Investigation of anticancer agents targeting exosomal uptake in OSCC

• Project/Area Number: 16K11688
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Kochi University
• Principal Investigator: Sento Shinya 高知大学, 教育研究部医療学系臨床医学部門, 助教 (30635264)
• Co-Investigator(Kenkyū-buntansha): 山本 哲也 高知大学, 教育研究部医療学系臨床医学部門, 教授 (00200824) ; 笹部 衣里 高知大学, 教育研究部医療学系臨床医学部門, 講師 (40363288) ; 北村 直也 高知大学, 教育研究部医療学系臨床医学部門, 講師 (70351921)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 口腔扁平上皮癌 / エクソソーム / EGFR / マクロピノサイトーシス / マイクロピノサイトーシス

Outline of Final Research Achievements

Exosomes are secreted from various cell types into their surrounding extracellular space, that transfer various components to recipient cells and affect their function and activity. Numerous studies have highlighted the crucial role that tumor cell-derived exosomes play in tumor growth and progression. However, the precise mechanisms remain unknown. In the present study, we demonstrated that oral squamous cell carcinoma (OSCC) cells express abundantly the epidermal growth factor receptor (EGFR) and its phosphorylated form. The treatment of OSCC cells with recombinant EGF induced active macropinocytosis and significantly promoted the cellular uptake of OSCC cell-derived exosomes into OSCC cells themselves. Conversely, the uptake of exosomes by OSCC cells was abrogated in the presence of EGFR inhibitors, including erlotinib and cetuximab.

Academic Significance and Societal Importance of the Research Achievements

セツキシマブはEGFRのリガンド結合部位にEGFと競合的に結合し、EGFRのシグナル伝達阻害を介して、癌細胞の増殖、遊走、生存、浸潤などの細胞機能を阻害することから、大腸癌、頭頸部癌に臨床応用されている。本研究では、セツキシマブの抗腫瘍効果の新たな作用機序として、癌細胞分泌エクソソームの癌細胞内への取り込み阻害作用を明らかにした。

Research Products

• [Presentation] Exosomes as targeting therapy in oral squamous cell carcinoma (2018)
  • Author(s): Sento S, Sasabe E, Tomita R, Kitamura N, Yamamoto T
  • Organizer: 96th General Session & Exhibition of the IADR IADR Pan European Regional Congress
  • Int'l Joint Research
• [Presentation] EGFR blockage inhibits uptake of tumor cell-derived exosomes through micropinocytosis in oral squamous cell carcinoma (2018)
  • Author(s): Sasabe E, Liu Hm Tomomura A, Tomita R, Sento S, Yamamoto T
  • Organizer: 14th Biennial Congress of the Europian Association of Oral Mericine
  • Int'l Joint Research
• [Presentation] エクソソーム取り込みを標的とする口腔癌治療薬の探索 (2017)
  • Author(s): 仙頭慎哉・笹部衣里・北村直也・山本哲也
  • Organizer: 第54回日本口腔組織培養学会学術大会