Elucidation of the role of oxygen-dependent dioxygenases on the development of tumor microenvironments

• Project/Area Number: 15K20970
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology; Pathological medical chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Tabu Kouichi 東京医科歯科大学, 難治疾患研究所, 助教 (10466469)
• Research Collaborator: TAGA Tetsuya 東京医科歯科大学, 難治疾患研究所, 教授 (40192629) ; KIMURA Taichi 北海道大学, 医学研究科, 特任助教 (90435959)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 癌 / 微小環境 / マクロファージ / 鉄 / ストレス応答

Outline of Final Research Achievements

This study has been carried out with the aim of elucidating the mechanisms how tumor microenvironments are developed during tumor progression. We have revealed that a subpopulation of glioma cells induces macrophages expressing iron-recycling genes　under the iron-deficient stress, which suggests that stress response by tumor cells plays important roles in the development of tumor microenvironments. We also found that the induction of macrophages is potentially mediated by the epigenetic upregulation of CCL2 and GMCSF genes　in tumor cells. Our findings could help establish new strategies for cancer therapy targeting microenvironments.

Research Products

• [Int'l Joint Research] University of Edinburgh(スコットランド)
• [Int'l Joint Research] University of Edinburgh(スコットランド)
• [Journal Article] Enhancement of 5-aminolevulinic acid-based fluorescence detection of side population-defined glioma stem cells by iron chelation (2017)
  • Author(s): Wang W, Tabu K, Hagiya Y, Sugiyama Y, Kokubu Y, Murota Y, Ogura SI and Taga T
  • Journal Title: Scientific Reports Volume: 7 Pages: 42070-42070
  • DOI: 10.1038/srep42070
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Requirement of ABC transporter inhibition and Hoechst 33342 dye deprivation for the assessment of side population-defined C6 glioma stem cell metabolism using fluorescent probes (2016)
  • Author(s): Murota Y, Tabu K and Taga T
  • Journal Title: BMC Cancer Volume: 16 Pages: 847-847
  • DOI: 10.1186/s12885-016-2895-8
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] A synthetic polymer scaffold reavels the self-maintenance strategies of rat glioma stem cells by organization of the advantageous niche. (2016)
  • Author(s): Tabu K, Muramatsu N, Mangani C, Wu M, Zhang R, Kimura T, Terashima K, Bizen N, Kimura R, Wang W, Murota Y, Kokubu Y, Nobuhisa I, Kagawa T, Kitabayashi I, Bradley M, Taga T.
  • Journal Title: Stem cells Volume: 34 Pages: 1151-1162
  • DOI: 10.1002/stem.2299
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Induction of protumoral CD11c(high) macrophages by glioma cancer stem cells through GM-CSF. (2016)
  • Author(s): Kokubu et al
  • Journal Title: Gene to Cell Volume: 21 Pages: 241-251
  • DOI: 10.1111/gtc.12333
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Up-regulation of lymphocyte antigen 6 complex expression in side-population cells derived from a human trophoblast cell line HTR-8/SVneo (2016)
  • Author(s): Inagaki T , Kusunoki S, Tabu K, Okabe H , Yamada I , Taga T , Matsuomoto A , Makino S , Takeda S , Kato K
  • Journal Title: Human Cell Volume: 29 Pages: 10-21
  • DOI: 10.1007/s13577-015-0121-7
  • Peer Reviewed
• [Journal Article] Identification and analysis of CXCR4-positive synovial sarcoma-initiating cells. (2016)
  • Author(s): Kimura T, Wang L, Tabu K, Tsuda M, Tanino M, Maekawa A, Nishihara H, Hiraga H, Taga T, Oda Y, Tanaka S.
  • Journal Title: Oncogene Volume: 未定
  • DOI: 10.1038/onc.2015.461
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Self-maintenance strategies of glioma stem cells (GSCs) involving GSC-induced protumoral macrophages (2017)
  • Author(s): Tabu K and Taga T
  • Organizer: 第11回研究所ネットワーク国際シンポジウム
  • Place of Presentation: 徳島大学（徳島県徳島市）
  • Year and Date: 2017-01-26
• [Presentation] Adaptive response of C6 glioma stem cells to iron deprivation through macrophage induction (2016)
  • Author(s): Tabu K, Wang W, Murota Y and Taga T
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Enhancement of 5-aminolevulinic acid-based fluorescence detection of glioma stem cells by chelating iron (2016)
  • Author(s): Wang W, Tabu K, Hagiya Y, Murota Y, Ogura SI and Taga T
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Adaptive response of rat C6 glioma stem cells to iron deprivation by which the development of tumor infiltrating macrophages is induced (2016)
  • Author(s): Tabu K, Kokubu Y, Muramatsu N, Nomoto S, Wang W and Taga T
  • Organizer: 第14回幹細胞シンポジウム
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県淡路市）
  • Year and Date: 2016-05-20
• [Presentation] Resistance of glioma stem cells to 5-aminolevulinic acid (ALA)-based detection due to enhanced metabolic conversion of protoporphyrin IX (2016)
  • Author(s): Wang W, Tabu K, Sugiyama Y, Hagiya Y, Ogura SI and Taga T
  • Organizer: 第14回幹細胞シンポジウム
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県淡路市）
  • Year and Date: 2016-05-20
• [Presentation] C6 glioma stem cell-derived extracellular vesicles promote the development of macrophages (2016)
  • Author(s): Murota Y, Tabu K and Taga T
  • Organizer: 第14回幹細胞シンポジウム
  • Place of Presentation: 淡路夢舞台国際会議場（兵庫県淡路市）
  • Year and Date: 2016-05-20
• [Presentation] Synthetic polymer-based approach revealed an adaptive capacity of glioma stem cells by inducing tumor-infiltrating and iron-accumulating macrophages (2015)
  • Author(s): Kouichi Tabu, Nozomi Muramatsu, and Tetsuya Taga
  • Organizer: 第38回日本分子生物学会年会
  • Place of Presentation: 神戸ポートアイランド（兵庫県、神戸市）
  • Year and Date: 2015-12-01
• [Presentation] Splenic abnormal erythropoiesis in C6 glioma-bearing mice: an implication for their environment of cancer stem cells (2015)
  • Author(s): Wenqian Wang, Kouichi Tabu, Yasuhiro Kokubu, Yuichiro Hagiya, Shun-ichiro Ogura, and Tetsuya Taga
  • Organizer: 第74回日本癌学会学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県、名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] Characterization of C6 glioma cancer stem cells and their niche (2015)
  • Author(s): Taga T and Tabu K
  • Organizer: Seoul National University, Cancer Research Institute (SNUCRI) Annual Symposium 2015 ‘Innovative Approaches to Explore Novel Druggable Targets’
  • Place of Presentation: Hwasun Kumho Resort (Hwasun, Korea)
  • Year and Date: 2015-04-01
• [Book] 合成ポリマーを用いた癌幹細胞ニッチの特性解明 (バイオマテリアル -生体材料-) (2017)
  • Author(s): 椨康一、室田吉貴、田賀哲也
  • Total Pages: 82
  • Publisher: 日本バイオマテリアル学会
• [Remarks] 東京医科歯科大学プレスリリース
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20170207_1.pdf
• [Remarks] 東京医科歯科大学プレスリリース
  • URL: http://www.tmd.ac.jp/archive-tmdu/kouhou/20160129.pdf