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Maintenance of tumor microenvironments by extracellular vesicles derived from glioblastoma cells

Research Project

Project/Area Number 18H02910
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 56010:Neurosurgery-related
Research InstitutionKanazawa University

Principal Investigator

Nakada Mitsutoshi  金沢大学, 医学系, 教授 (20334774)

Co-Investigator(Kenkyū-buntansha) 華山 力成  金沢大学, ナノ生命科学研究所, 教授 (40403191)
Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2020: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2018: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
Keywords悪性神経膠腫 / 膠芽腫 / エクソソーム / マイクログリア / 細胞外微小環境 / ミクログリア
Outline of Final Research Achievements

Glioblastoma is the most malignant brain tumor. In order to develop new treatments for glioblastoma, it is necessary to elucidate the mechanism of tumor growth and progression. Recently, extracellular vesicles called exosomes, which are secreted by cells, have been attracting attention in various malignant tumors. In this study, we studied the exosomes secreted by glioblastoma cells. We found that the exosomes containing WT1 protein are secreted by glioblastoma cells, then expression of thrombospondin-1, a negative regulator of angiogenesis, was downregulated in surrounding microglia. This intercellular regulatory pathway promotes glioblastoma progression. Our findings establish a novel model of tumor progression via exosome-mediated WT1-Thbs1, which may be a future diagnostic or therapeutic target.

Academic Significance and Societal Importance of the Research Achievements

今回の研究により、これまでは知られていなかった膠芽腫とエクソソームの関係が明らとなり、さらにそのメカニズムを細胞レベルだけではなく、生体レベルでも解明することができた。膠芽腫細胞のエクソソーム分泌を抑制するあるいは、そのエクソソームの中に含まれるタンパク質の量を変化させることで、膠芽腫細胞が形成する腫瘍の大きさを縮小し、その生命予後を改善させることが動物実験で証明できた。この研究結果を応用することで、従来の膠芽腫に対する治療とは一線を画する革新的な膠芽腫治療法を提案できる可能性がある。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • Research Products

    (23 results)

All 2020 2019 2018 Other

All Journal Article (19 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 19 results,  Open Access: 19 results) Presentation (3 results) Remarks (1 results)

  • [Journal Article] Ependymoma with C11orf95-MAML2 fusion: presenting with granular cell and ganglion cell features2020

    • Author(s)
      Tamai Sho、Nakano Yoshiko、Kinoshita Masashi、Sabit Hemragul、Nobusawa Sumihito、Arai Yasuhito、Hama Natsuko、Totoki Yasushi、Shibata Tatsuhiro、Ichimura Koichi、Nakada Mitsutoshi
    • Journal Title

      Brain Tumor Pathology

      Volume: 38 Issue: 1 Pages: 64-70

    • DOI

      10.1007/s10014-020-00388-6

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Awake surgery for right frontal lobe glioma can preserve visuospatial cognition and spatial working memory2020

    • Author(s)
      Nakada Mitsutoshi、Nakajima Riho、Okita Hirokazu、Nakade Yusuke、Yuno Takeo、Tanaka Shingo、Kinoshita Masashi
    • Journal Title

      Journal of Neuro-Oncology

      Volume: 151 Issue: 2 Pages: 221-230

    • DOI

      10.1007/s11060-020-03656-9

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glioma Stem-Like Cells Can Be Targeted in Boron Neutron Capture Therapy with Boronophenylalanine2020

    • Author(s)
      Kondo Natsuko、Hikida Masaki、Nakada Mitsutoshi、Sakurai Yoshinori、Hirata Eishu、Takeno Satoshi、Suzuki Minoru
    • Journal Title

      Cancers

      Volume: 12 Issue: 10 Pages: 3040-3040

    • DOI

      10.3390/cancers12103040

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] RBPJ contributes to the malignancy of glioblastoma and induction of proneural‐mesenchymal transition via IL‐6‐STAT3 pathway2020

    • Author(s)
      Zhang Guangtao、Tanaka Shingo、Jiapaer Shabierjiang、Sabit Hemragul、Tamai Sho、Kinoshita Masashi、Nakada Mitsutoshi
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 11 Pages: 4166-4176

    • DOI

      10.1111/cas.14642

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Leukemia-Associated Rho Guanine Nucleotide Exchange Factor and Ras Homolog Family Member C Play a Role in Glioblastoma Cell Invasion and Resistance2020

    • Author(s)
      Ding Zonghui、Dong Zhiwan、Yang Yuping、Fortin Ensign Shannon P.、Sabit Hemragul、Nakada Mitsutoshi、Ruggieri Rosamaria、Kloss Jean M.、Symons Marc、Tran Nhan L.、Loftus Joseph C.
    • Journal Title

      The American Journal of Pathology

      Volume: 190 Issue: 10 Pages: 2165-2176

    • DOI

      10.1016/j.ajpath.2020.07.005

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Multipotential of Leucine-Rich α-2 Glycoprotein 1 as a Clinicopathological Biomarker of Glioblastoma.2020

    • Author(s)
      Furuta T, Sugita Y, Komaki S, Ohshima K, Morioka M, Uchida Y, Tachikawa M, Ohtsuki S, Terasaki T, Nakada M.
    • Journal Title

      J Neuropathol Exp Neurol

      Volume: 79(8) Issue: 8 Pages: 873-879

    • DOI

      10.1093/jnen/nlaa058

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Laminin Subunit Alpha-4 and Osteopontin Are Glioblastoma-Selective Secreted Proteins That Are Increased in the Cerebrospinal Fluid of Glioblastoma Patients2020

    • Author(s)
      Kohata Tomohiro、Ito Shingo、Masuda Takeshi、Furuta Takuya、Nakada Mitsutoshi、Ohtsuki Sumio
    • Journal Title

      Journal of Proteome Research

      Volume: 19 Issue: 8 Pages: 3542-3553

    • DOI

      10.1021/acs.jproteome.0c00415

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Glioma-derived extracellular vesicles promote tumor progression by conveying WT12020

    • Author(s)
      Tsutsui Taishi、Kawahara Hironori、Kimura Ryouken、Dong Yu、Jiapaer Shabierjiang、Sabit Hemragul、Zhang Jiakang、Yoshida Takeshi、Nakada Mitsutoshi、Hanayama Rikinari
    • Journal Title

      Carcinogenesis

      Volume: 41 Issue: 9 Pages: 1238-1245

    • DOI

      10.1093/carcin/bgaa052

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Direct evidence of the relationship between brain metastatic adenocarcinoma and white matter fibers: A fiber dissection and diffusion tensor imaging tractography study2020

    • Author(s)
      Liu Xiaoliang、Kinoshita Masashi、Shinohara Harumichi、Hori Osamu、Ozaki Noriyuki、Hatta Toshihisa、Honma Satoru、Nakada Mitsutoshi
    • Journal Title

      Journal of Clinical Neuroscience

      Volume: S0967-5852 Pages: 55-61

    • DOI

      10.1016/j.jocn.2020.05.043

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Identification of 2-Fluoropalmitic Acid as a Potential Therapeutic Agent Against Glioblastoma2020

    • Author(s)
      Jiapaer Shabierjiang、Furuta Takuya、Dong Yu、Kitabayashi Tomohiro、Sabit Hemragul、Zhang Jiakang、Zhang Guangtao、Tanaka Shingo、Kobayashi Masahiko、Hirao Atsushi、Nakada Mitsutoshi
    • Journal Title

      Current Pharmaceutical Design

      Volume: 26 Issue: 36 Pages: 4675-4684

    • DOI

      10.2174/1381612826666200429092742

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Pyramid-Shape Crossings and Intercrossing Fibers Are Key Elements for Construction of the Neural Network in the Superficial White Matter of the Human Cerebrum2020

    • Author(s)
      Shinohara Harumichi、Liu Xiaoliang、Nakajima Riho、Kinoshita Masashi、Ozaki Noriyuki、Hori Osamu、Nakada Mitsutoshi
    • Journal Title

      Cerebral Cortex

      Volume: - Issue: 10 Pages: 5218-5228

    • DOI

      10.1093/cercor/bhaa080

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Gelsolin inhibits malignant phenotype of glioblastoma and is regulated by miR-654-5p and miR-450b-5p.2020

    • Author(s)
      Zhang J, Furuta T, Sabit H, Tamai S, Jiapaer S, Dong Y, Kinoshita M, Uchida Y, Ohtsuki S, Terasaki T, Zhao S, Nakada M.
    • Journal Title

      Cancer Sci

      Volume: 111(7) Issue: 7 Pages: 2413-2422

    • DOI

      10.1111/cas.14429

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Aquaporin 1 elicits cell motility and coordinates vascular bed formation by downregulating thrombospondin type-1 domain-containing 7A in glioblastoma2020

    • Author(s)
      Oishi M, Munesue S, Harashima A, Nakada M, Yamamoto Y, Hayashi Y
    • Journal Title

      Cancer Med

      Volume: 9 Issue: 11 Pages: 3904-3917

    • DOI

      10.1002/cam4.3032

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Nucleoporin TPR (translocated promoter region, nulear basket protein) upregulation alters MTOR-HSF1 trails and suppresses autophagy induction in ependymoma.2020

    • Author(s)
      Dewi FRP, Jiapear S, Kobayashi A, Hazawa M, Ikliptikawati DK, Hartono, Sabit H, Nakada M, Wong RW
    • Journal Title

      Autophagy

      Volume: 24 Issue: 4 Pages: 1-12

    • DOI

      10.1080/15548627.2020.1741318

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Receptor Tyrosine Kinases: Principles and Functions in Glioma Invasion2020

    • Author(s)
      Nakada Mitsutoshi、Kita Daisuke、Teng Lei、Pyko Ilya V.、Watanabe Takuya、Hayashi Yutaka、Hamada Jun-ichiro
    • Journal Title

      Adv Exp Med Biol

      Volume: 1 Pages: 151-178

    • DOI

      10.1007/978-3-030-30651-9_8

    • ISBN
      9783030306502, 9783030306519
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Ligand-dependent EphB4 activation serves as an anchoring signal in glioma cells2019

    • Author(s)
      Kawahara Yosuke、Furuta Takuya、Sabit Hemragul、Tamai Sho、Dong Yu、Jiapaer Shabierjiang、Zhang Jiakang、Zhang Guangtao、Oishi Masahiro、Miyashita Katsuyoshi、Hayashi Yasuhiko、Nakada Mitsutoshi
    • Journal Title

      Cancer Letters

      Volume: 449 Pages: 56-65

    • DOI

      10.1016/j.canlet.2019.02.021

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Identification of GSK3β inhibitor kenpaullone as a temozolomide enhancer against glioblastoma2019

    • Author(s)
      Kitabayashi Tomohiro、Dong Yu、Furuta Takuya、Sabit Hemragul、Jiapaer Shabierjiang、Zhang Jiakang、Zhang Guangtao、Hayashi Yasuhiko、Kobayashi Masahiko、Domoto Takahiro、Minamoto Toshinari、Hirao Atsushi、Nakada Mitsutoshi
    • Journal Title

      Scientific Reports

      Volume: 9 Issue: 1 Pages: 10049-10049

    • DOI

      10.1038/s41598-019-46454-8

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] MicroRNA regulating stanniocalcin-1 is a metastasis and dissemination promoting factor in glioblastoma2019

    • Author(s)
      Sakata Junichi、Sasayama Takashi、Tanaka Kazuhiro、Nagashima Hiroaki、Nakada Mitsutoshi、Tanaka Hirotomo、Hashimoto Naoya、Kagawa Naoki、Kinoshita Manabu、Nakamizo Satoshi、Maeyama Masahiro、Nishihara Masamitsu、Hosoda Kohkichi、Kohmura Eiji
    • Journal Title

      Journal of Neuro-Oncology

      Volume: 142 Issue: 2 Pages: 241-251

    • DOI

      10.1007/s11060-019-03113-2

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Fibulin-7 is overexpressed in glioblastomas and modulates glioblastoma neovascularization through interaction with angiopoietin-12019

    • Author(s)
      Susana de Vega, Akihide Kondo, MarioSuzuki, Hajime Arai, Shabierjiang Jiapaer, Hemragul Sabit, Mitsutoshi Nakada, Tomoko Ikeuchi, Muneaki Ishijima, Eri Arikawa-Hirasawa, Yoshihiko Yamada and Yasunori Okada
    • Journal Title

      International Journal of Cancer

      Volume: xx Issue: 8 Pages: 2157-2169

    • DOI

      10.1002/ijc.32306

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 膠芽腫における細胞外小胞の機能解明2020

    • Author(s)
      筒井 泰史、河原 裕憲、華山 力成、中田 光俊
    • Organizer
      第79回日本脳神経外科学会学術総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 膠芽腫由来細胞外小胞による腫瘍微小環境整備機構の解明2019

    • Author(s)
      筒井 泰史, 河原 裕憲, 華山 力成, 中田 光俊
    • Organizer
      第78回日本脳神経外科学会 学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 神経膠芽腫由来エクソソームによる腫瘍微小環境整備機構の解明2018

    • Author(s)
      筒井泰史, 河原裕憲, 淑瑠ヘムラサビット, Dong Yu, 華山力成, 中田光俊
    • Organizer
      第77回脳神経外科学会学術総会
    • Related Report
      2018 Annual Research Report
  • [Remarks] 金沢大学脳神経外科

    • URL

      https://neurosurgery.w3.kanazawa-u.ac.jp/j/

    • Related Report
      2020 Annual Research Report

URL: 

Published: 2018-04-23   Modified: 2022-01-27  

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