Targeting cancer cells resistant to hypoxia and nutrient starvation to improve anti-cancer therapy

• Project/Area Number: 23701047
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: The University of Tokyo
• Principal Investigator: OSAWA Tsuyoshi 東京大学, 先端科学技術研究センター, 特任助教 (50567592)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2013: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2012: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 癌 / 組織・細胞 / ストレス / エピジェネティクス / ヒストン / 細胞・組織 / ヒストン修飾

Research Abstract

Tumor microenvironment is critical determinant for tumor progression and metastasis. We reported that (1) hypoxia and nutrient starvation induced tumor aggressiveness, (2) and stimulated pro-cancer immunity, (3) histone demethylase JMJD1A and JHDM1D regulated tumorigenicity and tumor angiogenesis, and (4) inhibition of JMJD1A showed synergetic effect with antiangiogenesis. Thus, targeting cancer cells resistant to hypoxia and nutrient starvation can be an effective cancer treatment.

Research Products

• [Journal Article] BMP4/Thrombospondin-1 loop paracrinically inhibits tumor angiogenesis and suppresses the growth of solid tumors (2014)
  • Author(s): Tsuchida R, Osawa T, Wang F, Nishii R, Das B, Tsuchida S, Muramatsu M, Takahashi T, Inoue T, Wada Y, Minami T, Yuasa Y, Shibuya M
  • Journal Title: Oncogene Volume: 33 Issue: 29 Pages: 3803-3811
  • DOI: 10.1038/onc.2013.358
  • Peer Reviewed / Open Access
• [Journal Article] A major role for RCAN1 in atherosclerosis progression (2013)
  • Author(s): Mendez-Barbero N, Esteban V, Villahoz S, Escolano A, Urso K, Alfranca A, Rodriguez C, Sanchez SA, Osawa T, Andres V, Martinez-Gonzalez J, Minami T, Redondo JM, Campanero MR
  • Journal Title: EMBO Mol Med. Volume: Dec;5(12) Issue: 12 Pages: 1901-17
  • DOI: 10.1002/emmm.201302842
  • Peer Reviewed
• [Journal Article] The Calcineurin-NFAT-Angiopoietin-2 Signaling Axis in Lung Endothelium Is Critical for the Establishment of Lung Metastases (2013)
  • Author(s): Minami T, Jiang S, Schadler K, Suehiro JI, Osawa T, Oike Y, Miura M, Naito M, Kodama T, Ryeom S
  • Journal Title: Cell Reports Volume: Aug 14. pii:S2211-1247(13) Issue: 4 Pages: 383-5
  • DOI: 10.1016/j.celrep.2013.07.021
  • Peer Reviewed
• [Journal Article] Targeting cancer cells resistant to hypoxia and nutrient starvation to improve anti-angiogeneic therapy (2013)
  • Author(s): Osawa T (Co-correspondence) and Shibuya M
  • Journal Title: Cell Cycle Volume: Aug 15;12(16) Pages: 2519-20
  • Peer Reviewed
• [Journal Article] Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor associated macrophages (2013)
  • Author(s): Osawa T (Co-correspondence), Tsuchida R, Muramatsu M, Shimamura T, Wang F, Suehiro J, Kanki Y, Wada Y, Yuasa Y, Aburatani H, Miyano S, Minami T, Kodama T, and Shibuya M
  • Journal Title: Cancer Research Volume: May 15;73(10) Pages: 3019-3028
  • Peer Reviewed
• [Journal Article] Targeting cancer cells resistant to hypoxia and nutrient starvation to improve anti-angiogeneic therapy (2013)
  • Author(s): Osawa T and Shibuya
  • Journal Title: Cell Cycle Volume: 12 Issue: 16 Pages: 2519-20
  • DOI: 10.4161/cc.25729
  • Peer Reviewed
• [Journal Article] Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor associated macrophages (2013)
  • Author(s): Shimamura T, Wang F, Suehiro J, Kanki Y, Wada Y, Yuasa Y, Aburatani H, Miyano S, Minami T, Kodama T, Shibuya M
  • Journal Title: Cancer Res Volume: 73 Issue: 10 Pages: 3019-3028
  • DOI: 10.1158/0008-5472.can-12-3231
  • Peer Reviewed
• [Journal Article] Inhibition of histone demethylase JMJD1A improves anti-angiogenic therapy and reduces tumor-associated macrophages (2013)
  • Author(s): Osawa T, Tsuchida R, Muramatsu M, Shimamura T, Wang F, Suehiro J, Kanki Y, Wada Y, Yuasa Y, Aburatani H, Miyano S, Minami T, Kodama T, and Shibuya M
  • Journal Title: Cancer Research Volume: -
  • Peer Reviewed
• [Journal Article] Alternative splicing of CD44 mRNA by ESRP1 enhances lung colonization of metastatic cancer cell. (2012)
  • Author(s): Yae T, Tsuchihashi K, Ishimoto T, Motohara T, Yoshikawa M, Yoshida GJ, Wada T, Masuko T,Mogushi K, Tanaka H, Osawa T, Kanki Y, et al
  • Journal Title: Nature Communications Volume: 6;3 Issue: 1 Pages: 883-883
  • DOI: 10.1038/ncomms1892
  • Peer Reviewed
• [Journal Article] Increased expression of histone demethylase JHDM1D under nutrient starvation suppresses tumor growth via downregulating angiogenesis (2011)
  • Author(s): Osawa T, Muramatsu M, Tsuchida R, Wang F, Kodama T, Minami T and Shibuya M
  • Journal Title: PNAS Volume: Dec 20;108(51) Pages: 20725-9
  • Peer Reviewed
• [Journal Article] Down-regulation of receptor activated C-kinase 1 (RACK1) suppresses tumor growth by inhibiting tumor cell proliferation and tumor-associated angiogenesis (2011)
  • Author(s): Wang F, Osawa T, Tsuchida R, Yuasa Y, and Shibuya M
  • Journal Title: Cancer Science. Volume: Nov;102(11) Pages: 2007-13
  • Peer Reviewed
• [Journal Article] Mechanism of cell death resulting from DNA interstrand cross-linking in mammalian cells (2011)
  • Author(s): Osawa T, Davies D, and Hartley JA
  • Journal Title: Cell Death and Disease Volume: Aug 4; 2 Issue: 8 Pages: e187-e187
  • DOI: 10.1038/cddis.2011.70
  • Peer Reviewed
• [Journal Article] Increased expression of histone demethylase JHDM1D under nutrient starvation suppresses tumor growth via downregulating angiogenesis (2011)
  • Author(s): Osawa T., et al.
  • Journal Title: PNAS Volume: 108 Pages: 20725-20729
  • Peer Reviewed
• [Journal Article] Downregulation of receptor for activated C-kinase 1 (RACK1) suppresses tumor growth by inhibiting tumor cell proliferation and tumor-associated angiogenesis (2011)
  • Author(s): 王峰、土田里香
  • Journal Title: Cancer Science Volume: 102(11) Issue: 11 Pages: 2007-13
  • DOI: 10.1111/j.1349-7006.2011.02065.x
  • NAID: 10030244997
  • Peer Reviewed
• [Journal Article] RACK1 regulates VEGF/Flt-1-mediated cell migration via activation of a PI3-K/Akt pathway (2011)
  • Author(s): Wang F., Yamauchi M., Muramatsu M., Osawa T., et al.
  • Journal Title: J Biol Chem. Volume: 286 Pages: 9097-9106
  • Peer Reviewed
• [Journal Article] Human glioblastoma cells exposed to long-term hypoxia and nutrient starvation stimulated induction of secondary T cell leukemia in mice (2011)
  • Author(s): Osawa T, et al.
  • Journal Title: Blood Cancer J. Volume: 1 Issue: 2 Pages: e6-e6
  • DOI: 10.1038/bcj.2011.5
  • Peer Reviewed
• [Presentation] Histone Demetylases regulate tumor angiogenesis and metabolism (2014)
  • Author(s): Osawa T
  • Organizer: Keystone Symposia on Metabolism and Angiogenesis
  • Place of Presentation: Whistler, Canada
• [Presentation] HIstone demetylases regulate tumor angiogenesis and metabolism (2014)
  • Author(s): Osawa T et al.
  • Organizer: Keystone Symposia
  • Place of Presentation: Whistler (Canada)
• [Presentation] 低酸素・低栄養が癌悪性化を誘導する分子機構とその治療への応用 (2013)
  • Author(s): 大澤毅
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜、神奈川県
• [Presentation] 低酸素・低栄養に誘導されるヒストン脱メチル化酵素が腫瘍血管新生と癌代謝を制御する (2013)
  • Author(s): 大澤毅
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: 横浜、神奈川県
• [Presentation] Histone demethylases expressed under hypoxia and nutrient starvation regulate tumor growth by modulating tumor angiogenesis and metabolism, Poster Presentation (2013)
  • Author(s): Osawa T
  • Organizer: European Cancer Congress 2013
  • Place of Presentation: Amsterdam, Netherlands
• [Presentation] 低酸素・低栄養の腫瘍微小環境が脂質分解を促進し癌悪性化に寄与する (2013)
  • Author(s): 大澤毅ら
  • Organizer: 第１１回がんとハイポキシア研究会
  • Place of Presentation: 仙台
  • Invited
• [Presentation] 低酸素・低栄養の腫瘍微小環境と癌代謝 (2013)
  • Author(s): 大澤毅ら
  • Organizer: 第１回がんと代謝研究会
  • Place of Presentation: 鶴岡
• [Presentation] 低酸素・低栄養が癌悪性化を誘導する分子機構とその治療への応用 (2013)
  • Author(s): 大澤毅ら
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Invited
• [Presentation] 低酸素・低栄養に誘導されるヒストン脱メチル化酵素が腫瘍血管新生と癌代謝を制御する (2013)
  • Author(s): 大澤毅ら
  • Organizer: 第７２回日本癌学会学術総会
  • Place of Presentation: 横浜
• [Presentation] Histone demethylases expressed under hypoxia and nutrient starvation regulate tumor growth by modulating tumor angiogenesis and metabolism (2013)
  • Author(s): Osawa T et al.
  • Organizer: European Cancer Congress 2013
  • Place of Presentation: Amsterdam (Netherlands)
• [Presentation] Down's syndrome candidate region-1 mediates corneal opacity via corneal angiogenesis. Oral presentation (2012)
  • Author(s): Osawa T
  • Organizer: The 10th Korea-Japan Joint Symposium on Vascular Viology
  • Place of Presentation: Tokushima
• [Presentation] 低酸素・低栄養に誘導されるヒストン修飾酵素が血管新生を介して癌の増殖を制御する (2012)
  • Author(s): 大澤毅
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌、北海道
• [Presentation] Paradoxically Impaired Development of Atherosclerosis in Hyperlipidemic Down's syndrome candidate E-/region-1-/-and Apolipoprotein Double-Knockout Mice (2012)
  • Author(s): Osawa T
  • Organizer: The International Vascular Biology Meeting
  • Place of Presentation: Wiesbaden, Germany
• [Presentation] Inhibition of histone demethylase JHDM2A expressed under hypoxia and nutrient starvation suppresses tumor growth and enhances anti-angiogenic therapy (2012)
  • Author(s): Osawa T
  • Organizer: Keystone Symposia on Angiogenesis
  • Place of Presentation: Snowbird Utah
• [Presentation] Down’s syndrome candidate region-1 mediates corneal opacity via corneal angiogenesis (2012)
  • Author(s): Osawa T, Nakagawa S, Toyono T, Toyama K, Miura M, Suehiro J, Tanaka T, Usui T, Amano S, Aburatani H, Kodama T, and Minami T
  • Organizer: The 10th Korea-Japan Joint Symposium on Vascular Viology
  • Place of Presentation: 徳島
• [Presentation] 低酸素・低栄養に誘導されるヒストン修飾酵素が血管新生を介して癌の増殖を制御する (2012)
  • Author(s): 大澤毅, 土田里香、村松昌、王峰、島村徹平、宮野悟、南敬、児玉龍彦、澁谷正史
  • Organizer: 第7１回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Paradoxically Impaired Development of Atherosclerosis in Hyperlipidemic Down’s syndrome candidate region-1-/- and Apolipoprotein E-/- Double-Knockout Mice (2012)
  • Author(s): Osawa T, Toyama K, Nakagawa S, Miura M, Suehiro J, Tanaka T, Aburatani H, Kodama T, and Minami T
  • Organizer: The International Vascular Biology Meeting
  • Place of Presentation: Wiesbaden (Germany)
• [Presentation] Inhibition of histone demethylase JHDM2A expressed under hypoxia and nutrient starvation suppresses tumor growth and enhances anti-angiogenic therapy (2012)
  • Author(s): Osawa T
  • Organizer: Keystone Symposia(招待講演)
  • Place of Presentation: Snowbird Utah, USA
• [Presentation] 低酸素・低栄養で誘導されるヒストン脱メチル化酵素JHDM2Aは血管新生を介して癌の進展に寄与する (2011)
  • Author(s): 大澤毅
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 横浜、神奈川県
• [Presentation] Histone demethylases regulate tumor growth and enhances anti-angiogenic 1st therapy (2011)
  • Author(s): Osawa T
  • Organizer: The Asia-Pacific Vascular Biology Meeting
  • Place of Presentation: Tokyo
• [Presentation] 低酸素・低栄養下で生存する癌細胞を標的とした新規制癌法 (2011)
  • Author(s): 大澤毅
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋、愛知県
• [Presentation] Inhibition of histone demethylase JHDM2A suppresses tumor growth and 9th enhances anti-angiogenic therapy (2011)
  • Author(s): Osawa T
  • Organizer: The Japan-Korea Joint Symposium on Vascular Biology
  • Place of Presentation: Busan, Korea
• [Presentation] Targeting cancer cells resistant to hypoxia and nutrient starvation double-deprivation stress as a novel cancer therapy (2011)
  • Author(s): Osawa T
  • Organizer: The American Association for Cancer Research 102st Annual Meeting
  • Place of Presentation: Orlando, USA
• [Presentation] 低酸素・低栄養で誘導されるヒストン脱メチル化酵素ＪＨＤＭ２Ａは血管新生を介して癌の進展に寄与する (2011)
  • Author(s): 大澤毅ら
  • Organizer: 日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] Histone demethylases regulate tumor growth and enhances anti-angiogenic therapy (2011)
  • Author(s): Osawa T., et al.
  • Organizer: The 1st Asia-Pacific Vascular Biology Meeting(招待講演)
  • Place of Presentation: 東京駅カンファレンス（東京都）
• [Presentation] 低酸素・低栄養下で生存する癌細胞を標的とした新規制癌法 (2011)
  • Author(s): 大澤毅ら
  • Organizer: がんとハイポキシア研究会
  • Place of Presentation: 学習院大学（東京都）
• [Presentation] 低酸素・低栄養下で生存する癌細胞を標的とした新規制癌法 (2011)
  • Author(s): 大澤毅ら
  • Organizer: 日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（愛知県）
• [Presentation] 低酸素・低栄養によって誘導されるヒストン脱メチル化酵素JHDM2Aを標的とした新規制癌法 (2011)
  • Author(s): 大澤毅
  • Organizer: がん若手研究者ワークショップ
  • Place of Presentation: アートランド蓼科（長野県）
• [Presentation] Inhibition of histone demethylase JHDM2A suppresses tumor growth and enhances anti-angiogenic therapy (2011)
  • Author(s): Osawa T., et al.
  • Organizer: The 9th Japan-Korea Joint Symposium on Vascular Biology
  • Place of Presentation: Busan, Korea
• [Presentation] 低酸素・低栄養に抵抗性を持つ癌細胞を標的とした新規制癌法 (2011)
  • Author(s): 大澤毅ら
  • Organizer: 東京大学生命科学シンポジウム
  • Place of Presentation: 東京大学（東京都）
• [Remarks]
  • URL: http://ganshien.umin.jp/public/research/spotlight/oosawa/index.html
• [Remarks]
  • URL: http://www.lsbm.org/
• [Remarks]
  • URL: http://www.lsbm.org/
• [Remarks]
  • URL: http://ganshien.umin.jp/public/research/index.html
• [Patent(Industrial Property Rights)] 抗腫瘍剤 (2010)
  • Inventor(s): 澁谷正史、土田里香、大澤毅
  • Industrial Property Rights Holder: 東京医科歯科大学
  • Industrial Property Rights Type: 特許
  • Acquisition Date: 2010
  • Overseas