Analysis of the malignant progression of tumors affected by tumor angiogenesis

• Project/Area Number: 20H05698
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Review Section: Broad Section I
• Research Institution: Osaka University
• Principal Investigator: Takakura Nobuyuki 大阪大学, 微生物病研究所, 教授 (80291954)
• Project Period (FY): 2020-08-31 – 2025-03-31
• Project Status: Completed (Fiscal Year 2024)
• Budget Amount: ¥196,690,000 (Direct Cost: ¥151,300,000、Indirect Cost: ¥45,390,000); Fiscal Year 2024: ¥38,610,000 (Direct Cost: ¥29,700,000、Indirect Cost: ¥8,910,000); Fiscal Year 2023: ¥38,610,000 (Direct Cost: ¥29,700,000、Indirect Cost: ¥8,910,000); Fiscal Year 2022: ¥38,610,000 (Direct Cost: ¥29,700,000、Indirect Cost: ¥8,910,000); Fiscal Year 2021: ¥38,610,000 (Direct Cost: ¥29,700,000、Indirect Cost: ¥8,910,000); Fiscal Year 2020: ¥42,250,000 (Direct Cost: ¥32,500,000、Indirect Cost: ¥9,750,000)
• Keywords: 腫瘍 / 血管 / 血管新生 / 血管形成

Outline of Research at the Start

本研究は、血管とがん細胞との相互作用を、血管形成によりもたらされる腫瘍微小環境から解明していく研究である。血管形成単独、がん細胞の悪性化を単独のイベントとして解析する研究は国内外でも行われているが、我々は、血管形成の詳細な分子機序の解明を切り口にして、がん細胞の悪性化進展を解析する。がん細胞と血管系細胞との相互作用を分断させることで、がんの悪性化を抑制するような新しい治療法の開発に資する研究を計画している。

Outline of Final Research Achievements

Blood vessels in tumor not only deliver oxygen and nutrient but also secrete factors to induce malignant phenotype of cancer cells, i.e., invasion, metastasis, and drug resistance. For the regulation of tumor vasculature, we analyzed precise molecular mechanism of tumor angiogenesis and factors secreted from vascular endothelial cells. We found the biological significance of vascular endothelial stem cells in the pre-existing blood vessels for vascular integrity and factors to affect the malignancy of cancer.

Academic Significance and Societal Importance of the Research Achievements

がんは現在80歳までに二人に一人が罹患する疾患であり、５年生存率は高くはなってきているが、まだ死因の一位を占める。がん細胞に直接効果を示すような分子標的薬剤の開発が進められてきているところであるが、がん環境を形成する血管に対する治療薬はまだ十分に開発されてきていない。本研究では、腫瘍内の血管についてその特性などを捉えることができたことから、今後のがん治療への応用に期待が持てる。

Assessment Rating

Ex-post Assessment

A: 期待どおりの成果があった

Research Products

• [Int'l Joint Research] ヘルシンキ大学(フィンランド)
• [Int'l Joint Research] University of California-Davis(米国)
• [Journal Article] Hydrogel Use in Osteonecrosis of the Femoral Head (2024)
  • Author(s): Bal Zeynep、Takakura Nobuyuki
  • Journal Title: Gels Volume: 10 Issue: 8 Pages: 544-544
  • DOI: 10.3390/gels10080544
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial cell specific LAT1 ablation normalizes tumor vasculature (2024)
  • Author(s): Suehiro Jun-ichi、Kimura Toru、Fukutomi Toshiyuki、Naito Hisamichi、Kanki Yasuharu、Wada Youichiro、Kubota Yoshiaki、Takakura Nobuyuki、Sakurai Hiroyuki
  • Journal Title: JCI Insight Volume: 9 Issue: 18
  • DOI: 10.1172/jci.insight.171371
  • Peer Reviewed / Open Access
• [Journal Article] Tumor endothelial cell-derived Sfrp1 supports the maintenance of cancer stem cells via Wnt signaling (2024)
  • Author(s): Hayashi Yumiko、Hashimoto Masakazu、Takaoka Katsuyoshi、Takemoto Tatsuya、Takakura Nobuyuki、Kidoya Hiroyasu
  • Journal Title: In Vitro Cellular & Developmental Biology - Animal Volume: - Issue: 10 Pages: 1123-1131
  • DOI: 10.1007/s11626-024-00899-y
  • Peer Reviewed / Open Access
• [Journal Article] Brain-derived endothelial cells are neuroprotective in a chronic cerebral hypoperfusion mouse model (2024)
  • Author(s): Matsui Yuichi、Muramatsu Fumitaka、Nakamura Hajime、Noda Yoshimi、Matsumoto Kinnosuke、Kishima Haruhiko、Takakura Nobuyuki
  • Journal Title: Communications Biology Volume: 7 Issue: 1 Pages: 338-338
  • DOI: 10.1038/s42003-024-06030-x
  • Peer Reviewed / Open Access
• [Journal Article] Discovery of Transcription Factors Involved in the Maintenance of Resident Vascular Endothelial Stem Cell Properties (2024)
  • Author(s): Konishi Hirotaka、Rahmawati Fitriana N.、Okamoto Naoki、Akuta Keigo、Inukai Koichi、Jia Weizhen、Muramatsu Fumitaka、Takakura Nobuyuki
  • Journal Title: Molecular and Cellular Biology Volume: 44 Issue: 1 Pages: 17-26
  • DOI: 10.1080/10985549.2023.2297997
  • Peer Reviewed
• [Journal Article] Apelin provides an alternative function to estrogen in regulating lymphatic vascular integrity (2023)
  • Author(s): Sawane Mika、Gantumur Enkhtuul、Muramatsu Fumitaka、Kidoya Hiroyasu、Takakura Nobuyuki、Kajiya Kentaro
  • Journal Title: Journal of Dermatological Science Volume: 111 Issue: 3 Pages: 124-127
  • DOI: 10.1016/j.jdermsci.2023.07.006
  • Peer Reviewed
• [Journal Article] Single-cell sequencing reveals the existence of fetal vascular endothelial stem cell-like cells in mouse liver (2023)
  • Author(s): Fitriana Nur Rahmawati, Tomohiro Iba, Hisamichi Naito, Shota Shimizu, Hirotaka Konishi, Weizhen Jia, Nobuyuki Takakura
  • Journal Title: Stem Cell Research & Therapy Volume: 14 Issue: 1 Pages: 227-227
  • DOI: 10.1186/s13287-023-03460-y
  • Peer Reviewed / Open Access
• [Journal Article] Aging impairs the ability of vascular endothelial stem cells to generate endothelial cells in mice (2023)
  • Author(s): Shota Shimizu, Tomohiro Iba, Hisamichi Naito, Fitriana Nur Rahmawati, Hirotaka Konishi, Weizhen Jia, Fumitaka Muramatsu, Nobuyuki Takakura
  • Journal Title: Angiogenesis Volume: 26 Issue: 4 Pages: 567-580
  • DOI: 10.1007/s10456-023-09891-8
  • Peer Reviewed / Open Access
• [Journal Article] Cancer apelin receptor suppresses vascular mimicry in malignant melanoma (2023)
  • Author(s): Koichi Inukai, Kazuyoshi Kise, Yumiko Hayashi, Weizhen Jia, Fumitaka Muramatsu, Naoki Okamoto, Hirotaka Konishi, Keigo Akuta, Hiroyasu Kidoya, Nobuyuki Takakura
  • Journal Title: Pathology and Oncology Research Volume: 29 Pages: 1610867-1610867
  • DOI: 10.3389/pore.2023.1610867
  • Peer Reviewed / Open Access
• [Journal Article] Upregulation of Robo4 expression by SMAD signaling suppresses vascular permeability and mortality in endotoxemia and COVID-19 models (2023)
  • Author(s): Morita M, Yoneda A, Tokunoh N, Masaki T, Shirakura K, Kinoshita M, Hashimoto R, Shigesada N, Takahashi J, Tachibana M, Tanaka S, Obana M, Hino N, Ikawa M, Tsujikawa K, Ono C, Matsuura Y, Kidoya H, Takakura N, Kubota Y, Doi T, Takayama K, Yoshioka Y, Fujio Y, Okada Y.
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 120 Issue: 3
  • DOI: 10.1073/pnas.2213317120
  • Peer Reviewed / Open Access
• [Journal Article] Blood vessels sense dermal stiffness via a novel mechanotransducer, APJ (2022)
  • Author(s): Sawane Mika、Ogura Yuki、Nakamura Ayano、Otaka Hitomi、Kidoya Hiroyasu、Sato Katsujiro、Takakura Nobuyuki、Kajiya Kentaro
  • Journal Title: Angiogenesis Volume: 25 Issue: 2 Pages: 151-154
  • DOI: 10.1007/s10456-021-09821-6
  • Peer Reviewed / Open Access
• [Journal Article] Apelin Resistance Contributes to Muscle Loss during Cancer Cachexia in Mice (2022)
  • Author(s): Re Cecconi Andrea David、Barone Mara、Forti Mara、Lunardi Martina、Cagnotto Alfredo、Salmona Mario、Olivari Davide、Zentilin Lorena、Resovi Andrea、Persichitti Perla、Belotti Dorina、Palo Federica、Takakura Nobuyuki、Kidoya Hiroyasu、Piccirillo Rosanna
  • Journal Title: Cancers Volume: 14 Issue: 7 Pages: 1814-1814
  • DOI: 10.3390/cancers14071814
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of CD157-Positive Vascular Endothelial Stem Cells in Mouse Retinal and Choroidal Vessels: Fluorescence-Activated Cell Sorting Analysis. (2022)
  • Author(s): Wakabayashi T., Naito H., Iba T., Nishida K. & Takakura N.
  • Journal Title: Investigative Ophthalmology & Visual Science Volume: in press Issue: 4 Pages: 5-5
  • DOI: 10.1167/iovs.63.4.5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reduction in MIR-219 expression underlies cellular pathogenesis of oligodendrocytes in a mouse model of Krabbe disease. (2021)
  • Author(s): Inamura N, Go S, Watanabe T, Takase H, Takakura N, Nakayama A, Takebayashi H, Matsuda J, Enokido Y.
  • Journal Title: Brain Pathology Volume: － Issue: 5 Pages: 12951-12951
  • DOI: 10.1111/bpa.12951
  • Peer Reviewed / Open Access
• [Journal Article] Endothelial cell-derived Apelin inhibits tumor growth by altering immune cell localization (2021)
  • Author(s): Hu Liuying、Hayashi Yumiko、Kidoya Hiroyasu、Takakura Nobuyuki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1
  • DOI: 10.1038/s41598-021-93619-5
  • Peer Reviewed / Open Access
• [Journal Article] Indispensable role of Galectin-3 in promoting quiescence of hematopoietic stem cells (2021)
  • Author(s): Jia Weizhen、Kong Lingyu、Kidoya Hiroyasu、Naito Hisamichi、Muramatsu Fumitaka、Hayashi Yumiko、Hsieh Han-Yun、Yamakawa Daishi、Hsu Daniel K.、Liu Fu-Tong、Takakura Nobuyuki
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 2118-2118
  • DOI: 10.1038/s41467-021-22346-2
  • NAID: 120007096897
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vascular reconstitution in the tumor for more effective tumor immunotherapy (2021)
  • Author(s): Takakura Nobuyuki
  • Journal Title: Cancer Science Volume: 112 Issue: 4 Pages: 1348-1356
  • DOI: 10.1111/cas.14854
  • Peer Reviewed / Open Access
• [Journal Article] An in vivo model allowing continuous observation of human vascular formation in the same animal over time (2021)
  • Author(s): Tsukada Yohei、Muramatsu Fumitaka、Hayashi Yumiko、Inagaki Chiaki、Su Hang、Iba Tomohiro、Kidoya Hiroyasu、Takakura Nobuyuki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 745-745
  • DOI: 10.1038/s41598-020-80497-6
  • Peer Reviewed / Open Access
• [Journal Article] Zinc Finger Protein St18 Protects against Septic Death by Inhibiting VEGF-A from Macrophages (2020)
  • Author(s): Maruyama Kenta、Kidoya Hiroyasu、Takemura Naoki、Sugisawa Erika、Takeuchi Osamu、Kondo Takeshi、Eid Mohammed Mansour Abbas、Tanaka Hiroki、Martino Mika?l M.、Takakura Nobuyuki、Takayama Yasunori、Akira Shizuo、Vandenbon Alexis、Kumagai Yutaro
  • Journal Title: Cell Reports Volume: 32 Issue: 2 Pages: 107906-107906
  • DOI: 10.1016/j.celrep.2020.107906
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Loss of Down Syndrome Critical Region-1 Mediated-Hypercholesterolemia Accelerates Corneal Opacity Via Pathological Neovessel Formation (2020)
  • Author(s): Muramatsu Masashi、Nakagawa Suguru、Osawa Tsuyoshi、Toyono Tetsuya、Uemura Akiyoshi、Kidoya Hiroyasu、Takakura Nobuyuki、Usui Tomohiko、Ryeom Sandra、Minami Takashi
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 40 Issue: 10 Pages: 2425-2439
  • DOI: 10.1161/atvbaha.120.315003
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High expression of PSF1 promotes drug resistance and cell cycle transit in leukemia cells (2020)
  • Author(s): Han-Yun Hsieh, Weizhen Jia, Ze-Cheng Jin, Hiroyasu Kidoya, Nobuyuki Takakura
  • Journal Title: Cancer Science Volume: 111 Issue: 7 Pages: 2400-2412
  • DOI: 10.1111/cas.14452
  • Peer Reviewed / Open Access
• [Journal Article] Mechanisms of new blood-vessel formation and proliferative heterogeneity of endothelial cells (2020)
  • Author(s): Naito Hisamichi、Iba Tomohiro、Takakura Nobuyuki
  • Journal Title: International Immunology Volume: - Issue: 5 Pages: 295-305
  • DOI: 10.1093/intimm/dxaa008
  • Peer Reviewed / Open Access
• [Presentation] Roles of apelin/APJ for the suppression of age related disease onset (2024)
  • Author(s): 高倉伸幸
  • Organizer: 第８９回日本循環器学会学術集会
  • Int'l Joint Research / Invited
• [Presentation] Tie2活性化の治療概念 (2024)
  • Author(s): 高倉伸幸
  • Organizer: 日本血管生物医学会特別集会
  • Invited
• [Presentation] Biological significance of endothelial stem cells (2024)
  • Author(s): 高倉伸幸
  • Organizer: CVMW2024
  • Invited
• [Presentation] 既存の血管に存在する血管内皮幹細胞による血管の恒常性維持 (2024)
  • Author(s): 高倉伸幸
  • Organizer: 日本抗加齢医学会
  • Invited
• [Presentation] 既存の血管に存在する血管内皮幹細胞の生物学的意義 (2024)
  • Author(s): 高倉伸幸
  • Organizer: 第３９回日本糖尿病合併症学会
  • Invited
• [Presentation] Endothelial stem cell population in the pre-existing blood vessels for health and diseases (2024)
  • Author(s): 高倉伸幸
  • Organizer: Duke-NUS/NCCS & Kanazawa Univ-CRI Joint Symposium
  • Int'l Joint Research / Invited
• [Presentation] 血管内皮幹細胞による血管の再生と維持 (2023)
  • Author(s): 高倉伸幸
  • Organizer: 第10回日本細胞外小胞学会
  • Invited
• [Presentation] VEGFシグナルの抑制による腫瘍免疫環境の改善 (2023)
  • Author(s): 高倉伸幸
  • Organizer: 第33回泌尿器科分子・細胞研究会
  • Invited
• [Presentation] 血管の老化性変容と血管内皮細胞のステムセルエイジング (2022)
  • Author(s): 高倉伸幸
  • Organizer: CVMW2022心血管代謝週間
  • Invited
• [Presentation] Vascular Biology and hemophilia (2022)
  • Author(s): 高倉伸幸
  • Organizer: 第84回日本血液学会学術集会
  • Int'l Joint Research / Invited
• [Presentation] Development and senescence of resident vascular endothelial stem cells (2022)
  • Author(s): 高倉伸幸
  • Organizer: 国際血管生物学会（IVBM）
  • Int'l Joint Research / Invited
• [Presentation] Vascular integrity by endothelial stem cell population (2021)
  • Author(s): 高倉伸幸
  • Organizer: 第７回血管生物医学会
  • Invited
• [Presentation] Vascular integrity by resident endothelial stem cell population (2021)
  • Author(s): 高倉伸幸
  • Organizer: 第４４回 日本分子生物学会
  • Invited
• [Presentation] Tumor vascular regulation for effective cancer therapy (2021)
  • Author(s): 高倉伸幸
  • Organizer: 第８０回日本癌学会総会
  • Invited
• [Presentation] Vascular endothelial stem cell in health and ageing (2021)
  • Author(s): Nobuyuki Takakura
  • Organizer: International Society of Atherosclerosis
  • Int'l Joint Research / Invited
• [Presentation] 血管恒常性維持の幹細胞医学 (2021)
  • Author(s): 高倉伸幸
  • Organizer: 第９４回 日本生化学会
  • Invited
• [Presentation] 血管内皮幹細胞による血管の再生 (2021)
  • Author(s): 高倉伸幸
  • Organizer: 第42回日本炎症・再生医学会
  • Invited
• [Presentation] 既存の血管に存在する血管内皮幹細胞による 組織の維持と再生 (2021)
  • Author(s): 高倉伸幸
  • Organizer: 第483回日本皮膚科学会
  • Invited
• [Presentation] 腫瘍微小環境における血管新生と腫瘍免疫との関係 (2020)
  • Author(s): 高倉伸幸
  • Organizer: 第８２回日本血液学会
  • Invited
• [Presentation] 血管内皮幹細胞による血管新生の新しいパラダイム (2020)
  • Author(s): 高倉伸幸
  • Organizer: 第26回日本糖尿病眼学会総会
  • Invited
• [Presentation] Heterogeneity of endothelial cells in the pre-existing blood vessels (2020)
  • Author(s): Nobuyuki Takakura
  • Organizer: CVMW2020 202１
  • Int'l Joint Research / Invited
• [Presentation] Development and ageing of endothelial stem cells (2020)
  • Author(s): Nobuyuki Takakura
  • Organizer: International Vascular Biology Meeting 2020
  • Int'l Joint Research / Invited
• [Presentation] 老化による毛細血管の構造変化と組織の機能低下 (2020)
  • Author(s): 高倉伸幸
  • Organizer: 第20回日本抗加齢医学会総会
  • Invited
• [Remarks] 大阪大学微生物病研究所情報伝達分野ホームページ
  • URL: https://www.biken.osaka-u.ac.jp/laboratories/detail/12
• [Remarks] 情報伝達分野
  • URL: https://st.biken.osaka-u.ac.jp
• [Remarks] 大阪大学微生物病研究所情報伝達分野webページ
  • URL: https://st.biken.osaka-u.ac.jp
• [Remarks] 大阪大学微生物病研究所情報伝達分野ホームページ
  • URL: https://st.biken.osaka-u.ac.jp
• [Patent(Industrial Property Rights)] 肺再生用医薬および肺胞オルガノイドの製造方法 (2024)
  • Inventor(s): 高倉伸幸
  • Industrial Property Rights Holder: 大阪大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2024-096628
  • Filing Date: 2024
• [Patent(Industrial Property Rights)] 脳の血流低下に関連する疾患または状態の予防および/または治療用医薬 (2023)
  • Inventor(s): 高倉伸幸、松井雄一
  • Industrial Property Rights Holder: 大阪大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2023-041269
  • Filing Date: 2023