Therapeutic strategies targeting the crosstalk between osteosarcoma stem cell models and the microenvironment

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K09317
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Kanazawa University
• Principal Investigator: Takeuchi Akihiko 金沢大学, 医学系, 協力研究員 (70512218)
• Co-Investigator(Kenkyū-buntansha): 山本 靖彦 金沢大学, 医学系, 教授 (20313637)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 骨肉腫 / がん幹細胞

Outline of Final Research Achievements

We analyzed the expression of receptor for advanced glycation end-products (RAGE) in the mouse osteosarcoma cell line Dunn and LM8 (a highly metastatic cell line derived from Dunn), and identified membrane-type RAGE (mRAGE) and endogenous secretory RAGE (esRAGE). Dunn revealed that the expression of mRAGE and esRAGE was higher than that of LM8, and that LM8 had a higher spheroid-forming ability. In addition, Dunn-RAGE (RAGE overexpressing cell) showed the suppression of miR34a expression and increased expression of Wnt5a. Furthermore, the spheroid-forming ability of Dunn-RAGE was higher than that of Dunn-mock, and the ability to form subcutaneous tumors in mice was confirmed only with Dunn-RAGE. In the future, we will develop a new osteosarcoma treatment strategies through histological analysis of subcutaneous primary tumors and analysis of co-culture of tumor cells and fibroblasts to clarify the effects of the tumor and microenvironment on stem cell formation.

Free Research Field

整形外科

Academic Significance and Societal Importance of the Research Achievements

RAGEによりマウス骨肉腫細胞においても幹細胞様の性質を獲得することを見出し、そのメカニズムとして、miR34aの低下とWnt5aの亢進が関与していることを見い出した。近年、がんの微小環境のメカニズムや治療標的に関する研究が進んでおりmiR34aやWnt5aが重要な役割を担っていることも報告されつつある。今後、微小環境を担う線維芽細胞などとの共培養などにより骨肉腫幹細胞化の分子機構を明らかとし、miR34aやWnt5aを介する微小環境と腫瘍とのクロストークや治療戦略の創出に関する研究に発展させる予定である。