Elucidation of eicosanoid-related tumor progression mechanism in hepatocellular carcinoma microenvironment and research on novel treatment

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K17456
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: University of Fukui
• Principal Investigator: Nosaka Takuto 福井大学, 学術研究院医学系部門, 助教 (70748441)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 癌 / ロイコトリエン / がん微小環境 / 腫瘍関連マクロファージ / GM-CSF / 内科

Outline of Final Research Achievements

Leukotriene (LT), which is produced from arachidonic acid by 5-lipoxygenase (5-LOX), is known to promote cancer progression. In this study, we analyzed the mechanism of LT progression and immune cells producing LT in hepatocellular carcinoma and investigated the possibility of targeted therapy. In 86 resected hepatocellular carcinoma patients, the 5-LOX high-expressing group showed poorer postoperative recurrence period and overall survival than the 5-LOX low-expressing group. 5-LOX inhibitor suppressed tumor growth in a mouse model of hepatocellular carcinoma.
Our results suggest that GM-CSF produced by tumor cells and tumor-associated macrophages (TAMs) in the cancer microenvironment promotes LT production by TAMs and enhances the proliferative and stem cell potential of hepatocellular carcinoma cells, suggesting the possibility of a novel LT-regulated therapy for liver cancer.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

進行肝細胞がんの進展制御は、現治療法では未だ困難であり、詳細な進展機構の解明と、それに基づく治療法の開発が重要な課題である。申請者は、アラキドン酸を基質に生成される生理活性脂質(エイコサノイド)が炎症関連腫瘍進展分子であることに注目して、肝細胞がん肺転移の新規進展機構を報告してきた。本研究により肝細胞がんにおける新規のエイコサノイド産生および腫瘍進展に関する機構を解明し、エイコサノイド産生制御薬による治療法の可能性が示された。肝細胞がんの脂質代謝学・腫瘍免疫学的に新規知見が得られ、臨床応用性の高い、新規治療アプローチを展開できる可能性が示された。