Development of cancer metastasis suppression therapy focusing on the renin-angiotensin system

• Project/Area Number: 18K06907
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48030:Pharmacology-related
• Research Institution: University of Occupational and Environmental Health, Japan
• Principal Investigator: Ishikane Shin 産業医科大学, 医学部, 講師 (40470190)
• 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: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: アンギオテンシンII / 癌転移 / 悪性黒色腫 / 乳がん / 転移抑制薬 / アンギオテンII / アンジオテンシンII / 血管内皮細胞 / 血行性癌転移 / 高血圧 / レニン・アンジオテンシン系

Outline of Final Research Achievements

In this study, we sought to elucidate the mechanisms by which angiotensin II (Ang II) exacerbates hematogenous metastasis in mouse tumor cells. Ang II exacerbates hematogenous metastasis of melanoma cells by promoting adhesion molecules-mediated adhesion of cancer cells to vascular endothelial cells. Ang II affected the fibroblasts around cancer cells to accelerate the tumor growth and facilitate metastasis formation and suggests the possibility that Ang II modifies tumor microenvironment.

Academic Significance and Societal Importance of the Research Achievements

本邦の高血圧患者は、厚生労働省による平成26年度調査報告では約1100万人とされ、今後も患者数の増加が予測される。癌患者における最も多い併発症は高血圧症であることからも、本研究による癌転移抑制療法の適応範囲は広く、高額負担なく、安全な治療法を行うことができることは医療費削減の観点からも非常に有益である。

Research Products

• [Journal Article] Differentiation-inducing factor-1 potentiates adipogenic differentiation and attenuates the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (2021)
  • Author(s): Ishikane Shin、Ikushima Eigo、Igawa Kazunobu、Tomooka Katsuhiko、Takahashi-Yanaga Fumi
  • Journal Title: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research Volume: 1868 Issue: 2 Pages: 118909-118909
  • DOI: 10.1016/j.bbamcr.2020.118909
  • Peer Reviewed
• [Journal Article] Development of a novel and rapid measurement system for growth differentiation factor-15, progranulin, and osteopontin in uterine sarcoma (2020)
  • Author(s): Maeno Mitsuo、Mizutani Tetsuya、Tsuyoshi Hideaki、Yamada Shizuka、Ishikane Shin、Kawabe Shinya、Nishimura Kengo、Yamada Masami、Miyamoto Kaoru、Yoshida Yoshio
  • Journal Title: Endocrine Journal Volume: 67 Issue: 1 Pages: 91-94
  • DOI: 10.1507/endocrj.EJ18-0572
  • NAID: 130007790959
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Open Access
• [Journal Article] 2,5-Dimethylcelecoxib prevents isoprenaline-induced cardiomyocyte hypertrophy and cardiac fibroblast activation by inhibiting Akt-mediated GSK-3 phosphorylation. (2019)
  • Author(s): Morishige S, Takahashi-Yanaga F, Ishikane S, Arioka M, Igawa K, Kuroo A, Tomooka K, Shiose A, Sasaguri T.
  • Journal Title: Biochemical Pharmacology Volume: 168 Pages: 82-90
  • DOI: 10.1016/j.bcp.2019.06.018
  • Peer Reviewed
• [Journal Article] Angiotensin II promotes pulmonary metastasis of melanoma through the activation of adhesion molecules in vascular endothelial cells (2018)
  • Author(s): Ishikane S, Hosoda H, Nojiri T, Tokudome T, Mizutani T, Miura K, Akitake Y, Kimura T, Imamichi Y, Kawabe S, Toyohira Y, Yanagihara N, Takahashi-Yanaga F, Miyazato M, Miyamoto K, Kangawa K
  • Journal Title: Biochemical Pharmacology Volume: 154 Pages: 136-147
  • DOI: 10.1016/j.bcp.2018.04.012
  • Peer Reviewed
• [Presentation] Angiotensin II promotes tumor growth and metastatic lesion formation of murine TNBC 4T1 cells through the fibroblasts around cancer cells (2021)
  • Author(s): 瀧口 知浩, 高橋 富美, 石兼 真, 笹栗 俊之
  • Organizer: 第94回日本薬理学会年会
• [Presentation] 2,5-Dimethylcelecoxib attenuates cardiac remodeling after cryoinjury-induced myocardial infarction by suppressing the fibroblast-myofibroblast transformation (2021)
  • Author(s): 幾島栄悟, 石兼 真, 岸上 赳大, 松永 洋明, 瀧口 知浩, 豊平 由美子, 高橋 富美
  • Organizer: 第94回日本薬理学会年会
• [Presentation] Differentiation-inducing factor-1 accelerates adipogenic differentiation and suppresses the osteogenic differentiation of bone marrow-derived mesenchymal stem cells (2021)
  • Author(s): 石兼 真, 幾島 栄悟, 瀧口 知浩, 松永 洋明, 岸上 赳大, 豊平 由美子, 高橋 富美
  • Organizer: 第94回日本薬理学会年会
• [Presentation] 心筋梗塞後心臓リモデリングにおける筋線維芽細胞形質転換に対する ジメチルセレコキシブの作用の検討 (2021)
  • Author(s): 幾島栄悟，石兼真，岸上赳大，松永洋明，瀧口知浩，豊平由美子，高橋 富美
  • Organizer: 第73回日本薬理学会西南部会
• [Presentation] Differentiation-inducing factor-1による骨髄由来間葉系幹細胞の脂 肪細胞分化促進・骨芽細胞分化抑制作用 (2021)
  • Author(s): 石兼真，幾島栄悟，瀧口知浩，松永洋明，岸上赳大，豊平由美子，高橋 富美
  • Organizer: 第73回日本薬理学会西南部会
• [Presentation] Differentiation-including factor-1は骨髄由来間葉系幹細胞の脂肪細胞分化を促進し、骨芽細胞文化を抑制する (2021)
  • Author(s): 石兼真, 幾島栄悟, 瀧口知浩, 豊平由美子, 高橋富美
  • Organizer: 第38回産業医科大学学会
• [Presentation] アンギオテンシンⅡは癌周囲環境を変化させることによりトリプルネガティブ乳癌4T1細胞の増殖と転移を促進する (2019)
  • Author(s): 瀧口 知浩, 高橋 富美, 石兼 真, 笹栗 俊之
  • Organizer: 第93回日本薬理学会年会
• [Presentation] AngiotensinⅡは癌周囲環境を変化させ、乳癌自然肺転移を促進する (2019)
  • Author(s): 瀧口知浩, 高橋富美, 石兼真, 笹栗俊之
  • Organizer: 第72回日本薬理学会西南部会
• [Presentation] Differentiation-inducing factor-1 accelerates bone marrow-derived mesenchymal stem cells differentiation into adipocyte (2019)
  • Author(s): 石兼 真, 幾島 栄悟, 瀧口 知浩, 豊平 由美子, 高橋 富美
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 2,5-Dimethylcelecoxib attenuates cardiac fibrosis after cryoinjury-induced myocardial infarction by suppressing the fibroblast-myofibroblast differentiation (2019)
  • Author(s): 幾島 栄悟, 石兼 真, 瀧口 知浩, 豊平 由美子, 高橋 富美
  • Organizer: 第93回日本薬理学会年会
• [Presentation] 骨髄由来間葉系幹細胞に対するdifferentiation-inducing factor-1による分化誘導調節機序の解明 (2019)
  • Author(s): 石兼真, 幾島栄悟, 瀧口知浩, 豊平由美子, 高橋富美
  • Organizer: 第72回日本薬理学会西南部会
• [Presentation] Glycogen synthase kinase-3 調整薬による間葉系幹細胞の分化制御機序の解明 (2019)
  • Author(s): 石兼真, 豊平由美子, 高橋富美
  • Organizer: 第37回産業医科大学学会
• [Presentation] Angiotensin II increase the pulmonary metastasis through the vascular endothelial cell adhenent pathway in hematogenous metastasis of melanoma cells. (2018)
  • Author(s): Shin Ishikane, Hiroshi Hosoda, Takashi Nojiri, Takeshi Tokudome, Tetsuya Mizutani, Yumiko Toyohira, Mikiya Miyazato, Kaoru Miyamoto, Kenji Kangawa, Fumi Takahashi-Yanaga.
  • Organizer: WCP2018- 18th WORLD CONGRESS OF BASIC AND CLINICAL PHARMACOLOGY
  • Int'l Joint Research
• [Presentation] Angiotensin II promotes hematogenous cancer metastasis through the activation of vascular endothelial adhesion molecules. (2018)
  • Author(s): Shin Ishikane, Fumi Takahashi-Yanaga.
  • Organizer: 第77回日本癌学会学術総会