Inhibition of lymphatic metastasis in oral squamous cell carcinoma with the new anti-lymphangiogenic factor

• Project/Area Number: 18K09564
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57020:Oral pathobiological science-related
• Research Institution: Hyogo Medical University
• Principal Investigator: YAMANAEGI KOJI 兵庫医科大学, 医学部, 講師 (00434944)
• Co-Investigator(Kenkyū-buntansha): 中正 恵二 兵庫医科大学, 医学部, 教授 (00217712) ; 山田 直子 兵庫医科大学, 医学部, 講師 (10319858) ; 野口 一馬 兵庫医科大学, 医学部, 准教授 (50309473) ; 西浦 弘志 兵庫医科大学, 医学部, 助教 (90284760)
• 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: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 扁平上皮癌 / 新生リンパ管抑制 / 転移抑制 / エピジェネティック阻害剤 / 口腔扁平上皮癌 / リンパ管新生 / エピジェネティック試薬 / 口腔扁平上皮f癌 / リンパ管新生抑制 / 腫瘍リンパ管新生 / 腫瘍血管新生

Outline of Final Research Achievements

We investigated the endogenous anti-angiogenic factors inhibited lymphangiogenesis on oral squamous cell carcinoma cells (OSCC). Real time Microarray PCR revealed that some candidate of endogenous anti-angiogenic factors were found out OSCC treated with epigenetic modulators, such histone deacetylase inhibitor, DNA methylation inhibitor and mTOR inhibitor. To narrow down them further, we focus on the type 3 semaphorin and its related receptors in these candidate factors. Treatment of epigenetic modulators enhanced expression of these factors and inhibits growth of OSCC and lymphendothelial cells, and also tube formation. These results suggested that type 3 semaphorin and its related receptors could be inhibited cancer-induced lymphangiogenesis as a result of removed the epigenetic restriction.

Academic Significance and Societal Importance of the Research Achievements

口腔扁平上皮癌の発症率はわが国においても年々増加傾向にある。口腔扁平上皮癌は比較的早期に頸部リンパ節や肺転移を来たす事が指摘されており、頸部リンパ節転移を認めた症例ではその生存率は半減するといわれている。従って、口腔扁平上皮癌の治療成績の向上のためには、リンパ節転移および肺転移を抑制させる新たな治療法を開発し、外科・化学療法と併用して行う必要がある。
本研究では既知の薬剤（他の疾患の治療薬として承認済み）を用い、口腔扁平上皮癌が誘導する新生リンパ管形成を抑制する事を見出し、口腔扁平上皮癌のリンパ節転移および肺転移を抑制できる可能性を示した。

Research Products

• [Journal Article] Epigenetic modulators hydralazine and sodium valproate act synergistically in VEGI-mediated anti-angiogenesis and VEGF interference in human osteosarcoma and vascular endothelial cells (2019)
  • Author(s): SHUNSUKE KUMANISHI, KOJI YAMANEGI, HIROSHI NISHIURA, YUKI FUJIHARA, KENTA KOBAYASHI, KEIJI NAKASHO, HIROYUKI FUTANI and SHINICHI YOSHIYA
  • Journal Title: INTERNATIONAL JOURNAL OF ONCOLOGY Volume: 55 Pages: 167-178
  • DOI: 10.3892/ijo.2019.4811
  • Peer Reviewed
• [Presentation] Epigenetic modulator modulates the vascular endothelial growth inhibitor (VEGI)-mediated cell death in human osteosarcoma and vascular endothelial cells (2019)
  • Author(s): Shunsuke Kumanishi, Koji Yamanegi, Hiroshi Nishiura, Yuki Fujihara, Kenta Kobayashi, Hiroyuki Futani and Shinichi Yoshiya
  • Organizer: 2nd International Combined Meeting of Orthopaedic Research Societies 2019 Annual meeting
  • Int'l Joint Research