Requirements of LEFTY and Nodal overexpression for tumor cell survival under hypoxia in glioblastoma

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K16567
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Kitasato University
• Principal Investigator: Akiya Masashi 北里大学, 医学部, 助教 (80836099)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: LEFTY / Nodal / Glioblastoma / Hypoxia

Outline of Final Research Achievements

We investigated the roles of LEFTY and Nodal in glioblastoma (GBM) hypoxic foci. In clinical samples, significantly higher expression of LEFTY and Nodal, as well as higher apoptotic and lower proliferation rates, were observed in non-pseudopalisading (Ps) perinecrotic lesions as compared to Ps and non-necrotic tumor lesions. In KS-1, a GBM cell line that lacks endogenous Nodal expression, treatment with the hypoxic mimetic CoCl2 increased LEFTY expression. LEFTY and Nodal overexpression increased proliferation rates and reduced susceptibility to CoCl2-induced apoptosis, and increased the expression of epithelial-mesenchymal transition (EMT) /GSC-related markers. An increased ALDH1high population and more efficient spheroid formation was also observed in LEFTY-overexpressing cells. These findings suggest that LEFTY and Nodal may contribute to cell survival in non-Ps GBM perinecrotic lesions, leading to alterations in apoptosis, proliferation, or EMT/GCS features.

Free Research Field

分子病理学

Academic Significance and Societal Importance of the Research Achievements

＜学術的意義＞①膠芽腫のグリオーマ幹細胞の新規マーカーとしてLEFTYを同定し、LEFTY関連シグナルカスケードの検索から新たなグリオーマ幹細胞の誘導・維持機構を解明した。②LEFTY陽性グリオーマ幹細胞による血管新生制御の観点からみた膠芽腫の新たな生物学的特性を解明した。＜社会的意義＞③小化学化合物などによるLEFTY関連シグナルカスケード阻害によりグリオーマ幹細胞の“幹”形質の消失や血管新生抑制による膠芽腫の分子標的治療の基盤を築くことができる。