Molecular mechanism in early establishment of peritoneal metastasis from gastric cancer.

• Project/Area Number: 17K10588
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Tottori University
• Principal Investigator: FUJIWARA Yoshiyuki 鳥取大学, 医学部, 教授 (40314330)
• Co-Investigator(Kenkyū-buntansha): 尾崎 知博 鳥取大学, 医学部附属病院, 助教 (10457161) ; 齊藤 博昭 鳥取大学, 医学部, 准教授 (20335532) ; 三吉 範克 地方独立行政法人大阪府立病院機構大阪国際がんセンター(研究所), その他部局等, がん医療創生部プロジェクトリーダー (20528624) ; 黒田 博彦 鳥取大学, 医学部附属病院, 助教 (30743273) ; 福本 陽二 鳥取大学, 医学部附属病院, 助教 (40623947) ; 松永 知之 鳥取大学, 医学部, 助教 (40743274) ; 宮谷 幸造 鳥取大学, 医学部附属病院, 助教 (30758173)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 胃癌 / 腹膜播種 / 癌局所免疫 / フェロトーシス / 微小環境 / 制御性リンパ球 / 予後因子 / フローサイトメーター / 5-ALA / マクロフアージ / エクソソーム / 5－アミノレブリン酸 / 組織培養

Outline of Final Research Achievements

1, Photodynamic diagnosis with 5-aminolevulinic acid (5-ALA) could not improve the detection sensitivity for invisible peritoneal metastasis of gastric cancer by multicenter clinical trials in Japan. However, we demonstrated that 5-ALA itself had anti-tumor activity through gene regulation of ferroptosis-associated proteins such as down-regulation of GPX4 and up-regulation of HMOX. We also confirmed that overexpression of GPX4 and lower expression of HMOX1 had been poorer prognostic factors in human cancer.
2, We also demonstrated that accumulation of regulatory B cells and PD-1 positive macrophages were observed in human gastric cancer, which were worse prognostic factors in patients with gastric cancer. Regulatory B cells and PD-1-positive macrophages may have a potential function of immune evasion in gastric cancer microenvironment.

Academic Significance and Societal Importance of the Research Achievements

１、消化器癌に対する5-ALAの抗腫瘍効果のメカニズムが、フェロトーシスの誘導であることを明らかにした。フェロトーシスは、薬剤耐性のメカニズムにも関与していることが知られており、抗癌剤に5-ALAを併用することで感受性増強効果が期待される。
２、現在癌局所の微小環境が注目されているが、我々の研究により癌局所においてＴリンパ球以外の制御性Ｂリンパ球や、PD-1陽性マクロファージが集積し、免疫寛容状態を作り出していることが示唆された。今後、癌の免疫治療が開発されていく上で重要な知見となると考える。

Research Products

• [Journal Article] Increased regulatory B cells are involved in immune evasion in patients with gastric cancer (2019)
  • Author(s): Murakami, Y. Saito, H. Shimizu, S. Kono, Y. Shishido, Y. Miyatani, K. Matsunaga, T. Fukumoto, Y. Ashida, K. Sakabe, T. Nakayama, Y. Fujiwara, Y.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 13083-13083
  • DOI: 10.1038/s41598-019-49581-4
  • Peer Reviewed / Open Access
• [Journal Article] PD-1 Expression on Circulating CD8+ T-Cells as a Prognostic Marker for Patients With Gastric Cancer. (2019)
  • Author(s): Saito H, Shimizu S, Kono Y, Murakami Y, Shishido Y, Miyatani K, Matsunaga T, Fukumoto Y, Ashida K, Fujiwara Y.
  • Journal Title: Anticancer Res. Volume: 39 Issue: 1 Pages: 443-448
  • DOI: 10.21873/anticanres.13132
  • Peer Reviewed
• [Journal Article] Identification of genes involved in the regulation of TERT in hepatocellular carcinoma. (2019)
  • Author(s): Amisaki M, Tsuchiya H, Sakabe T, Fujiwara Y, Shiota G.
  • Journal Title: Cancer Sci. Volume: 110 Issue: 2 Pages: 550-560
  • DOI: 10.1111/cas.13884
  • Peer Reviewed / Open Access
• [Journal Article] Protoporphyrinogen oxidase is involved in the fluorescence intensity of 5-aminolevulinic acid-mediated laser-based photodynamic endoscopic diagnosis for early gastric cancer (2018)
  • Author(s): Kurumi Hiroki、Kanda Tsutomu、Kawaguchi Koichiro、Yashima Kazuo、Koda Hiroki、Ogihara Kumi、Matsushima Kayoko、Nakao Kazuhiko、Saito Hiroaki、Fujiwara Yoshiyuki、Osaki Mitsuhiko、Okada Futoshi、Isomoto Hajime
  • Journal Title: Photodiagnosis Photodyn Ther Volume: S1572-1000(17) Pages: 1-2
  • DOI: 10.1016/j.pdpdt.2018.02.005
  • Peer Reviewed
• [Journal Article] Highly Activated PD-1/PD-L1 Pathway in Gastric Cancer with PD-L1 Expression. (2018)
  • Author(s): Saito H, Kono Y, Murakami Y, Shishido Y, Kuroda H, Matsunaga T, Fukumoto Y, Osaki T, Ashida K, Fujiwara Y.
  • Journal Title: Anticancer Res Volume: ３８ Pages: 30522-30527
  • Peer Reviewed