Investigation of activation mechanisms and exploration of inhibition therapy of HGF-MET signal in cancer microenvironment

• Project/Area Number: 20K16175
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: University of Miyazaki
• Principal Investigator: Kiwaki Takumi 宮崎大学, 医学部, 助教 (40866068)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: MET / HGF / がん周囲微小環境 / 分子標的薬 / 合成HGF活性化阻害剤 / 患者腫瘍由来オルガノイド / 患者腫瘍由来移植マウス / がん三次元培養 / HAI-1 / プロテアーゼイメージング / がん / 分子標的治療

Outline of Research at the Start

チロシンキナーゼ型受容体とそのリガンドから構成される HGF-MET シグナルは，がんの進展に重要な役割を果たしている．しかしながら，HGF-MET シグナルを標的とした分子標的治療は未だ発展途上にある．本研究では，がん周囲微小環境における HGF 依存性 MET 活性化に焦点を当て，独自の動物モデルを用いて HGF-MET シグナル阻害療法の開発を目指す．さらに，生体内イメージングにより HGF-MET シグナルに関連するプロテアーゼ群の腫瘍組織におけるダイナミズムを解明する．

Outline of Final Research Achievements

We analyzed the significance and inhibitory therapy of the HGF-dependent MET activation signaling, which consists of the stromal-derived hepatocyte growth factor (HGF) and its receptor MET on cancer cells. We showed that HGF-dependent MET signaling is regulated by hepatocyte growth factor inhibitor-1 (HAI-1), and that decreased expression of HAI-1 enhanced MET-mediated cell proliferation. Synthetic HGF activation inhibitors with functions similar to HAI-1 increased necrotic areas in tumors with reduced HAI-1 expression. The results suggest the usefulness of synthetic HGF activation inhibitors.

Academic Significance and Societal Importance of the Research Achievements

HGF 依存性 MET 活性化の制御は，転移性腫瘍や抗がん剤耐性を獲得した腫瘍に対して，新たな治療選択肢を提供しうる．本研究では，HGF-MET シグナルが亢進している一部の腫瘍において，合成 HGF 活性化阻害剤が治療効果を発揮することが実験動物レベルで示唆された．今後の研究の進展により，合成 HGF 活性化阻害剤の臨床応用が期待できる．

Research Products

• [Int'l Joint Research] Washington University(米国)
• [Int'l Joint Research] Washington University(米国)
• [Int'l Joint Research] Washington University(米国)
• [Journal Article] Possible role of combined therapy targeting MET and pro-HGF activation for renal cell carcinoma: analysis by human HGF-producing SCID mice. (2023)
  • Author(s): Fujii M, Akioka T, Kimura S, Nagai T, Kiwaki T, Fukushima T, Mukai S, Kamoto T
  • Journal Title: Human cell Volume: 36 Issue: 2 Pages: 775-785
  • DOI: 10.1007/s13577-023-00857-y
  • Peer Reviewed
• [Journal Article] Adrenomedullin alleviates mucosal injury in experimental colitis and increases claudin‐4 expression in the colonic epithelium (2023)
  • Author(s): Kawaguchi Makiko、Kataoka Hiroaki、Kiwaki Takumi、Weiting Liang、Nagata Sayaka、Kitamura Kazuo、Fukushima Tsuyoshi
  • Journal Title: FEBS Open Bio Volume: 13 Issue: 4 Pages: 713-723
  • DOI: 10.1002/2211-5463.13577
  • Peer Reviewed / Open Access
• [Journal Article] Role of the polycystic kidney disease domain in matriptase chaperone activity and localization of hepatocyte growth factor activator inhibitor‐1 (2022)
  • Author(s): Yamashita Fumiki、Kaieda Takashi、Shimomura Takeshi、Kawaguchi Makiko、Lin Chen‐Yong、Johnson Michael D.、Tanaka Hiroyuki、Kiwaki Takumi、Fukushima Tsuyoshi、Kataoka Hiroaki
  • Journal Title: The FEBS Journal Volume: - Issue: 12 Pages: 3422-3439
  • DOI: 10.1111/febs.16348
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Insufficiency of hepatocyte growth factor activator inhibitor-1 confers lymphatic invasion of tongue carcinoma cells (2022)
  • Author(s): Aya Izumi, Koji Yamamoto, Makiko Kawaguchi, Fumiki Yamashita, Tsuyoshi Fukushima, Takumi Kiwaki, Hiroyuki Tanaka, Yoshihiro Yamashita, Hiroaki Kataoka
  • Journal Title: Cancer Science Volume: 00 Issue: 6 Pages: 1-15
  • DOI: 10.1111/cas.15346
  • Peer Reviewed / Open Access
• [Journal Article] Patient-Derived Organoids of Colorectal Cancer: A Useful Tool for Personalized Medicine (2022)
  • Author(s): Kiwaki Takumi、Kataoka Hiroaki
  • Journal Title: Journal of Personalized Medicine Volume: 12 Issue: 5 Pages: 695-695
  • DOI: 10.3390/jpm12050695
  • Peer Reviewed / Open Access
• [Journal Article] Decreased prostasin expression is associated with aggressiveness of oral squamous cell carcinoma (2021)
  • Author(s): Koji Yamamoto, Fumiki Yamashita, Makiko Kawaguchi, Aya Izumi, Takumi Kiwaki, Hiroaki Kataoka, Takeshi Kaneuji, Yoshihiro Yamashita & Tsuyoshi Fukushima
  • Journal Title: Human Cell Volume: 34 Issue: 5 Pages: 1434-1445
  • DOI: 10.1007/s13577-021-00575-3
  • Peer Reviewed
• [Presentation] 患者由来がんオルガノイドを用いた新規抗がん療法の開発 (2021)
  • Author(s): 木脇 拓道
  • Organizer: 第３９回日本ヒト細胞学会学術集会
  • Invited
• [Presentation] ヒト HGF 導入 SCID マウスを用いた HGF-MET シグナル解析と阻害治療の開発 (2020)
  • Author(s): 木脇 拓道
  • Organizer: 第３８回日本ヒト細胞学会学術集会
  • Invited
• [Remarks] 宮崎大学医学部病理学講座腫瘍・再生病態学分野
  • URL: http://www.med.miyazaki-u.ac.jp/patho2/
• [Remarks] ResearchGate
  • URL: https://www.researchgate.net/profile/Kiwaki-Takumi