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Development of a novel therapy targeting cancer stem cell niches

Research Project

Project/Area Number 19K09834
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56040:Obstetrics and gynecology-related
Research InstitutionTeikyo University

Principal Investigator

Nagasaka Kazunori  帝京大学, 医学部, 教授 (30624233)

Co-Investigator(Kenkyū-buntansha) Kim SooHyeon  東京大学, 生産技術研究所, 講師 (80709189)
Project Period (FY) 2019-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords癌幹細胞 / 微小環境 / マイクロ流体デバイス / 単一細胞解析 / 卵巣癌 / 子宮頸癌 / がん幹細胞 / 進行卵巣癌 / 腹膜播種 / 新規腹膜播種阻害剤 / 卵巣癌腹水 / 腫瘍微小環境 / 一細胞解析 / 3次元培養 / 共培養モデル / 血管新生 / がん幹細胞ニッチ / 婦人科癌
Outline of Research at the Start

婦人科では良・悪性診断、病期診断目的で細胞診が多く用いられるが、得られる情報は診断医が鏡検下で観察した上皮細胞の形態変化が主であり、病態を数値化することは難しい。本研究では、婦人科癌のliquid biopsy中に存在する癌細胞、少数しか存在しない癌幹細胞や、幹細胞の維持や分化の調整を行うとされる微小環境の構成細胞に対して、精度の高い一細胞解析技術を用いて、幹細胞ニッチの分子生物学的な解明を行い、「一細胞の解像度で細胞内外の情報を収集する」ことを目指す。 幹細胞ニッチに対し一細胞の解像度で解明することで、新規治療法の開発への応用ができる可能性がある。

Outline of Final Research Achievements

Patient-derived cells and xenografts retain the biological characteristics of clinical cancers, aiding in understanding chemoresistance. We established patient-derived spheroids from ovarian cancer, revealing varied sensitivity to platinum-based compounds. Cancer stem cells (CSCs) in a supportive niche contribute to tumorigenesis and metastasis. We developed a methodology to investigate ovarian cancer stem cells (OCSCs) and their interaction with endothelial cells using the NICO-1 model, providing insights into angiogenesis and metastasis. We developed an automated on-chip immunostaining method using an electroactive microwell array (EMA) microfluidic device for p16/Ki-67 dual staining, enabling parallel single-cell analysis.

Academic Significance and Societal Importance of the Research Achievements

がん治療における薬剤耐性を克服する標的療法を開発するための基盤となる。卵巣癌幹細胞の腫瘍形成能と内皮細胞との相互作用を調べることで、微小環境の役割に関する重要な知見が得られる。癌幹細胞のニッチを標的とした新たな治療アプローチが可能となり、転移や再発を予防できる可能性がある。またマイクロ流体デバイスを用いた自動オンチップ免疫染色法の開発により、正確でハイスループットな単一細胞解析が可能になった。研究成果は、がん生物学の理解を進め、革新的な診断・治療手段を提供することで、重要な科学的価値を有している。社会的には、患者ケアの改善、医療費の削減、公衆衛生教育の強化につながる。

Report

(6 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (15 results)

All 2023 2021 2020 2019

All Journal Article (11 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 11 results,  Open Access: 10 results) Presentation (4 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Validation of an on-chip p16<sup>ink4a</sup>/Ki-67 dual immunostaining cervical cytology system using microfluidic device technology2023

    • Author(s)
      Hashimoto Kei、Kumagai Tomoo、Nomura Kyosuke、Miyagawa Yuko、Tago Saori、Takasaki Kazuki、Takahashi Yuko、Nishida Haruka、Ichinose Takayuki、Hirano Mana、Hiraike Haruko、Wada-Hiraike Osamu、Sasajima Yuko、Kim Soo Hyeon、Nagasaka Kazunori
    • Journal Title

      Scientific Reports

      Volume: 13 Issue: 1 Pages: 17052-17052

    • DOI

      10.1038/s41598-023-44273-6

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The TGF-β/UCHL5/Smad2 Axis Contributes to the Pathogenesis of Placenta Accreta2023

    • Author(s)
      Hashimoto Kei、Miyagawa Yuko、Watanabe Saya、Takasaki Kazuki、Nishizawa Miki、Yatsuki Keita、Takahashi Yuko、Kamata Hideo、Kihira Chikara、Hiraike Haruko、Sasamori Yukifumi、Kido Koichiro、Ryo Eiji、Nagasaka Kazunori
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 24 Issue: 18 Pages: 13706-13706

    • DOI

      10.3390/ijms241813706

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] High-grade endometrial stromal sarcoma with YWHAE-NUTM2B fusion gene abnormality identified after 10 years of recurrent pulmonary metastases: A case report2023

    • Author(s)
      Takahashi Yuko、Kikuchi Yoshinao、Mukaiyama Junji、Watabe Shiori、Haga Toshihiro、Miyagawa Yuko、Yamamoto Asako、Yamauchi Yoshikane、Hiraike Haruko、Sone Kenbun、Sasajima Yuko、Yoshida Akihiko、Nagasaka Kazunori
    • Journal Title

      Gynecologic Oncology Reports

      Volume: 48 Pages: 101248-101248

    • DOI

      10.1016/j.gore.2023.101248

    • URL

      https://pure.teikyo.jp/en/publications/1b526d56-6aeb-4760-8892-4398e31914ab

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Serum vascular endothelial growth factor associated with the progression of granulosa cell tumor: a report of two cases2023

    • Author(s)
      Takasaki Kazuki、Ichinose Takayuki、Miyagawa Yuko、Fukui Shiho、Hashimoto Kei、Nishida Haruka、Takahashi Yuko、Hiraike Haruko、Saito Koji、Sasajima Yuko、Nagasaka Kazunori
    • Journal Title

      Journal of Ovarian Research

      Volume: 16 Issue: 1

    • DOI

      10.1186/s13048-023-01197-z

    • URL

      https://pure.teikyo.jp/en/publications/484f0b25-88b8-4f7c-9be4-8795ef665545

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Integrative analyses of gene expression and chemosensitivity of patient-derived ovarian cancer spheroids link G6PD-driven redox metabolism to cisplatin chemoresistance2021

    • Author(s)
      Yamawaki K, Mori Y Sakai H, Kanda Y, Shiokawa D, Ueda U, Ishiguro T, Yoshihara K, Nagasaka K, Onda T, Kato T, Kondo T, Enomoto T, *Okamoto K.
    • Journal Title

      Cancer Lett.

      Volume: 521 Pages: 29

    • DOI

      10.1016/j.canlet.2021.08.018

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evaluating the angiogenetic properties of ovarian cancer stem-like cells using the three-dimensional co-culture system, nico-12020

    • Author(s)
      Miyagawa Yuko、Nagasaka Kazunori、Yamawaki Kaoru、Mori Yutaro、Ishiguro Tatsuya、Hashimoto Kei、Koike Ryoko、Fukui Siho、Sugihara Takeru、Ichinose Takayuki、Hiraike Haruko、Kido Koichiro、Okamoto Koji、Enomoto Takayuki、Ayabe Takuya
    • Journal Title

      Journal of Visualized Experiments

      Volume: 2020 Issue: 166 Pages: 1

    • DOI

      10.3791/61751

    • URL

      https://pure.teikyo.jp/en/publications/e3c76071-8db9-4ca1-8bc2-e3184a75505f

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Use of Cap Analysis Gene Expression to detect human papillomavirus promoter activity patterns at different disease stages2020

    • Author(s)
      Taguchi A, Nagasaka K, Plessy C, Nakamura H, Kawata Y, Kato S, Hashimoto K, Nagamatsu T, Oda K, Kukimoto I, Kawana K, Carninci P, Osuga Y, Fujii T.
    • Journal Title

      Sci Rep

      Volume: 10 Issue: 1 Pages: 17991-17991

    • DOI

      10.1038/s41598-020-75133-2

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Effect of murine double-minute 2 inhibitors in preclinical models of advanced clear cell carcinomas originating from ovaries and kidneys2020

    • Author(s)
      Kawata Yoshiko、Nagasaka Kazunori、Oda Katsutoshi、Makii Chinami、Takeuchi Makoto、Oki Shinya、Honjo Harunori、Kojima Machiko、Miyagawa Yuko、Taguchi Ayumi、Tanikawa Michihiro、Sone Kenbun、Hiraike Haruko、Matsumoto Yoko、Wada‐Hiraike Osamu、Ayabe Takuya、Osuga Yutaka、Fujii Tomoyuki
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 10 Pages: 3824

    • DOI

      10.1111/cas.14583

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Anti-tumor effect of inhibition of DNA damage response proteins, ATM and ATR, in endometrial cancer cells2019

    • Author(s)
      Takeuchi Makoto、Tanikawa Michihiro、Nagasaka Kazunori、Oda Katsutoshi、Kawata Yoshiko、Oki Shinya、Agapiti Chuwa、Sone Kenbun、Miyagawa Yuko、Hiraike Haruko、Wada-Hiraike Osamu、Kuramoto Hiroyuki、Ayabe Takuya、Osuga Yutaka、Fujii Tomoyuki
    • Journal Title

      Cancers

      Volume: 11 Issue: 12 Pages: 1913-1913

    • DOI

      10.3390/cancers11121913

    • URL

      https://pure.teikyo.jp/en/publications/5c41367b-5e04-4c85-98ed-26c93d8ab201

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The proteasome deubiquitinase inhibitor bAP15 downregulates TGF-β/Smad signaling and induces apoptosis via UCHL5 inhibition in ovarian cancer.2019

    • Author(s)
      Fukui S, Nagasaka K, Miyagawa Y, Kikuchi-Koike R, Kawata Y, Kanda R, Ichinose T, Sugihara T, Hiraike H, Wada-Hiraike O, Sasajima Y, Ayabe T
    • Journal Title

      Oncotarget

      Volume: 10 Issue: 57 Pages: 5932-5948

    • DOI

      10.18632/oncotarget.27219

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Detection of HPV RNA molecules in stratified mucin-producing intraepithelial lesion (SMILE) with concurrent cervical intraepithelial lesion: A case report2019

    • Author(s)
      Fukui S, Nagasaka K, Iimura N, Kanda R, Ichinose T, Sugihara T, Hiraike H, Nakagawa S, Sasajima Y, Ayabe T.
    • Journal Title

      Virol J

      Volume: 16 Issue: 1 Pages: 76-76

    • DOI

      10.1186/s12985-019-1180-2

    • URL

      https://pure.teikyo.jp/en/publications/6905dc0d-5a2f-42e8-9588-fd00bfaad3a6

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Presentation] 血液循環腫瘍細胞の多様性を解析するための誘電泳動を用いたマイクロ流体デバイスの開発(Electroactive microwell array device for the investigation of the diversity of circulating tumor cells)(英語)2023

    • Author(s)
      杉谷 善信, 長阪 一憲, 藤井 輝夫, キム・スーヒョン
    • Organizer
      日本癌学会総会記事(0546-0476)82回 Page1579(2023.09)
    • Related Report
      2023 Annual Research Report
  • [Presentation] 子宮頸癌スクリーニングのためのマイクロ流体デバイス技術を用いたオンチップp16/Ki67二重免疫染色システムの開発(Development of on-chip p16/Ki67 double immunostaining system using microfluidic device technology for cervical cancer screening)(英語)2023

    • Author(s)
      Hashimoto Kei, Miyagawa Yuko, Kumagai Tomoo, Koike Ryoko, Takahashi Yuko, Nishida Haruka, Ichinose Takayuki, Kihira Chikara, Hiraike Haruko, Kim Soo Hyeon, Nagasaka Kazunori
    • Organizer
      日本産科婦人科学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 胎盤におけるTGF-β/Smads/UCHL5 axisでの血管新生制御の差違(Differential regulation of angiogenesis in TGF-β/Smads/UCHL5 axis in placenta)2023

    • Author(s)
      Hashimoto Kei, Miyagawa Yuko, Takasaki Kazuki, Nakagawa Ippei, Koike Ryoko, Takahashi Yuko, Nishida Haruka, Ichinose Takayuki, Kihira Chikara, Sasamori Yukifumi, Ryo Eiji, Nagasaka Kazunori
    • Organizer
      日本産科婦人科学会
    • Related Report
      2023 Annual Research Report
  • [Presentation] Comparison of the angiogenetic properties of ALDH1-positive and CD44-positive ovarian cancer stem-like cells using the three-dimensional co-culture system.2020

    • Author(s)
      Kazunori Nagasaka, Yuko Miyagawa, Kaoru Yamawaki, Shiho Fukui, Ryoko Koike, Yoshiko Kawata, Ranka Kanda, Takeru Sugihara, Haruko Hiraike, Koichiro Kido, Takuya Ayabe
    • Organizer
      第72回日本産科婦人科学会学術講演会
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-04-18   Modified: 2025-01-30  

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