Elucidation of the mechanism for cancer metastasis induced by oral cancer exosome and development of novel therapy for metastatic cancer

• Project/Area Number: 18H02996
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Hokkaido University
• Principal Investigator: Hida Kyoko 北海道大学, 歯学研究院, 教授 (40399952)
• Co-Investigator(Kenkyū-buntansha): 北村 哲也 北海道大学, 医学研究院, 客員研究員 (00451451) ; 菊地 奈湖 (間石奈湖) 北海道大学, 歯学研究院, 助教 (00632423) ; 樋田 泰浩 北海道大学, 大学病院, 准教授 (30399919) ; 大廣 洋一 北海道大学, 歯学研究院, 准教授 (40301915) ; 大賀 則孝 北海道大学, 歯学研究院, 助教 (40548202)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥8,450,000 (Direct Cost: ¥6,500,000、Indirect Cost: ¥1,950,000)
• Keywords: 悪性腫瘍 / 血管新生 / 転移 / エクソソーム / 腫瘍血管 / がん / 腫瘍血管内皮細胞 / miRNA / microRNA

Outline of Final Research Achievements

Cancer actively undergoes angiogenesis due to its progression and metastasis, and exosomes secreted by cancer cells are attracting attention because they change the traits of surrounding stromal cells. In this study, we will identify the exosome miRNA of cancer that causes phenotypic changes in the blood vessels of the primary lesion and distant organs and is involved in metastasis, clarify its molecular mechanism, and lead to the construction of a cancer metastasis inhibition strategy.
In an in vivo tumor model, we showed that cancer miRNA X is transported by exosomes and taken up by tumor vascular endothelial cells. We found that miRNA X attenuates the barrier function of the vascular endothelium and promotes metastasis, and clarified a new metastasis mechanism.

Academic Significance and Societal Importance of the Research Achievements

転移はがんの死因の約9割を占めるといわれ，その制御はがん治療戦略の最重要課題の1つである．今回の研究により，原発巣と転移先臓器両方の血管のバリア機構を抑制するがんのエクソソームのmiRNAが見出された．本miRNAは血中エクソソームにも検出されることから，がんの転移診断，予後予測診断にも重要である．さらにこのmiRNAを標的とすることで，がんの転移を原発巣からの癌細胞の離脱，遠隔臓器の血管からの転移組織への侵入といった複数のステップで転移を抑制することが可能となる．新しい治療法につながる重要な成果である．

Research Products

• [Journal Article] Biglycan, tumor endothelial cell secreting proteoglycan, as possible biomarker for lung cancer (2021)
  • Author(s): Morimoto Hirofumi、Hida Yasuhiro、Maishi Nako、Nishihara Hiroshi、Hatanaka Yutaka、Li Cong、Matsuno Yoshihiro、Nakamura Toru、Hirano Satoshi、Hida Kyoko
  • Journal Title: Thoracic Cancer Volume: - Issue: 9 Pages: 1-11
  • DOI: 10.1111/1759-7714.13907
  • Peer Reviewed / Open Access
• [Journal Article] Correlation between endothelial CXCR7 expression and clinicopathological factors in oral squamous cell carcinoma (2021)
  • Author(s): Yanagiya Misa、Dawood Randa I. H.、Maishi Nako、Hida Yasuhiro、Torii Chisaho、Annan Dorcas A.、Kikuchi Hiroshi、Yanagawa Matsuda Aya、Kitamura Tetsuya、Ohiro Yoichi、Shindoh Masanobu、Tanaka Shinya、Kitagawa Yoshimasa、Hida Kyoko
  • Journal Title: Pathology International Volume: - Issue: 6 Pages: 1-9
  • DOI: 10.1111/pin.13094
  • Peer Reviewed / Open Access
• [Journal Article] Chemotherapy-induced IL-8 upregulates MDR1/ABCB1 in tumor blood vessels and results in unfavorable outcome (2020)
  • Author(s): Kikuchi Hiroshi、Maishi Nako、Annan Dorcas A.、Towfik Alam Mohammad、Sato Masumi、Morimoto Masahiro、Takeda Ryo、Ishizuka Keita、Matsumoto Ryuji、Akino Tomoshige、Matsuno Yoshihiro、Hida Yasuhiro、Shinohara Nobu、Hida Kyoko
  • Journal Title: Cancer Research Volume: 80 Issue: 14 Pages: 2996-3008
  • DOI: 10.1158/0008-5472.can-19-3791
  • Peer Reviewed
• [Journal Article] TNF-α enhances TGF-β-induced endothelial-to-mesenchymal transition via TGF-β signal augmentation (2020)
  • Author(s): Yasuhiro Yoshimatsu, Ikumi Wakabayashi, Shiori Kimuro, Naoya Takahashi, Kazuki Takahashi, Miho Kobayashi, Nako Maishi, Katarzyna A. Podyma-Inoue, Kyoko Hida, Kohei Miyazono, Tetsuro Watabe
  • Journal Title: Cancer Sciense Volume: - Issue: 7 Pages: 2385-2399
  • DOI: 10.1111/cas.14455
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tumor Endothelial Cell-A Biological Tool for Translational Cancer Research (2020)
  • Author(s): Annan Dorcas Akuba-Muhyia、Kikuchi Hiroshi、Maishi Nako、Hida Yasuhiro、Hida Kyoko
  • Journal Title: International Journal of Molecular Sciences Volume: 21 Issue: 9 Pages: 3238-3238
  • DOI: 10.3390/ijms21093238
  • Peer Reviewed / Open Access
• [Journal Article] 腫瘍血管内皮細胞における異常性解明とその制御 (2020)
  • Author(s): 間石奈湖, 樋田京子
  • Journal Title: 高倉伸幸編「細胞」－特集 がんの進展における血管新生と免疫－，ニューサイエンス社 Volume: 53(2) Pages: 49-52
  • NAID: 40022508078
• [Journal Article] 血管内皮増殖因子 (2020)
  • Author(s): 樋田京子, 間石奈湖
  • Journal Title: 産科と婦人科 特集 分子標的薬を極める―基礎から臨床まで―」, 診断と治療社1145 Volume: 87(10) Pages: 1145-1149
• [Journal Article] がん治療標的としての腫瘍血管内皮細胞の特異性 (2020)
  • Author(s): 間石奈湖, Annan DA, 樋田京子
  • Journal Title: 『炎症と免疫』, 先端医学社35 Volume: 28(5) Pages: 35-40
• [Journal Article] Role of dimerized C16orf74 in aggressive pancreatic cancer: A novel therapeutic target. (2020)
  • Author(s): Kushibiki T, Nakamura T, Tsuda M, Tsuchikawa T, Hontani K, Inoko K, Takahashi M, Asano T, Okamura K, Murakami S, Kurashima Y, Ebihara Y, Noji T, Nakanishi Y, Tanaka K, Maishi N, Sasaki K, Park W-R, Shichinohe T, Hida K, Tanaka S, Hirano S.
  • Journal Title: Mol Cancer Ther Volume: 19 Issue: 1 Pages: 187-198
  • DOI: 10.1158/1535-7163.mct-19-0491
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Tumor Blood Vessels as Targets for Cancer Therapy. (2019)
  • Author(s): Hida K, Maishi N, Hida Y.
  • Journal Title: Springer Volume: - Pages: 41-56
• [Journal Article] 腫瘍血管内皮細胞の異常性と腫瘍免疫 (2019)
  • Author(s): 樋田京子, 間石奈湖
  • Journal Title: 実験医学 Volume: 37 Pages: 3201-3205
• [Journal Article] 血管新生阻害療法の展望 (2019)
  • Author(s): 樋田京子
  • Journal Title: 北海道歯学雑誌 Volume: 39 Pages: 151-155
  • NAID: 120006606622
• [Journal Article] Tumor endothelial heterogeneity in cancer progression (2019)
  • Author(s): Nako Maishi, Dorcas A. Annan, Hiroshi Kikuchi, Yasuhiro Hida and Kyoko Hida
  • Journal Title: Cancers Volume: 11 Issue: 10 Pages: 1511-1511
  • DOI: 10.3390/cancers11101511
  • Peer Reviewed / Open Access
• [Journal Article] Carbonic anhydrase 2 (CAII) supports tumor blood endothelial cell survival under lactic acidosis in the tumor microenvironment (2019)
  • Author(s): Dorcas Akuba Muhyia Annan, Nako Maishi, Tomoyoshi Soga, Randa Dawood, Cong Li, Hiroshi Kikuchi, Takayuki Hojo, Masahiro Morimoto, Tetsuya Kitamura, Mohammad Towfik Alam, Kazuyuki Minowa, Nobuo Shinohara, Jin-Min Nam, Yasuhiro Hida, Kyoko Hida
  • Journal Title: Cell Communication and Signaling Volume: 17 Issue: 1 Pages: 169-169
  • DOI: 10.1186/s12964-019-0478-4
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Development of immortalized human tumor endothelial cells from renal cancer (2019)
  • Author(s): Nako Maishi, Hiroshi Kikuchi, Masumi Sato, Hiroko Nagao-Kitamoto, Dorcas A. Annan, Shogo Baba, Takayuki Hojo, Misa Yanagiya, Yusuke Ohba, Genichiro Ishii, Kenkichi Masutomi, Nobuo Shinohara, Yasuhiro Hida, Kyoko Hida
  • Journal Title: Int J Mol Sci Volume: 20 Issue: 18 Pages: 4595-4595
  • DOI: 10.3390/ijms20184595
  • Peer Reviewed / Open Access
• [Journal Article] Two modes of toxicity of lipid nanoparticles containing a pH-sensitive cationic lipid on human A375 and A375-SM melanoma cell lines (2019)
  • Author(s): AlBaloul A, Sato Y, Maishi N, Hida K, Harashima H
  • Journal Title: BPB Reports Volume: 2 Pages: 48-55
  • NAID: 130007940514
  • Peer Reviewed
• [Journal Article] Synergistic enhancement of cellular uptake with CD44-expressing malignant pleural mesothelioma by combining cationic liposome and hyaluronic acid-lipid conjugate (2019)
  • Author(s): Sakurai Y., Kato A., Hida Y., Hamada J., Maishi N., Hida K., Harashima H
  • Journal Title: J Pharm Sci Volume: 108 Issue: 10 Pages: 3218-3224
  • DOI: 10.1016/j.xphs.2019.06.012
  • NAID: 120006941697
  • Peer Reviewed
• [Journal Article] Fibroblast growth factor signals regulate transforming growth factor-β-induced endothelial-to-myofibroblast transition of tumor endothelial cells via Elk1 (2019)
  • Author(s): Akatsu Y*, Takahashi N*, Yoshimatsu Y*, Kimuro S, Muramatsu T, Katsura A, Maishi N, Suzuki HI, Inazawa J, Hida K, Miyazono K, Watabe T. (＊equal contribution)
  • Journal Title: Molecular Oncology Volume: 13 Issue: 8 Pages: 1706-1724
  • DOI: 10.1002/1878-0261.12504
  • Peer Reviewed / Open Access
• [Journal Article] Abnormalities of tumor endothelial cells and cancer progression (2018)
  • Author(s): Hida K., Maishi N.:
  • Journal Title: Oral Sci Int Volume: 15(1) Issue: 1 Pages: 1-6
  • DOI: 10.1016/s1348-8643(17)30041-1
  • NAID: 10031168583
  • Peer Reviewed / Open Access
• [Journal Article] Contribution of Tumor Endothelial Cells in Cancer Progression (2018)
  • Author(s): Hida K., Maishi N., Dorcas A. Annan, Hida Y.
  • Journal Title: Int J Mol Sci Volume: 19 Issue: 5 Pages: 1272-1272
  • DOI: 10.3390/ijms19051272
  • Peer Reviewed / Open Access
• [Presentation] 腫瘍血管内皮細胞とがんの悪性化 (2021)
  • Author(s): 樋田京子
  • Organizer: 第94回日本薬理学会年会シンポジウム
  • Invited
• [Presentation] 腫瘍血管と免疫小環境 (2020)
  • Author(s): 樋田京子
  • Organizer: Breast Cancer Investigator’s Meeting in Sapporo
  • Invited
• [Presentation] 治療標的としての腫瘍血管内皮細胞の異常性 (2020)
  • Author(s): 樋田京子
  • Organizer: 第79回日本癌学会学術総会
  • Invited
• [Presentation] The role of tumor endothelial cells in the immune environment (2020)
  • Author(s): 樋田京子
  • Organizer: 第79回日本癌学会学術総会
  • Invited
• [Presentation] New Insights Into Drug-Resistance: Abnormality in Tumor Endothelial Cells (2020)
  • Author(s): Kyoko Hida
  • Organizer: The 21th International Vascular Biology Meeting
  • Int'l Joint Research / Invited
• [Presentation] 腫瘍血管内皮細胞の特性解析とがん治療への応用 (2020)
  • Author(s): 樋田京子
  • Organizer: 第109回日本病理学会総会
  • Invited
• [Presentation] 腫瘍血管の多様性 (2019)
  • Author(s): 樋田京子
  • Organizer: 日本薬物動態学会第34回年会シンポジウム4「血管を標的としたDDSの潮流」
  • Invited
• [Presentation] がん微小環境に対する創薬の幕開け (2019)
  • Author(s): 樋田京子
  • Organizer: 第57回日本癌治療学会スポンサードシンポジウム４「がんの増悪・浸潤・転移に関わる腫瘍微小環境の重要性」,“がん微小環境に対する創薬の幕開け”,2019.10.25（福岡）
  • Invited
• [Presentation] 治療標的としての腫瘍血管の特性 (2019)
  • Author(s): 樋田京子
  • Organizer: 第60回日本脈管学会総会学術委員会シンポジウム２「がん治療～脈管を攻める、脈管を守る」
  • Invited
• [Presentation] 血管新生とがんの悪性化 (2019)
  • Author(s): 樋田京子
  • Organizer: 第30回日本臨床口腔病理学会合同シンポジウム「口腔に症状が現れる全身疾患へのアプローチ」
  • Invited
• [Presentation] Roles of tumor endothelial cells in tumor progression (2019)
  • Author(s): Hida K
  • Organizer: the 2019 AVBS SCIENTIFIC MEETING-JOINT VASCULAR BIOLOGY MEETING
  • Int'l Joint Research / Invited
• [Presentation] 腫瘍組織の多様性と相互作用 (2019)
  • Author(s): 樋田京子
  • Organizer: 文部科学省新学術領域研究 細胞社会ダイバースシテ－の統合的解明と制御_第92回日本生化学会共催シンポジウム「臓器の構築と制御の統合的理解を目指した細胞ダイバーシティー研究」
  • Invited
• [Presentation] 腫瘍血管研究と今後の展望～Bench to Bedの実現にむけて～ (2019)
  • Author(s): 樋田京子
  • Organizer: 令和元年北海道大学歯学部口腔外科同門会学術大会
  • Invited
• [Presentation] Abnormalities of tumor endothelial cells and cancer progression (2019)
  • Author(s): Hida K
  • Organizer: The 38th Sapporo International Cancer Symposium
  • Invited
• [Presentation] 腫瘍血管の多様性とその制御 (2019)
  • Author(s): 樋田京子
  • Organizer: 文部科学省科学研究費補助金 新学術領域研究「細胞社会ダイバーシティの統合的解明と制御」第四回公開シンポジウム
  • Invited
• [Presentation] 腫瘍免疫における血管の役割 (2019)
  • Author(s): 樋田京子
  • Organizer: 第119回北海道癌談話会春季シンポジウム「がん免疫療法：基礎と臨床のコラボレーション」
• [Presentation] 継続は力なり～双子連れ留学、研究室開設の経験から (2019)
  • Author(s): 樋田京子
  • Organizer: 第57回日本小児歯科学会大会 将来計画検討委員会・女性歯科医委員会合同企画シンポジウム
• [Presentation] VEGF阻害による腫瘍微小環境の制御 (2019)
  • Author(s): 樋田京子
  • Organizer: Lung Cancer Expert Meeting in Sapporo
• [Presentation] 腫瘍血管内皮の遺伝子異常 (2019)
  • Author(s): 樋田京子
  • Organizer: 第108回日本病理学会総会 特別シンポジウム1「がんゲノム医療と病理」
• [Presentation] 腫瘍血管新生の多様性と腎癌の悪性化 (2019)
  • Author(s): 樋田京子
  • Organizer: 腎癌の血管と免疫を見つめる会
• [Presentation] 血管新生阻害と微小環境の変化 (2018)
  • Author(s): 樋田京子
  • Organizer: AIR in Sapporo－Angiogenesis & Immunology Research
  • Invited
• [Presentation] 腫瘍血管内皮細胞によるがんの転移促進 (2018)
  • Author(s): 樋田京子
  • Organizer: 第77回日本癌学会学術総会シンポジウム
  • Invited
• [Presentation] 血管新生阻害療法の展開 (2018)
  • Author(s): 樋田京子
  • Organizer: 第16回日本臨床腫瘍学会学術集会シンポジウム
  • Invited
• [Presentation] 治療抵抗性における腫瘍血管の役割 (2018)
  • Author(s): 樋田京子
  • Organizer: 第107回日本病理学会総会
  • Invited
• [Presentation] MDR1/ABCB1 upregulation in tumor blood vessels by chemotherapy-induced IL-8 (2018)
  • Author(s): Hida K., Kikuchi H., Maishi N., Abe T., Maruyama S., Harabayashi T., Ameda K., Matsuno Y., Hida Y., Shinohara N.
  • Organizer: 20th International Vascular Biology Meeting
  • Int'l Joint Research
• [Presentation] Promotion of metastasis via alteration of vascular endothelium by tumor exosome miRNA (2018)
  • Author(s): Morimoto M., Maishi N., Matsuda A. Kitamura T., Higashino F., Kitagawa Y., Hida Y., Hida K
  • Organizer: Annual Meeting ISEV2019, 2019.4.26, Kyoto
  • Int'l Joint Research
• [Remarks] 北海道大学大学院歯学研究院 口腔病態学分野 血管生物分子病理学教室 ホームページ
  • URL: https://www.den.hokudai.ac.jp/vascular-biol-pathol/
• [Remarks] 北海道大学大学院歯学研究院 血管生物分子病理学教室
  • URL: https://www.den.hokudai.ac.jp/vascular-biol-pathol/