Development of a multidisciplinary anti-metastasis treatment against lymph node metastasis of head and neck squamous cell carcinomas

• Project/Area Number: 18K09379
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56050:Otorhinolaryngology-related
• Research Institution: Ehime University
• Principal Investigator: Yano Hajime 愛媛大学, 医学系研究科, 准教授 (00284414)
• 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: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 頭頚部扁平上皮がん / リンパ節転移 / リジルオキシダーゼ / ナトリウムイオン / プロトン交換輸送体１ / 細胞外小胞 / エクソソーム / 患者血清エクソソーム / LOXL2 / 頭頸部扁平上皮がん / 細胞外基質 / 頭頸部がん / 患者血清 / バイオマーカー / 前転移期ニッチェ / 細胞内 pH / 集団的細胞運動 / がん微小環境

Outline of Final Research Achievements

Cancer metastases are multi-factorial as well as multi-dimensional events. This study was aimed at proving multidisciplinary treatment against factors responsible for metastases is effective on "anti-metastasis" therapy. We have reported that one of the target molecules of the multidisciplinary treatment, LOXL localizes to exosomal fraction derived from the Head and Neck Squamous Cell Carcinoma (HNSCC) both in cultured cells as well as serum from patients. Amounts of LOXL2 were higher in relatively early phase of the HNSCC patients suggesting the participation of LOXL2 on the early phase of metastasis. The HNSCC cell with double knockdown of LOXL2 together with another target protein NHE1 exhibited decreased primary engraftment to non-tumor tissues, makes the HNSCC cell, possibly, much less metastatic than each single knockdown.

Academic Significance and Societal Importance of the Research Achievements

血清エクソソーム様画分に注目することで、リンパ節転移がないか少ない比較的初期の頭頸部がん患者においてLOXL2 含量が亢進していることが示された。動物実験においては LOXL2 がリンパ節転移に寄与することはすでに確認されていたので、それを肯定的に支持する患者血清データが得られたことの臨床的意義は大きい。一方 NHE1 / LOXL2 両ノックダウン細胞のマウス舌移植における生着性の低下はこれまで各因子の単独ノックダウンにおいては観察されておらず、目指していた相加的な抗-転移性のみならず、さらに強い相乗的抗-転移性が生じている可能性がある。

Research Products

• [Journal Article] Elevated Exosomal Lysyl Oxidase Like 2 Is a Potential Biomarker for Head and Neck Squamous Cell Carcinoma (2019)
  • Author(s): Sanada T, Islam A, Kaminota T, Kirino Y, Tanimoto R, Yoshimitsu H, Yano H, Mizuno Y, Okada M, Mitani S, Ugumori T, Tanaka J, Hato N.
  • Journal Title: The Laryngoscope Volume: Jan 20 Issue: 5 Pages: 1-8
  • DOI: 10.1002/lary.28142
  • Peer Reviewed
• [Presentation] Roles of LOXL2 in exosomal fraction on lymph node metastasis of head and neck squamous cell carcinoma (2020)
  • Author(s): Yano H, Islam A, Tanimoto R, Kaminota T, Hato N and Tanaka J.
  • Organizer: 第97回日本生理学会大会 (誌上開催)
• [Presentation] Roles of lysyl oxidase like 2 (LOXL2) in exosomal fraction on lymph node metastasis of head and neck squamous cell carcinoma (2019)
  • Author(s): Yano H, Islam A, Kaminota T, Tanimoto R, Hato N and Tanaka J
  • Organizer: Annual meeting of INTERNATIONAL SOCIETY FOR EXTRACELLULAR VESICLES
  • Int'l Joint Research
• [Presentation] 頭頸部扁平上皮がんのリンパ節転移における LOXL2 のエクソソーム画分への局在の意義 (2019)
  • Author(s): 矢野 元、谷本 玲奈、吉光 華、真田 朋昌、上田 哲平、羽藤 直人、田中 潤也
  • Organizer: 第71回日本生理学会中四国地方会
• [Presentation] 頭頸部扁平上皮がんのリンパ節転移における LOXL2 のエクソソームへの局在の意義 (2018)
  • Author(s): 矢野 元、谷本 玲奈、真田 朋昌、上田 哲平、羽藤 直人、田中 潤也
  • Organizer: 分子生物学会