Development of novel therapies targeting the dynamics of tumor microenvironment and HIF-1

• Project/Area Number: 18K15589
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52040:Radiological sciences-related
• Research Institution: Kyoto University
• Principal Investigator: Kobayashi Minoru 京都大学, 生命科学研究科, 特定助教 (40644894)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 低酸素 / 腫瘍内微小環境 / 放射線抵抗性

Outline of Final Research Achievements

It is known that cancer cells in hypoxic region are radioresistant and contribute to recurrence after radiotherapy. Therefore, the development of therapies that target the tumor microenvironment is desired. However, therapies targeting the tumor microenvironment have yet to be established because of the lack of knowledge about the dynamics of tumor microenvironment.
In order to understand the dynamics of tumor microenvironment, especially the HIF-1 activated cells, we constructed the artificial genes 5HREp-Luc and 5HREp-Cre-ERT2, which labeled and tracked cells in a HIF-1-dependent manner. And we generated these genes knock-in mice from TIGRE locus.
We expect that these mice will be used to get insight into the dynamics of tumor microenvironment.

Academic Significance and Societal Importance of the Research Achievements

本研究で作成したTIGRE遺伝子座に5HREp-Lucをknock-inしたマウスを発がんモデルマウスと掛け合わせることで、刻一刻と変化する腫瘍内の低酸素領域とそこに存在するがん細胞を可視化するとともに、さらに現在作成に取り掛かっている5HREp-Cre-ERT2をknock-inしたマウスを用いることで上記した低酸素がん細胞がその後どのような運命を辿るのかを知ることが可能になる。これらのマウスを用いて、抗がん剤治療や放射線治療を行った後の低酸素がん細胞の動態を知ることで、化学放射線療法や放射線多分割照射の効果を最大限に発揮することを可能とする、新たな治療戦略につながることが期待される。

Research Products

• [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
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] HIF-1-Dependent Reprogramming of Glucose Metabolic Pathway of Cancer Cells and Its Therapeutic Significance (2019)
  • Author(s): Nagao Ayako、Kobayashi Minoru、Koyasu Sho、Chow Christalle C. T.、Harada Hiroshi
  • Journal Title: International Journal of Molecular Sciences Volume: 20 Issue: 2 Pages: 238-238
  • DOI: 10.3390/ijms20020238
  • NAID: 120006778264
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Regulatory mechanisms of hypoxia-inducible factor 1 activity: Two decades of knowledge (2018)
  • Author(s): Koyasu Sho、Kobayashi Minoru、Goto Yoko、Hiraoka Masahiro、Harada Hiroshi
  • Journal Title: Cancer Science Volume: 109 Issue: 3 Pages: 560-571
  • DOI: 10.1111/cas.13483
  • NAID: 120006454672
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Elucidation of regulatory mechanisms underlying hypoxic responses and its physiological role. (2019)
  • Author(s): Minoru Kobayashi
  • Organizer: 第21回 生命科学研究科シンポジウム
• [Presentation] Generation of EGFP-53BP1 knock-in mouse which is able to be visualized DNA double-strand break (2019)
  • Author(s): Minoru Kobayashi, Hiroshi Harada
  • Organizer: 第62回放射線影響学会
  • Int'l Joint Research
• [Presentation] 低酸素下でのp53タンパク質の蓄積メカニズムの解明 (2019)
  • Author(s): 長尾 綾子、小林 稔、諏訪 達也、河原康一、古川 龍彦、原田 浩
  • Organizer: 第17回がんとハイポキシア研究会
• [Presentation] A Circadian Clock Gene, PER2, Activates HIF-1 as an Effector Molecule for Recruitment of HIF-1α to Promoter Regions of Its Downstream Genes (2018)
  • Author(s): Minoru Kobayashi, Akiyo Morinibu, Sho Koyasu, Yoko Goto, Masahiro Hiraoka, Hiroshi Harada
  • Organizer: 第34回放生研国際シンポジウム
• [Presentation] HIF-1 maintains a functional relationship between pancreatic cancer cells and stromal fibroblasts by upregulating Shh. (2018)
  • Author(s): Minoru Kobayashi, Tomohiro Katagiri, Masahiro Hiraoka, Hiroshi Harada
  • Organizer: 第77回 日本癌学会学術総会
• [Presentation] A circadian clock gene, PER2, activates HIF-1 as an effector molecule for recruitment of HIF-1α to promoter regions of Its downstream genes (2018)
  • Author(s): Minoru Kobayashi, Akiyo Morinibu, Sho Koyasu, Yoko Goto, Masahiro Hiraoka, Hiroshi Harada
  • Organizer: The 17th International Joint Mini-Symposium on Molecular and Cell Biology
• [Presentation] A circadian clock gene, PER2, activates HIF-1 as an effector molecule for recruitment of HIF-1α to promoter regions of Its downstream genes (2018)
  • Author(s): 5.Minoru Kobayashi, Akiyo Morinibu, Sho Koyasu, Yoko Goto, Masahiro Hiraoka, Hiroshi Harada
  • Organizer: Keystone symposia Therapeutic Targeting of Hypoxia-Sensitive Pathways (V1)
  • Int'l Joint Research
• [Book] 実験医学2020年6月号 「酸素環境感知の基本メカニズムとがん」 (2020)
  • Author(s): 小林 稔、原田 浩
  • Total Pages: 7
  • Publisher: 羊土社
  • ISBN: 9784758125321
• [Remarks] 京都大学大学院生命科学研究科がん細胞生物学
  • URL: http://www.rbc.kyoto-u.ac.jp/cancer_biology/