Functional analysis of fibulin-7 in glioma

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K08770
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Juntendo University
• Principal Investigator: de Vega Susana 順天堂大学, 医学部, 非常勤助教 (30623590)
• Co-Investigator(Kenkyū-buntansha): 岡田 保典 順天堂大学, 医学(系)研究科(研究院), 客員教授 (00115221)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 神経膠腫 / 細胞外マトリックス / フィビュリン-7 / 組織内微小環境 / 異常血管形成 / 血管内皮細胞 / 周皮細胞

Outline of Final Research Achievements

Malignant transformation and abnormal angiogenesis of glioma may involve a tissue microenvironment created by the production of extracellular matrix (ECM). Here we show that fibulin-7 (Fbln7), an ECM molecule, is overexpressed in endothelial cells and pericytes of abnormal blood vessels in glioblastoma. Vascular endothelial cells stimulated with VEGF upregulate Fbln7, which specifically binds to angiopoietin-1 (Ang1), resulting in suppression of Ang1-Tie2 signaling. In a coculture assay using HUVEC and HBVP, multilayered and irregular-shaped tube-like structures of HUVEC were induced with 500 ng/ml VEGF.VEGF-induced aberrant tube-like structures were attenuated with antibody or synthetic peptides specific to Fbln7 or knockdown of Fbln7. These data demonstrate that Fbln7 is overexpressed by endothelial cells and pericytes of the abnormal microvessels in glioblastoma and suggest that Fbln7 may contribute to the aberrant vessel formation by modulation of the Ang1/Ang2-Tie2 axis.

Free Research Field

分子病理学

Academic Significance and Societal Importance of the Research Achievements

膠芽腫は術後の再発や放射線療法や化学療法の治療効果は限定的であることから、きわめて予後不良である。本研究で得られたFbln7によるAng1との特異的な結合とそれによるAng2-Tie2シグナル優位に基づく異常血管新生のデータは、再発性膠芽腫患者に現在汎用されている抗VEGF抗体薬と化学療法の併用療法に、Ang1の正常化を誘導する治療法を加えることの重要性を示唆している。