Endoglin as therapeutic target in angiosarcoma.

• Project/Area Number: 20K08675
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Kumamoto University
• Principal Investigator: Kajihara Ikko 熊本大学, 大学院生命科学研究部(医), 助教 (90433036)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2021: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: angiosarcoma / endoglin / TGF-beta / 血管肉腫 / siRNA / 抗腫瘍効果 / エンドグリン / 分子標的薬 / TGF-β / ALK

Outline of Research at the Start

希少且つ難治な血管肉腫に対する病態解明に関して、endoglinを中心としたTGF-βシグナル伝達経路の視点から解明し、新規治療法を探索する。TGF-βシグナル伝達経路は腫瘍の悪性度に関与し、TGF-β III型受容体(TβRIII)であるendoglinは血管内皮細胞特異的に発現している。研究項目は、①血管肉腫におけるTGF-βシグナル伝達経路に関連する各種分子の発現レベル解析②血管肉腫に関するendoglin阻害による抗腫瘍効果の検討③endoglinが関与する血管肉腫進展の分子メカニズム解明④疾患モデルマウスを用いた新規治療法の探索⑤血管肉腫の新規セルライン開発である。

Outline of Final Research Achievements

Endoglin acts as a coreceptor for TGF-b signaling and is overexpressed in tumor-associated endothelial cells and enhances tumor angiogenesis. Here, we investigated the role of endoglin in the pathogenesis of angiosarcoma and whether endoglin inhibition results in antitumor activity. Endoglin was overexpressed in angiosarcoma, and its inhibition was effective in promoting apoptosis and the suppression of migration, invasion, tube formation, and Warburg effect in angiosarcoma cells. Knockdown of endoglin activated caspase 3/7 that is essential for apoptosis, reduced survivin levels, and decreased paxillin and vascular endothelial cadherin phosphorylation and matrix metalloproteinase 2 and matrix metalloproteinase 9 activities in angiosarcoma cells. Although endoglin is a coreceptor that regulates TGF-b signaling, the antitumor effect of endoglin in angiosarcoma was not based on Smad signaling regulation but on non-Smad TGF-b signaling.

Academic Significance and Societal Importance of the Research Achievements

血管肉腫は、標準治療が確立されておらず、難治性の肉腫である。進行例では、化学療法が主体となるが、未だ有効な治療法が確立されていない。そのために、血管肉腫に対する新規治療の開発は急務である。今回、endoglin阻害による血管肉腫の抗腫瘍効果およびその分子メカニズムを解明した。

Research Products

• [Journal Article] Upregulated androgen receptor variant‐7 mRNA and protein in extramammary Paget's disease (2022)
  • Author(s): Yamada‐Kanazawa S., Mijiddorj M.T., Kajihara I., et al.
  • Journal Title: Journal of the European Academy of Dermatology and Venereology Volume: 36 Issue: 9
  • DOI: 10.1111/jdv.18229
  • Peer Reviewed
• [Journal Article] Clinical significance of maximum standardized uptake value of positron emission tomography/computed tomography as prognostic factor in extramammary Paget’s disease (2022)
  • Author(s): Kusaba Yudo、Kajihara Ikko、Sawamura Soichiro、Kanemaru Hisashi、Makino Katsunari、Aoi Jun、Masuguchi Shinichi、Morinaga Jun、Fukushima Satoshi
  • Journal Title: The Journal of Dermatology Volume: 49 Issue: 6 Pages: 508-514
  • DOI: 10.1111/1346-8138.16328
  • Peer Reviewed
• [Journal Article] Intertumor and intratumor heterogeneity of PIK3CA mutations in extramammary Paget’s disease (2022)
  • Author(s): Kusaba Yudo、Kajihara Ikko、Myangat Tselmeg Mijiddorj、Tanaka Kenichiro、Sakamoto Ryoko、Maeda‐Otsuka Saki、Yamada‐Kanazawa Saori、Sawamura Soichiro、Kanemaru Hisashi、Nishimura Yuki、Nakamura‐Kashiwada Kayo、Makino Katsunari、Miyashita Azusa、Aoi Jun、Masuguchi Shinichi、Fukushima Satoshi
  • Journal Title: The Journal of Dermatology Volume: - Issue: 5 Pages: 508-514
  • DOI: 10.1111/1346-8138.16343
  • Peer Reviewed
• [Journal Article] Genomic landscape of circulating tumour DNA in metastatic extramammary Paget's disease (2021)
  • Author(s): S. Sawamura, T. Mijiddorj Myangat, I. Kajihara, K. Tanaka, M. Ide, R. Sakamoto, S. Otsuka-Maeda, H. Kanemaru, Y. Nishimura, S. Kanazawa-Yamada, K. Kashiwada-Nakamura, N. Honda, K. Makino, J. Aoi, T. Igata, T. Makino, S. Masuguchi, S. Fukushima, H. Ihn
  • Journal Title: Experimental Dermatology Volume: － Issue: 3 Pages: 341-348
  • DOI: 10.1111/exd.14476
  • Peer Reviewed
• [Presentation] 乳房外パジェット病の悪性化機序 (2022)
  • Author(s): 梶原一亨
  • Organizer: 第121回日本皮膚科学会総会
  • Invited