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Monitoring Tumor Hypoxia and Sensitizing Radiotherapy Effects by Using Hypoxia-Inducible Secreted Proteins

Research Project

Project/Area Number 20H03621
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 52040:Radiological sciences-related
Research InstitutionKyoto University

Principal Investigator

Harada Hiroshi  京都大学, 生命科学研究科, 教授 (80362531)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2022: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2021: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2020: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000)
Keywordsがん / 微小環境 / 低酸素 / マーカー / 増感
Outline of Research at the Start

がん放射線治療において個別化医療を実現するには、放射線抵抗性の腫瘍内低酸素の量をモニターし、放射線治療効果を予測する系を確立すること、また、低酸素がん細胞の放射線抵抗性に関わる遺伝子を阻害する手法を確立することが肝要である。本研究では、「低酸素がん細胞が発現・分泌し、自身の放射線抵抗性を誘導するHISP2に着目し、1)がんが低酸素環境下でHISP2を発現・分泌する機序と、HISP2ががんの放射線抵抗性を亢進する機序を解明する、2)血中内のHISP2量で「腫瘍内低酸素の量・放射線抵抗性・予後」を予測する系を確立する、3)放射線治療効果を増強する手段としてHISP2を治療標的とする意義を確認する。

Outline of Final Research Achievements

Since cancer cells become radioresistant under hypoxic conditions and cause poor patient prognosis, there is a need to monitor tumor hypoxia differently in each patient and to establish therapies that target tumor hypoxia. In this study, we identified SPINK1 as a protein secreted by hypoxia-stimulated cancer cells and found that its plasma concentration can be used to monitor the hypoxic fraction in tumors, and that inhibition of SPINK1 can enhance therapeutic effect of radiation.

Academic Significance and Societal Importance of the Research Achievements

悪性固形腫瘍(がん)の内部に存在する低酸素環境は、がんの悪性化を引き起こす問題として認識されている。本研究で見出した知見により、血漿内のSPINK1濃度を指標に腫瘍内低酸素画分の多いがん患者を選出し、SPINK1を標的とする治療により放射線治療の効果を増強する、個別化医療の実現に繋がる可能性がある。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Annual Research Report
  • 2020 Annual Research Report
  • Research Products

    (33 results)

All 2023 2022 2021 2020 Other

All Int'l Joint Research (3 results) Journal Article (8 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 7 results,  Open Access: 7 results) Presentation (17 results) (of which Int'l Joint Research: 4 results,  Invited: 10 results) Remarks (2 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 2 results)

  • [Int'l Joint Research] University of Oxford/University of Sussex(英国)

    • Related Report
      2022 Annual Research Report
  • [Int'l Joint Research] University of Oxford(英国)

    • Related Report
      2021 Annual Research Report
  • [Int'l Joint Research] University of Oxford(英国)

    • Related Report
      2020 Annual Research Report
  • [Journal Article] ZBTB2 links p53 deficiency to HIF-1-mediated hypoxia signaling to promote cancer aggressiveness2022

    • Author(s)
      Koyasu Sho、Horita Shoichiro、Saito Keisuke、Kobayashi Minoru、Ishikita Hiroshi、Chow Christalle CT、Kambe Gouki、Nishikawa Shigeto、Menju Toshi、Morinibu Akiyo、Okochi Yasushi、Tabuchi Yoshiaki、Onodera Yasuhito、Takeda Norihiko、Date Hiroshi、Semenza Gregg L、Hammond Ester M、Harada Hiroshi
    • Journal Title

      EMBO reports

      Volume: 24 Issue: 1 Pages: 54042-54042

    • DOI

      10.15252/embr.202154042

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Proteolysis of a histone acetyl reader, ATAD2, induces chemoresistance of cancer cells under severe hypoxia by inhibiting cell cycle progression in S phase2022

    • Author(s)
      Haitani Takao、Kobayashi Minoru、Koyasu Sho、Akamatsu Shusuke、Suwa Tatsuya、Onodera Yasuhito、Nam Jin-Min、Nguyen Phuong Thi Lien、Menju Toshi、Date Hiroshi、Ogawa Osamu、Harada Hiroshi
    • Journal Title

      Cancer Letters

      Volume: 528 Pages: 76-84

    • DOI

      10.1016/j.canlet.2021.12.028

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 放射線による細胞死と組織障害2022

    • Author(s)
      百海享洲、武内智史、王美惠、宮長真広、嶋貫悠、小林稔、原田浩
    • Journal Title

      医学のあゆみ

      Volume: 283 Pages: 23445-23450

    • Related Report
      2022 Annual Research Report
  • [Journal Article] Tumor microenvironment and radioresistance.2021

    • Author(s)
      Suwa T, Kobayashi M, Nam JM, Harada H.
    • Journal Title

      Exp Mol Med.

      Volume: 53 Issue: 6 Pages: 1029-1029

    • DOI

      10.1038/s12276-021-00640-9

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] An Overview of the Recent Development of Anticancer Agents Targeting the HIF-1 Transcription Factor2021

    • Author(s)
      Shirai Y, Chow CCT, Kambe G, Suwa T, Kobayashi M, Takahashi I, Harada H, Nam JM.
    • Journal Title

      Cancers

      Volume: 13 Issue: 11 Pages: 2813-2813

    • DOI

      10.3390/cancers13112813

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] SPINK1 as a plasma marker for tumor hypoxia and a therapeutic target for radiosensitization.2021

    • Author(s)
      Suwa T, Kobayashi M, Shirai Y, Nam JM, Tabuchi Y, Takeda N, Akamatsu S, Ogawa O, Mizowaki T, Hammond EM, Harada H.
    • Journal Title

      JCI Insight.

      Volume: 6 Issue: 21

    • DOI

      10.1172/jci.insight.148135

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Space radiation biology for “Living in Space”2020

    • Author(s)
      Furukawa S, Nagamatsu A, Nenoi M, Fujimori A, Kakinuma S, Katsube T, Wang B, Tsuruoka C, Shirai T, Nakamura AJ, Sakaue-Sawano A, Miyawaki A, Harada H, Kobayashi M, Kobayashi J, Kunieda T, Funayama T, Suzuki M, Miyamoto T, Hidema J, Yoshida Y, Takahashi A.
    • Journal Title

      BioMed Res Int.

      Volume: 2020 Issue: 1 Pages: 4703286-4703286

    • DOI

      10.1155/2020/4703286

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Development of Antibody-Oligonucleotide Complexes for targeting Exosomal microRNA.2020

    • Author(s)
      Asako Yamayoshi, Shota Oyama, Yusuke Kishimoto, Ryo Konishi, Tsuyoshi Yamamoto, Akio Kobori, Hiroshi Harada, Eishi Ashihara, Hiroshi Sugiyama, Akira Murakami.
    • Journal Title

      Pharmaceutic

      Volume: 12 Issue: 6 Pages: 545-545

    • DOI

      10.3390/pharmaceutics12060545

    • NAID

      120006988115

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Hypoxic tumor cells: their dynamics during tumor growth and involvement in recurrence after radiation therapy2023

    • Author(s)
      Hiroshi HARADA
    • Organizer
      Sussex-Japan Genome Stability Meeting
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Crosstalk between cellular hypoxia signaling and DNA damage response mediated by a HIF-1 activator, ZBTB22023

    • Author(s)
      Gouki KAMBE, Minoru KOBAYASHI, Sho KOYASU, Hiroshi HARADA
    • Organizer
      ATW2023
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] がん抑制機構と低酸素応答機構をつなぐ新規遺伝子の同定と活用2022

    • Author(s)
      原田浩
    • Organizer
      第27回癌治療増感研究会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 血漿内SPINK1濃度を指標にした腫瘍内低酸素分画のモニタリング2022

    • Author(s)
      原田浩、諏訪達也
    • Organizer
      第59回JASTRO生物部会学術大会
    • Related Report
      2022 Annual Research Report
  • [Presentation] 固形腫瘍内の不均一な酸素環境におけるがん細胞の動態と転移2022

    • Author(s)
      原田浩
    • Organizer
      第31回 日本がん転移学会学術集会・総会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 酸素生物学で迫るがん細胞の素顔2022

    • Author(s)
      原田浩
    • Organizer
      名古屋大学大学院創薬科学研究科 第154回創薬科学セミナー
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Radioresistance of hypoxic tumor cells; lessons from hypoxia and HIF-1 biology2022

    • Author(s)
      Hiroshi HARADA
    • Organizer
      The 5th Asian Congress of Radiation Research
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Tumor Hypoxic Fraction (THF)を予測する血漿バイオマーカーSPINK12022

    • Author(s)
      諏訪達也、小林稔、白井友香理、武田憲彦、溝脇尚志、原田浩
    • Organizer
      がんとハイポキシア研究会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Radioresistance of Hypoxic Tumor Cells2022

    • Author(s)
      Hiroshi HARADA
    • Organizer
      The 13th isDDRHD-2022
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 酸素生物学と放射線腫瘍学の接点2021

    • Author(s)
      原田浩
    • Organizer
      日本量子医科学会第1回学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 高線量放射線照射後の腫瘍内酸素環境の変化に基づく分割照射法の再考2021

    • Author(s)
      原田浩
    • Organizer
      第34回日本放射線腫瘍学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] HIFシグナルが加速する悪性固形腫瘍内の細胞社会ダイバーシティー2021

    • Author(s)
      原田浩
    • Organizer
      第94回日本生化学学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] 分泌タンパク質 SPINK1 を活用した腫瘍内低酸素のモニタリングと放射線増感2021

    • Author(s)
      諏訪達也
    • Organizer
      低酸素研究会2021
    • Related Report
      2021 Annual Research Report
  • [Presentation] 低酸素バイオロジーの視点で見るハイパーサーミアによる放射線増感2021

    • Author(s)
      原田浩
    • Organizer
      第38回日本ハイパーサーミア学会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Hypoxia-inducible secretory protein 2 (HISP2); a novel marker and therapeutic target for hypoxia2020

    • Author(s)
      Suwa T, Kobayashi M, Shirai Y, Mizowaki T, Harada H
    • Organizer
      JASTRO 2020
    • Related Report
      2020 Annual Research Report
  • [Presentation] Gene expression regulatory mechanism of a novel radioresistance-related gene, HISP22020

    • Author(s)
      Shirai Y, Suwa T, Kobayashi M, Harada H
    • Organizer
      第79回日本癌学会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 新規低酸素誘導性分泌タンパク質hypoxia-inducible secretory protein2 (HISP2)の発現機構の解析2020

    • Author(s)
      白井友香理、諏訪達也、小林稔、原田浩
    • Organizer
      第72回日本細胞生物学会大会
    • Related Report
      2020 Annual Research Report
  • [Remarks] 京都大学大学院生命科学研究科がん細胞生物学分野ホームページ

    • URL

      http://www.rbc.kyoto-u.ac.jp/cancer_biology/

    • Related Report
      2022 Annual Research Report
  • [Remarks]

    • URL

      http://www.rbc.kyoto-u.ac.jp/cancer_biology/

    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] 低酸素バイオマーカー及びその利用2022

    • Inventor(s)
      諏訪達也、小林稔、原田浩
    • Industrial Property Rights Holder
      諏訪達也、小林稔、原田浩
    • Industrial Property Rights Type
      特許
    • Filing Date
      2022
    • Related Report
      2022 Annual Research Report
    • Overseas
  • [Patent(Industrial Property Rights)] 低酸素バイオマーカー及びその利用2021

    • Inventor(s)
      諏訪達也、小林稔、原田浩
    • Industrial Property Rights Holder
      諏訪達也、小林稔、原田浩
    • Industrial Property Rights Type
      特許
    • Industrial Property Number
      2021-108196
    • Filing Date
      2021
    • Related Report
      2021 Annual Research Report
  • [Patent(Industrial Property Rights)] がんを治療するための医薬組成物2020

    • Inventor(s)
      原田浩、子安翔
    • Industrial Property Rights Holder
      (国)京都大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2020
    • Related Report
      2020 Annual Research Report
    • Overseas

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Published: 2020-04-28   Modified: 2024-01-30  

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