Establishment of New Strategies for Treatment of Cancer Using TGF-beta Signaling

2009 Fiscal Year Final Research Report

• Project/Area Number: 17016011
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: MIYAZONO Kohei The University of Tokyo, 大学院・医学系研究科, 教授 (90209908)
• Co-Investigator(Kenkyū-buntansha): MIYAZAWA Keiji 山梨大学, 大学院・医学工学総合研究部, 教授 (40209896) ; IMAMURA Takeshi (財)癌研究会, 癌研究所生化学部, 部長 (70264421) ; MAEDA Shingo (財)癌研究会, 癌研究所生化学部, 研究員 (60353463) ; WATABE Tetsuro 東京大学, 大学院・医学系研究科, 准教授 (00334235) ; SAITOH Masao 山梨大学, 大学院・医学系研究科, 准教授 (90345041) ; KANO Mitsunobu 東京大学, 大学院・医学系研究科, 講師 (80447383)
• Co-Investigator(Renkei-kenkyūsha): KOINUMA Daizo 東京大学, 大学院・医学系研究科, 講師 (80375071) ; EHATA Shogo 東京大学, 大学院・医学系研究科, 助教 (90506726)
• Project Period (FY): 2005 – 2009
• Keywords: TGF-β / 分子標的治療 / シグナル伝達 / がん幹細胞 / 転移 / 血管新生

Research Abstract

TGF-βは強力な増殖抑制因子であるが、一方で上皮-間葉分化転換の促進などによりがんの浸潤・転移を促進する。本研究では、TGF-βシグナルの抑制が乳がんの転移を抑制し、脳腫瘍ではがん幹細胞の分化を促進することを示した。一方、スキルス胃がんではTGF-βは血管新生を抑制してがんの増殖を抑制することを見出した。またTGF-β拮抗剤とミセル型抗がん剤の併用は膵臓がんなどに有効であることを明らかにした。

Research Products

• [Journal Article] GF-βsignalling: a complex web in cancer progression (2010)
  • Author(s): Ikushima, H., Miyazono, K.
  • Journal Title: Nature Rev. Cancer 10(6) Pages: 415-424
• [Journal Article] Cellular context-dependent "colors" of transforming growth factor-βsignaling. (2010)
  • Author(s): Ikushima, H., Miyazono, K.
  • Journal Title: Cancer Sci. 101(2) Pages: 306-312
• [Journal Article] Context-dependent regulation of the expression of c-Ski protein by Arkadia in human cancer cells. (2010)
  • Author(s): Nagano, Y., Koinuma, D., Miyazawa, K., Miyazono, K.
  • Journal Title: J. Biochem. 147(4) Pages: 545-554
• [Journal Article] Bone morphogenetic protein receptors and signal transduction. (2010)
  • Author(s): Miyazono, K., Kamiya, Y., Morikawa, M.
  • Journal Title: J. Biochem. 147(1) Pages: 35-51
• [Journal Article] Autocrine TGF-βsignaling maintains tumorigenicity of glioma-initiating cells through Sry-related HMG-box factors. (2009)
  • Author(s): Ikushima, H., Todo, T., Ino, Y., Takahashi, M., Miyazawa, K., Miyazono, K.
  • Journal Title: Cell Stem Cell 5(5) Pages: 504-514
• [Journal Article] Promoter-wide analysis of Smad4 binding sites in human epithelial cells. (2009)
  • Author(s): Koinuma, D., Tsutsumi, S., Kamimura, N., Imamura, T., Aburatani, H., Miyazono, K.
  • Journal Title: Cancer Sci. 100(11) Pages: 2133-2142
• [Journal Article] Autophagy is activated by TGF-βand potentiates TGF- β-mediated growth inhibition in human hepatocellular carcinoma cells. (2009)
  • Author(s): Kiyono, K., Suzuki, H.I., Matsuyama, H., Morishita, Y., Komuro, A., Kano, M.R., Sugimoto, K., Miyazono, K.
  • Journal Title: Cancer Res. 69(23) Pages: 8844-8852
• [Journal Article] Thyroid transcription factor-1 inhibits transforming growth factor- β- mediated epithelial-to-mesenchymal transition in lung adenocarcinoma cells. (2009)
  • Author(s): Saito, R.A., Watabe, T., Horiguchi, K., Kohyama, T., Saitoh, M., Nagase, T., Miyazono, K.
  • Journal Title: Cancer Res. 69(7) Pages: 2783-2791
• [Journal Article] c-Ski overexpression promotes tumor growth and angiogenesis through inhibition of transforming growth factor-βsignaling in diffuse-type gastric carcinoma. (2009)
  • Author(s): Kiyono, K., Suzuki, H.I., Morishita, Y., Komuro, A., Iwata, C., Yashiro, M., Hirakawa, K., Kano, M.R., Miyazono, K.
  • Journal Title: Cancer Sci. 100(10) Pages: 1809-1816
• [Journal Article] Modulation of microRNA processing by p53. (2009)
  • Author(s): Suzuki, H.I., Yamagata, K., Sugimoto, K., Iwamoto, T., Kato, S., Miyazono, K.
  • Journal Title: Nature 460(7254) Pages: 529-533
• [Journal Article] Diffuse-type gastric carcinoma: Progression, angiogenesis, and transforming growth factor-βsignaling. (2009)
  • Author(s): Komuro, A., Yashiro, M., Iwata, C., Morishita, Y., Johansson, E., Matsumoto, Y., Watanabe, A., Aburatani, H., Miyoshi, H., Kiyono, K., Shirai, Y., Suzuki, H.I., Hirakawa, K., Kano, M.R., Miyazono, K.
  • Journal Title: J. Natl. Cancer Inst. 101(8) Pages: 592-604
• [Journal Article] SKI and MEL1 cooperate to inhibit transforming growth factor-βsignal in gastric cancer cells. (2009)
  • Author(s): Takahata, M., Inoue, Y., Tsuda, H., Imoto, I., Koinuma, D., Hayashi, M., Ichikura, T., Yamori, T., Nagasaki, K., Yoshida, M., Matsuoka, M., Morishita, K., Yuki, K., Hanyu, A., Miyazawa, K., Inazawa, J., Miyazono, K., Imamura T.
  • Journal Title: J. Biol. Chem. 284(5) Pages: 3334-3344
• [Journal Article] Comparison of the effects of the kinase inhibitors imatinib, sorafenib, and transforming growth factor-βreceptor inhibitor on extravasation of nanoparticles from neovasculature. (2009)
  • Author(s): Kano, M.R., Komuta, Y., Iwata, C., Oka, M., Shirai, Y., Morishita, Y., Ouchi, Y., Kataoka, K., Miyazono, K.
  • Journal Title: Cancer Sci. 100(1) Pages: 173-180
• [Journal Article] Chromatin immunoprecipitation on microarray analysis of Smad2/3 binding sites reveals roles of ETS1 and TFAP2A in transforming growth factorβsignaling. (2009)
  • Author(s): Koinuma, D., Tsutsumi, S., Kamimura, N., Taniguchi, H., Miyazawa, K., Sunamura, M., Imamura, T., Miyazono, K., Aburatani, H.
  • Journal Title: Mol. Cell. Biol. 29(1) Pages: 172-186
• [Journal Article] Role of Ras signaling in the induction of snail by transforming growth factor-β. (2009)
  • Author(s): Horiguchi, K., Shirakihara, T., Nakano, A., Imamura, T., Miyazono, K., Saitoh, M.
  • Journal Title: J. Biol. Chem. 284(1) Pages: 245-253
• [Journal Article] Inhibition of endogenous TGF-βsignaling enhances lymphangiogenesis. (2008)
  • Author(s): Oka, M., Iwata, C., Suzuki, H.I., Kiyono, K., Morishita, Y., Watabe, T., Komuro, A., Kano, M.R., Miyazono, K.
  • Journal Title: Blood 111(9) Pages: 4571-4579
• [Journal Article] Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway. (2008)
  • Author(s): Katsuno, Y., Hanyu, A., Kanda, H., Ishikawa, Y., Akiyama, F., Iwase, T., Ogata, E., Ehata, S., Miyazono, K., Imamura, T.
  • Journal Title: Oncogene 27(49) Pages: 6322-6333
• [Journal Article] Snail is required for TGF- β-induced endothelial-mesenchymal transition of embryonic stem cell-derived endothelial cells. (2008)
  • Author(s): Kokudo, T., Suzuki, Y., Yoshimatsu, Y., Yamazaki, T., Watabe, T., Miyazono, K.
  • Journal Title: J. Cell Sci. 121(20) Pages: 3317-3324
• [Journal Article] An Id-like molecule, HHM, is a synexpression group-restricted regulator of TGF-βsignaling. (2008)
  • Author(s): Ikushima, H., Komuro, A., Isogaya, K., Shinozaki, M., Hellman, U., Miyazawa, K., Miyazono, K.
  • Journal Title: EMBO J. 27(22) Pages: 2955-2965
• [Journal Article] Differential regulation of epithelial and mesenchymal markers byδEF1 proteins in epithelial mesenchymal transition induced by TGF-β. (2007)
  • Author(s): Shirakihara, T., Saitoh, M., Miyazono K.
  • Journal Title: Mol. Biol. Cell 18(9) Pages: 3533-3544
• [Journal Article] Selective inhibitory effects of Smad6 on bone morphogenetic protein type I receptors. (2007)
  • Author(s): Goto, K., Kamiya, Y., Imamura, T., Miyazono, K., Miyazawa, K.
  • Journal Title: J. Biol. Chem. 282(28) Pages: 20603-20611
• [Journal Article] Arkadia induces degradation of SnoN and c-Ski to enhance TGF-βsignaling. (2007)
  • Author(s): Nagano, Y., Mavrakis, K.J., Lee, K.L., Fujii, T., Koinuma, D., Sase, H., Yuki, K., Isogaya, K., Saitoh, M., Imamura, T., Episkopou, V., Miyazono, K., Miyazawa, K.
  • Journal Title: J. Biol. Chem. 282(28) Pages: 20492-20501
• [Journal Article] Transforming growth factor-βpromotes survival of mammary carcinoma cells through induction of anti-apoptotic transcription factor DEC1. (2007)
  • Author(s): Ehata, S., Hanyu, A., Hayashi, M., Aburatani, H., Kato, Y., Fujime, M., Saitoh, M., Miyazawa, K., Imamura, T., Miyazono, K.
  • Journal Title: Cancer Res. 67(20) Pages: 9694-9703
• [Journal Article] Modulation of the functional binding sites for TGF-βon the type II receptor leads to suppression of TGF-βsignaling. (2007)
  • Author(s): Shimanuki, T., Hara, T., Furuya, T., Imamura, T., Miyazono, K.
  • Journal Title: Oncogene 26(23) Pages: 3311-3320
• [Journal Article] Ki26894, a novel transforming growth factor-βtype I receptor kinase inhibitor, inhibits in vitro cell motility and invasion and in vivo bone metastasis of a human breast cancer cell line. (2007)
  • Author(s): Ehata, S., Hanyu, A., Katsuno, Y., Fukunaga, E., Goto, K., Ishikawa, Y., Nomura, K., Ogata, E., Fujime, M., Miyazono, K., Shimizu, K., Imamura, T.
  • Journal Title: Cancer Sci. 98(1) Pages: 127-133
• [Journal Article] Improvement of cancer-targeting therapy using nanocarriers for intractable solid tumors by inhibition of TGF-βsignalling. Proc. (2007)
  • Author(s): Kano, M.R., Bae, Y., Iwata, C., Morishita, Y., Yashiro, M., Oka, M., Fujii, T., Komuro, A., Kiyono, K., Kaminishi, M., Hirakawa, K., Ouchi, Y., Nishiyama, N., Kataoka, K., Miyazono, K.
  • Journal Title: Natl. Acad. Sci. USA 104(9) Pages: 3460-3465
• [Journal Article] Execution of BMP-4- induced apoptosis by p53-dependent ER dysfunction in myeloma and B-cell hybridoma cells. (2006)
  • Author(s): Fukuda, N., Saitoh, M., Kobayashi, N., Miyazono, K.
  • Journal Title: Oncogene 25(25) Pages: 3509-3517
• [Journal Article] Nuclear and cytoplasmic c-Ski differentially modulate cellular functions. (2006)
  • Author(s): Nagata, M., Goto, K., Ehata, S., Kobayashi, N., Saitoh, M., Miyoshi, H., Imamura, T., Miyazawa, K., Miyazono, K.
  • Journal Title: Genes Cells 11(11) Pages: 1267-1280
• [Journal Article] VEGF-A and FGF-2 synergistically promote neoangiogenesis through enhancement of endogenous PDGF-B/PDGFRβsignaling. (2005)
  • Author(s): Kano, M.R., Morishita, Y., Iwata, C., Iwasaka, S., Watabe, T., Ouchi, Y., Miyazono, K., Miyazawa, K.
  • Journal Title: J. Cell Sci. 118(16) Pages: 3759-3768
• [Journal Article] The ALK-5 Inhibitor A-83-01 inhibits Smad signaling and epithelial-to-mesenchymal transition by transforming growth factor-β. (2005)
  • Author(s): Tojo, M., Hamashima, Y., Hanyu, A., Kajimoto, T., Saitoh, M., Miyazono, K., Node, M., Imamura, T.
  • Journal Title: Cancer Sci. 96(11) Pages: 791-800
• [Journal Article] Effect of Smad7 expression on metastasis of mouse mammary carcinoma JygMC(A) cells. (2005)
  • Author(s): Azuma, H., Ehata, S., Miyazaki, H., Watabe, T., Maruyama, O., Imamura, T., Sakamoto, T., Kiyama, S., Kiyama, Y., Ubai, T., Inamoto, T., Takahara, S., Itoh, Y., Otsuki, Y., Katsuoka, Y., Miyazono, K., Horie, S.
  • Journal Title: J. Natl. Cancer Inst. 97(23) Pages: 1734-1746
• [Book] The TGF-βFamily. (2008)
  • Author(s): Derynck, R., Miyazono, K., eds.
  • Total Pages: 1-1114
  • Publisher: Cold Spring Harbor Laboratory Press
• [Remarks]
  • URL: http://beta-lab.umin.ac.jp/
• [Patent(Industrial Property Rights)] グリオーマ幹細胞の分化促進剤 (2010)
  • Inventor(s): 宮園浩平、生島弘彬、宮澤恵二, 他
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Number: PCT, PCT/JP2010/0519503
  • Filing Date: 2010-02-10
• [Patent(Industrial Property Rights)] TGF-βシグナル阻害剤と抗腫瘍剤の組合せ使用 (2006)
  • Inventor(s): 宮園浩平、片岡一則、狩野光伸、べーユンスー、西山伸宏、平川弘聖、八代正和、野出學
  • Industrial Property Rights Holder: 東京大学
  • Industrial Property Number: PCT, PCT/JP2006/317593
  • Acquisition Date: 2006-02-01