Basic research for elucidation of the mechanisms of tumor metastasis by tumor endothelial cells

• Project/Area Number: 18K09715
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Hokkaido University
• Principal Investigator: Kikuchi (Maishi) Nako 北海道大学, 歯学研究院, 助教 (00632423)
• Co-Investigator(Kenkyū-buntansha): 樋田 京子 北海道大学, 歯学研究院, 教授 (40399952) ; 大賀 則孝 北海道大学, 歯学研究院, 助教 (40548202) ; 樋田 泰浩 北海道大学, 大学病院, 准教授 (30399919)
• 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: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 腫瘍血管新生 / 腫瘍血管内皮細胞 / 転移

Outline of Final Research Achievements

We previously reported that endothelial cells of tumor blood vessels contribute to tumor metastasis. Since it is known that tumor cells aggregate in blood, which are involved in tumor malignancy, we investigated the possibility that endothelial cells also contribute to form tumor aggregation in this study. Tumor cells and endothelial cells formed cell aggregations when they were co-cultured in non-adherent condition. We found that the characteristics of endothelial cells were involved in tumor cell survival and proliferation in the cell aggregations. After forming cell aggregations, we isolated tumor cells and endothelial cells respectively by flow cytometory and analyzed gene expression patterns and activated pathways by IPA.

Academic Significance and Societal Importance of the Research Achievements

がん患者の死亡原因の9割は転移であるが，がん転移を制御する有効な治療法はいまだない．本研究では，血管内皮を含むがんの細胞塊が転移形成に関与するという新たな視点で検討しており，がんの転移の機序解明やその阻害を目的としている．本研究によりがん細胞が血管内皮細胞と細胞塊を形成しうること，血管内皮細胞の性質ががんの生存能などに関与しうることを明らかにした．細胞塊形成や転移促進に関与する分子を網羅的解析により絞り込んでいるところであり，それが明らかになれば，がんの転移予測としてのバイオマーカーやその制御による治療薬開発へとつなげられることが期待される．

Research Products

• [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] 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] 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 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 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 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): Ahmed Y AlBaloul, Yusuke Sato, Nako Maishi, Kyoko Hida, Hideyoshi Harashima
  • 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] 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
• [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
• [Presentation] Crosstalk of tumor cells and tumor endothelial cells by forming cell clusters promotes tumor metastasis (2021)
  • Author(s): 間石 奈湖，梅山 悠伊，菊地 央，古御堂 純，佐藤 峰嘉，武田 遼，Dorcas A. Annan, 篠原 信雄，樋田 泰浩，樋田 京子
  • Organizer: 第28回日本血管生物医学会学術集会
• [Presentation] 抗癌剤治療がもたらす腫瘍血管トランスポーター発現亢進とその機序 (2020)
  • Author(s): 間石奈湖, 菊地 央, 樋田泰浩, 篠原信雄，樋田京子
  • Organizer: 第6回北海道大学部局横断シンポジウム
  • Invited
• [Presentation] Novel Antiangiogenic Therapy Targeting Biglycan in Tumor Endothelial Cell Using Liposomal-siRNA Delivery System (2020)
  • Author(s): Maishi N, Sakurai Y, Hatakeyama H, Li C, Alam MT, Kikuchi H, Morimoto H, Morimoto M, Akiyama K, Ohga N, Hida Y, Harashima H, Hida K
  • Organizer: The 21st International Vascular Biology Meeting (IVBM 2020)
  • Int'l Joint Research
• [Presentation] 腫瘍血管によるがん悪性化促進機構の解明とその制御 (2020)
  • Author(s): 間石奈湖, 樋田京子
  • Organizer: 第６回血管生物医学会若手研究会
• [Presentation] 抗癌剤治療がもたらす腫瘍血管ABCB1発現亢進とそのメカニズム解明 (2020)
  • Author(s): 間石奈湖, 樋田京子
  • Organizer: 第31回日本臨床口腔病理学会学術大会
• [Presentation] リポソーム siRNA デリバリーシステムを用いた腫瘍血管 biglycan を標的とした新規血管新生阻害療法 (2020)
  • Author(s): 間石奈湖, 櫻井 遊, 畠山浩人, Li C, Alam MT, 菊地 央, 森本浩史, 森本真弘, 樋田泰浩, 原島秀吉, 樋田京子
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 抗癌剤治療がもたらす腫瘍血管ABCB1発現亢進とそのメカニズム解明 (2020)
  • Author(s): 間石奈湖，樋田京子
  • Organizer: 第31回日本臨床口腔病理学会総会・学術大会
• [Presentation] 抗癌剤治療がもたらす腫瘍血管ABCB1発現亢進とその機序 (2020)
  • Author(s): 間石奈湖，赤堀永倫香，樋田京子
  • Organizer: 第74回日本口腔科学会学術集会
• [Presentation] がんの転移における腫瘍血管内皮細胞の役割解明 (2020)
  • Author(s): 間石奈湖, 樋田京子
  • Organizer: 第１回日本癌学会若手の会
• [Presentation] 抗癌剤治療がもたらす腫瘍血管ABCB1発現亢進とその機序 (2020)
  • Author(s): 間石奈湖, 菊地 央, 樋田京子
  • Organizer: 細胞社会ダイバーシティーの統合的解明と制御 第5回公開シンポジウム
• [Presentation] 腫瘍血管内皮細胞によるBiglycanの分泌を介したがんの転移促進 (2019)
  • Author(s): 間石奈湖, 樋田京子
  • Organizer: 第61回歯科基礎医学会学術大会
  • Invited
• [Presentation] Contribution of Tumor Endothelial Cells to Tumor Metastasis (2019)
  • Author(s): Maishi N. Hida K.
  • Organizer: International Symposium between National Yang-Ming University and Hokkaido University
  • Int'l Joint Research / Invited
• [Presentation] 腫瘍血管内皮細胞によるBiglycanの分泌を介したがんの転移促進 (2019)
  • Author(s): 間石奈湖, 樋田京子
  • Organizer: 第28回日本がん転移学会学術集会・総会
  • Invited
• [Presentation] Increased ABCB1 expression in tumor blood vessels of urothelial carcinoma after chemotherapy (2019)
  • Author(s): Maishi N., Kikuchi H., Abe T., Matsuno Y., Hida Y., Shinohara N., Hida K.
  • Organizer: The 38th Sapporo International Cancer Symposium
  • Int'l Joint Research
• [Presentation] Carbonic anhydrase 2 (CAⅡ) is essential for tumor endothelial cell proliferation (2019)
  • Author(s): Maishi N., Dorcas A. Annan, Soga T., Dawood Randa, Li Cong, Kikuchi H., Hojo T., Morimoto M., Kitamura T., Mohammad Towfik Alam, Shinohara N., Hida Y., Hida K.
  • Organizer: 第79回日本癌学会学術総会
• [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., Yokoyama A., Kitagawa Y., Hida K.,
  • Organizer: The 66th Annual Meeting of Japanese Association for Dental Research
  • Int'l Joint Research
• [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] Biglycan, tumor endothelial cell secreting proteoglycan, as possible biomarker for lung cancer (2018)
  • Author(s): Hida Y., Morimoto H., Maishi N., Nishihara H., Hatanaka Y., Matsuno Y., Nakamura T., Hirano S., Hida K.
  • Organizer: 20th International Vascular Biology Meeting
  • Int'l Joint Research
• [Presentation] Tumor endothelial cells survive under lactic acidosis (2018)
  • Author(s): D.A.Annan, Maishi N., Soga T. R.Dawood, Hida Y., Hida K.
  • Organizer: AACR ANNUAL MEETING 2018
  • Int'l Joint Research
• [Presentation] Biglycan, tumor endothelial secreting proteoglycan, as possible biomarker for lung cancer (2018)
  • Author(s): Morimoto H., Maishi N., Hida Y., Nishihara H., Hatanaka Y., Matsuo Y., Nakamura Y., Hirano S., Hida K.
  • Organizer: AACR ANNUAL MEETING 2018
  • Int'l Joint Research
• [Presentation] 高転移性腫瘍エクソソーム による血管内皮の形質変化によってがんの転移が促進される (2018)
  • Author(s): 森本真弘，間石奈湖，樋田泰浩，北川善政，樋田京子
  • Organizer: 第26回日本血管生物医学会学術集会
• [Presentation] The involvement of stromal biglycan in tumor angiogenesis and metastasis (2018)
  • Author(s): Li Cong, 間石奈湖，Young Marian F, 森本浩史, 森本真弘，Annan Dorcas A., 樋田泰浩，樋田京子
  • Organizer: 第51回北海道病理談話会
• [Presentation] Carbonic anhydrase 2 (CAⅡ) is essential for tumor endothelial cell proliferation (2018)
  • Author(s): Annan Dorcas A., 間石奈湖，曽我朋義，篠原信雄，Dawood Randa, Li Cong, 菊地 央，北條敬之，森本真弘，樋田泰浩，樋田京子
  • Organizer: 第51回北海道病理談話会
• [Presentation] 高転移性腫瘍由来エクソソーム miRNA による血管内皮の形質変化と転移促進メカニズムの解明 (2018)
  • Author(s): 森本真弘，間石奈湖，樋田泰浩，北川善政, 樋田京子
  • Organizer: 第51回北海道病理談話会
• [Presentation] 高転移性腫瘍由来エクソソーム miRNA による血管内皮の形質変化による転移促進メカニズムの解明 (2018)
  • Author(s): 森本真弘，間石奈湖，樋田泰浩，樋田京子
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 尿路上皮癌における抗癌剤治療後の腫瘍血管ABCB1発現亢進 (2018)
  • Author(s): 菊地 央，間石奈湖，土屋邦彦，安部崇重，樋田泰浩，原林 透，松野吉弘，篠原信雄，樋田京子
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] 高転移性腫瘍由来エクソソーム miRNA による血管内皮の形質変化と転移促進メカニズムの解明 (2018)
  • Author(s): 森本真弘，間石奈湖，樋田京子
  • Organizer: 第60回歯科基礎医学会学術大会
• [Presentation] 高転移性腫瘍由来エクソソームmiRNAによる血管内皮の形質変化と転移促進メカニズムの解明 (2018)
  • Author(s): 森本真弘, 間石奈湖, 北川善政, 樋田京子
  • Organizer: 第27回日本がん転移学会学術集会・総会
• [Presentation] Glutamine Metabolism in Tumor Endothelial Cells (2018)
  • Author(s): Dorcas A. Annan, Maishi N., Soga T., Randa Dawood, Hida Y. and Hida K.
  • Organizer: 第107回日本病理学会総会
• [Presentation] MDR1/ABCB1 upregulation in tumor blood vessels by chemotherapy-induced IL-8 (2018)
  • Author(s): Maishi N., Kikuchi H., Abe T., Maruyama S., Harabayashi T., Ameda K., Matsuno Y., Hida Y., Shinohara N., Hida K.
  • Organizer: 第107回日本病理学会総会
• [Presentation] 高転移性腫瘍由来エクソソームmiRNAによる血管内皮の形質変化と転移促進 (2018)
  • Author(s): 森本真弘, 間石奈湖, 菊地 央, 北川善政, 樋田京子
  • Organizer: 第107回日本病理学会総会
• [Presentation] 肺癌症例における腫瘍血管内皮マーカーbiglycanの発現解析 (2018)
  • Author(s): 森本浩史, 間石奈湖, 樋田泰浩, 西原広史, 畑中 豊, 松野吉宏, 中村 透, 平野 聡, 樋田京子
  • Organizer: 第107回日本病理学会総会
• [Presentation] 高転移性腫瘍由来エクソソームmiRNAによる血管内皮の形質変化と転移促進メカニズムの解明 (2018)
  • Author(s): 森本真弘, 間石奈湖, 北川善政, 樋田京子
  • Organizer: 第72回日本口腔科学会学術集会
• [Book] Cancer Drug Delivery Systems Based on the Tumor Microenvironment: Tumor Blood Vessels as Targets for Cancer Therapy (2019)
  • Author(s): Hida K., Maishi N., Hida Y.
  • Total Pages: 16
  • Publisher: Springer
• [Book] がん免疫の効果を左右する腫瘍血管と免疫環境，“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
  • Total Pages: 5
  • Publisher: 羊土社
• [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/