Development of a comprehensive treatment approach targeting the CXCR4 system and cancer-associated fibroblasts for oral cancer

• Project/Area Number: 20K10095
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: Ehime University
• Principal Investigator: Nobuyuki Kuribayashi 愛媛大学, 医学系研究科, 助教 (80617332)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2022: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: CXCR4 / 癌関連線維芽細胞 / CAFs

Outline of Research at the Start

われわれは，口腔癌のリンパ節転移においてCXCR4 を発現している癌細胞が，リガンドSDF-1 に引き寄せられながら転移していること，この転移がCXCR4 阻害剤にて抑制されることを明らかにした．しかしながら，CXCR4 阻害剤では原発腫瘍に対する増殖抑制効果が得られなかった．近年，癌が生命予後に大きな影響を与える因子として癌微小環境との連携が重要であることが知られており，その主要な構成成分であるCAFs は，癌細胞の増殖・転移に密接に関与している．そこで本研究では，CXCR4 システムと癌微小環境におけるCAFs を標的とした集学的治療法の開発を行う．

Outline of Final Research Achievements

In the experiment, primary cultures were established from oral cancer cases to obtain cultured CAFs from the tumor region. The effect of an anti-fibrotic drug on the proliferation of CAFs was investigated. As a result, a tendency of growth inhibition in CAFs was observed with pirfenidone. Subsequently, the impact of anti-fibrotic drugs on the cell proliferation of oral cancer cells was examined under CAFs and B88 cell co-culture conditions, but no significant difference in the inhibition of oral cancer cell proliferation was observed. Therefore, these results suggest that the proliferation of oral cancer cells, mediated through the CXCR4 system, is primarily influenced by the growth factors produced by the oral cancer cells themselves, rather than the cancer microenvironment.

Academic Significance and Societal Importance of the Research Achievements

現在のところ，SDF-1/CXCR4 システムを介した口腔癌におけるCAFs の特性を明らかになっていない．従って，本研究成果での SDF-1/CXCR4 システムを介した口腔癌における CAFs の細胞増殖の影響を明らかにしたことは学術的意義があると考えられる．さらに，CAFs の特性を明らかにすることは，がん患者の生存率向上につながる可能性があり，口腔癌の治療において社会的に意義のある事と思われる．

Research Products

• [Journal Article] The mutational spectrum in whole exon of p53 in oral squamous cell carcinoma and its clinical implications (2022)
  • Author(s): Hyodo Toshiki、Kuribayashi Nobuyuki、Fukumoto Chonji、Komiyama Yuske、Shiraishi Ryo、Kamimura Ryouta、Sawatani Yuta、Yaguchi Erika、Hasegawa Tomonori、Izumi Sayaka、Wakui Takahiro、Nakashiro Koh-ichi、Uchida Daisuke、Kawamata Hitoshi
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 21695-21695
  • DOI: 10.1038/s41598-022-25744-8
  • Peer Reviewed / Open Access
• [Presentation] A case of oral verrucous squamous cell carcinoma with mediastinal lymph node metastasis: mutation analysis on custom gene panel by next generation sequencing. (2022)
  • Author(s): Kuribayashi N, Nakashiro K, Adachi T, Goda H, Hino S, Uchida D
  • Organizer: 第60回日本癌治療学会学術集会
• [Presentation] Clinical significance of CXCL13 as a novel biomarker in advance oral squamous cell carcinoma (2022)
  • Author(s): Tojo S,Kuribayashi N,Nakashiro K,Tokuzen N,Goda H,Kojima S,Uchida D
  • Organizer: 第81回日本癌学会学術総会
• [Presentation] Investigation of the antimicrobial effects of various oral care supplies (2021)
  • Author(s): Kojima Sayaka, Tokuzen Norihiko, Kuribayashi Nobuyuki, Hino Satoshi, Uchida Daisuke
  • Organizer: The 1st Annual Meeting of the International Society of Oral Care
  • Int'l Joint Research