yagita, M.J.Smyth, K.Okumura
  • Journal Title: Blood 106 Pages: 184-192
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TRAIL identifies immature natural killer cells in newborn mice and adult mouse liver. (2005)
  • Author(s): Takeda, K., E.Cretney, Y.Hayakawa, T.Ota, H.Akiba, K.Ogasawara, H.Yagita, K.Kinoshita, K.Okumura, M.J.Smyth
  • Journal Title: Blood 105 Pages: 2082-2089
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Beta2-microglobulin required for cell surface expression of blastocyst MHC. (2005)
  • Author(s): Tanaka, T., T Ebata, A.Tajima, K.Kinoshita, K.Okumura, H.Yagita
  • Journal Title: Biochem Biophys Res Commun 332 Pages: 311-317
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] 2005.Regulation of murine chronic colitis by CD4+CD25-programmed death-1+ T cells. (2005)
  • Author(s): Totsuka, T., T.Kanai, S.Makita, R.Fujii, Y.Nemoto, S.Oshima, R.Okamoto, A.Koyanagi, H.Akiba, K.Okumura, H.Yagita, M.Watanabe
  • Journal Title: Eur J Immunol 35 Pages: 1773-1785
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Critical contribution of CD8O and CD86 to induction of anterior chamber-associated immune deviation. (2005)
  • Author(s): Tsukahara, R., M.Takeuchi, H.Akiba, T.Kezuka, K.Takeda, Y.Usui, M.Usui, H.Yagita, K.Okumura
  • Journal Title: Int Immunol 17 Pages: 523-530
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Tumor necrosis factor alpha (TNFalpha) induces the unfolded protein response (UPR) in a reactive oxygen species (ROS)-dependent fashion, and the UPR counteracts ROS accumulation by TNFalpha. (2005)
  • Author(s): Xue, X., J.H.Piao, A.Nakajima, S.Sakon-Komazawa, Y.Kojima, K.Mori, H.Yagita, K.Okumura, H.Harding, H.Nakano
  • Journal Title: J Biol Chem 280 Pages: 33917-33925
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Blockade of B7-H1 on macrophages suppresses CD4+ T cell proliferation by augmenting IFN-gamma-induced nitric oxide production. (2005)
  • Author(s): Yamazaki, T., H.Akiba, A.Koyanagi, M.Azuma, H.Yagita, K.Okumura
  • Journal Title: J Immunol 175 Pages: 1586-1592
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Contribution of CD1d-unrestricted hepatic DX5+ NKT cells to liver injury in Plasmodium berghei-parasitized erythrocyte-injected mice. (2004)
  • Author(s): Adachi, K. et al.
  • Journal Title: Int Immunol 16 Pages: 787-898
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Induction of RANTES by TWEAK/Fn14 interaction on human keratinocytes. (2004)
  • Author(s): Jin, L.et al.
  • Journal Title: J Invest Dermatol 122 Pages: 1175-1179
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Sensitization of human glioblastomas to tumor necrosis factor-related apoptosisi-inducing ligand (TRAIL) by NF-kappaB inhibitors. (2004)
  • Author(s): Kasuga, C. et al.
  • Journal Title: Cancer Sci 95 Pages: 840-844
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Inducible costimulator-dependent IL-10 production by regulatory T cells specific for self-antigen. (2004)
  • Author(s): Kohyama, M. et al.
  • Journal Title: Proc Natl Acad Sci USA 101 Pages: 4192-4197
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Genome wide analysis of TNF-inducible genes reveals that antioxidant enzymes are induced by TNF and responsible for elimination of ROS. (2004)
  • Author(s): Sasazuki, T. et al.
  • Journal Title: Mol Immunol 41 Pages: 547-551
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] CAM and NK Cells. (2004)
  • Author(s): Takeda, K. et al.
  • Journal Title: Evid Based Complement Alternat Med 1 Pages: 17-27
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. (2004)
  • Author(s): Takeda, K. et al.
  • Journal Title: J Exp Med 199 Pages: 437-448
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TWEAK/Fn14 interaction stimulates human bronchial epithelial cells to produce IL-8 and GM-CSF. (2004)
  • Author(s): Xu, H.et al.
  • Journal Title: Biochem Biophys Res Commun 318 Pages: 422-427
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TRAIL and its receptors as targets for cancer therapy. (2004)
  • Author(s): Yagita, H. et al.
  • Journal Title: Cancer Sci 95 Pages: 777-783
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Contribution of CD1d-unrestricted hepatic DX5+ NKT cells to liver injury in Plasmodium berghei-parasitized erythrocyte-injected mice. (2004)
  • Author(s): Adachi, K., H.Tsutsui, E.Seki, H.Nakano, K.Takeda, K.Okumura, L.Van Kaer, K.Nakanishi
  • Journal Title: Int Immunol 16 Pages: 787-798
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Induction of RANTES by TWEAK/Fn14 interaction in human keratinocytes. (2004)
  • Author(s): Jin, L., A.Nakao, M.Nakayama, N.Yamaguchi, Y.Kojima, N.Nakano, R.Tsuboi, K.Okumura, H.Yagita, H.Ogawa
  • Journal Title: J Invest Dermatol 122 Pages: 1175-1179
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Sensitization of human glioblastomas to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by NF-kappaB inhibitors. (2004)
  • Author(s): Kasuga, C., T.Ebata, N.Kayagaki, H.Yagita, M.Hishii, H.Arai, K.Sato, K.Okumura
  • Journal Title: Cancer Sci 95 Pages: 840-844
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Inducible costimulator-dependent IL-10 production by regulatory T cells specific for self-antigen. (2004)
  • Author(s): Kohyama, M., D.Sugahara, S.Sugiyama, H.agita, K.Okumura, N.Hozumi
  • Journal Title: Proc Natl Acad Sci USA 101 Pages: 4192-4197
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Genome wide analysis of TNF-inducible genes reveals that antioxidant enzymes are induced by TNF and responsible for elimination of ROS. (2004)
  • Author(s): Sasazuki, T., T.Okazaki, K.Tada, S.Sakon-Komazawa, M.Katano, M.Tanaka, H.Yagita, K.Okumura, N.Tominaga, Y.Hayashizaki, Y.Okazaki, H.Nakano
  • Journal Title: Mol Immunol 41 Pages: 547-551
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CAM and NK Cells. (2004)
  • Author(s): Takeda, K., K.Okumura
  • Journal Title: Evid Based Complement Alternat Med 1 Pages: 17-27
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Induction of tumor-specific T cell immunity by anti-DR5 antibody therapy. (2004)
  • Author(s): Takeda, K., N.Yamaguchi, H.Akiba, Y.Kojima, Y.Hayakawa, J.E.Tanner, T.J.Sayers, N.Seki, K.Okumura, H.Yagita, M.J.Smyth
  • Journal Title: J Exp Med 199 Pages: 437-448
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TWEAK/Fn14 interaction stimulates human bronchial epithelial cells to produce IL-8 and GM-CSF. (2004)
  • Author(s): Xu, H., A.Okamoto, J.Ichikawa, T.Ando, K.Tasaka, K.Masuyama, H.Ogawa, H.Yagita, K.Okumura, A.Nakao
  • Journal Title: Biochem Biophys Res Commun 318 Pages: 422-427
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TRAIL and its receptors as targets for cancer therapy. (2004)
  • Author(s): Yagita, H., K.Takeda, Y.Hayakawa, M.J.Smyth, K.Okumura
  • Journal Title: Cancer Sci 95 Pages: 777-783
  • Description: 「研究成果報告書概要(欧文)」より