Exploring the mechanism of stemness suppression by iron chelators and applying a novel therapeutic modality for cancer stem cells

• Project/Area Number: 18K08539
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: Okayama University
• Principal Investigator: Ohara Toshiaki 岡山大学, 医歯薬学総合研究科, 助教 (40623533)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 癌 / 幹細胞 / 鉄 / キレート / がん幹細胞 / 幹細胞性

Outline of Final Research Achievements

Cancer stem cells (CSCs) are reportedly responsible for therapeutic resistance such as recurrence and metastasis. We found that iron metabolism is a key factor in the stemness of CSCs. We demonstrated that iron chelators (DFX, DFO and SP10) suppressed the proliferation and stemness markers of cancer cells in vitro and in vivo. Among 134 immunohistochemically analyzed cases, high Nanog expression, correlated with low overall survival. In conclusion, iron chelators can be a novel therapeutic strategy for CSCs.

Academic Significance and Societal Importance of the Research Achievements

今回の研究によって癌細胞の幹細胞性は、iPS細胞から誘導したモデル細胞だけなく、広く鉄代謝に依存的であり、鉄キレート剤を用いて鉄代謝を阻害する事が、癌幹細胞の治療になり得る事が示された。また、鉄キレート剤による幹細胞性抑制効果は、既存のSTAR3のリン酸化を阻害する癌幹細胞治療薬よりも高い事が示された。これらの結果は治療困難であった幹細胞性を有する癌の理解を深め、さらに治療に結び付く一助になる事が期待される。

Research Products

• [Journal Article] Nanog is a promising chemoresistant stemness marker and therapeutic target by iron chelators for esophageal cancer (2021)
  • Author(s): Toru Narusaka, Toshiaki Ohara, Kazuhiro Noma, Noriyuki Nishiwaki, Yuki Katsura, Takuya Kato, Hiroaki Sato, Yasuko Tomono, Satoru Kikuchi, Hiroshi Tazawa, Yasuhiro Shirakawa, Akihiro Matsukawa, Toshiyoshi Fujiwara
  • Journal Title: International Journal of Cancer Volume: - Issue: 2 Pages: 347-357
  • DOI: 10.1002/ijc.33544
  • Peer Reviewed
• [Journal Article] A Promising New Anti-Cancer Strategy: Iron Chelators Targeting CSCs (2020)
  • Author(s): Yuehua Chen, Toshiaki Ohara, Boyi Xing, Jiping Qi, Kazuhiro Noma, Akihiro Matsukawa
  • Journal Title: Acta Medica Okayama Volume: 74 Issue: 1 Pages: 1-6
  • DOI: 10.18926/AMO/57946
  • NAID: 120006795613
  • URL: https://ousar.lib.okayama-u.ac.jp/57946
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness. (2019)
  • Author(s): Yuki Katsura, Toshiaki Ohara, Kazuhiro Noma, Takayuki Ninomiya, Hajime Kashima, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Toru Narusaka, Yasuko Tomono, Boyi Xing, Yuehua Chen, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa and Toshiyoshi Fujiwara
  • Journal Title: Cancers Volume: 11 Issue: 67 Pages: 117-117
  • DOI: 10.18632/oncotarget.25973
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 鉄キレート剤による幹細胞性制御による新規食道癌治療法 (2019)
  • Author(s): 大原 利章、桂 佑貴 、野間 和広、西脇 紀之、河本 慧、田澤 大、香川 俊輔、藤原 俊義
  • Organizer: 第78回日本癌学会総会
• [Presentation] Stemness control by iron chelator is a novel therapeutic strategy for esophageal cancer (2019)
  • Author(s): Toru Narusaka, Toshiaki Ohara, Kazuhiro Noma, Yuki Katsura, Noriyuki Nishiwaki, Motoyasu Tabuchi, Takuro Fushimi, Toshihiro Ogawa, Sho Takeda, Satoshi Komoto, Hiroaki Sato, Takuya Kato, Satoru Kikuchi, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara.
  • Organizer: 110th Annual Meeting American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] 除鉄による幹細胞性制御による新規食道癌治療法の開発 (2019)
  • Author(s): 鳴坂徹 、木村 文昭 、大原 利章
  • Organizer: 第43回日本鉄バイオサイエンス学会学術集会
• [Presentation] Iron depletion suppress the stemness markers and functions of cancer stem cells (2018)
  • Author(s): Toshiaki Ohara, Yuki Katsura, Kazuhiro Noma, Toru Narusaka, Takayuki Ninomiya, Hiroaki Sato, Satoshi Komoto, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara
  • Organizer: 109th Annual Meeting American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] 除鉄による癌幹細胞の幹細胞性マーカーと機能は制御される (2018)
  • Author(s): 大原 利章、Sun, Yingfu、友野 靖子、松川 昭博
  • Organizer: 第107回日本病理学会総会
• [Presentation] 鉄キレート剤の幹細胞性制御による新規癌治療法 (2018)
  • Author(s): 大原利章、桂佑貴、野間 和広、鳴坂 徹、佐藤浩明、河本慧、加藤卓也、田澤大、香川 俊輔、藤原 俊義
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 鉄キレート剤の幹細胞性制御による新規癌治療法の確立 (2018)
  • Author(s): 大原利章、桂佑貴、野間 和広、鳴坂 徹、二宮 卓之、友野靖子、田澤大、香川 俊輔、白川 靖博、松川 昭博、藤原 俊義
  • Organizer: 第29回日本消化器癌発生学会総会