Functional analysis of fibulin-7 in glioma

• 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
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• 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 / 組織内微 / 小環境 / 腫瘍 / 浸潤 / 血管形成 / Fibulin-7

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.

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。

Research Products

• [Journal Article] Implication of HYBID (Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization) in Hyaluronan Degradation by Synovial Fibroblasts in Patients with Knee Osteoarthritis. (2020)
  • Author(s): Shiozawa J, de Vega S, Cilek MZ, Yoshinaga C, Nakamura T, Kasamatsu S, Yoshida H, Kaneko H, Ishijima M, Kaneko K, Okada Y.
  • Journal Title: American Journal of Pathology Volume: 190 Issue: 5 Pages: 1046-1058
  • DOI: 10.1016/j.ajpath.2020.01.003
  • Peer Reviewed / Open Access
• [Journal Article] Fibulin-7 C-terminal fragment and its active synthetic peptide suppress choroidal and retinal neovascularization (2020)
  • Author(s): Ikeuchi Tomoko、Kanan Yogita、Long Da、de Vega Susana、Hozumi Kentaro、Nomizu Motoyoshi、Campochiaro Peter A.、Yamada Yoshihiko
  • Journal Title: Microvascular Research Volume: 129 Pages: 103986-103986
  • DOI: 10.1016/j.mvr.2020.103986
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The extracellular domain of teneurin-4 promotes cell adhesion for oligodendrocyte differentiation (2020)
  • Author(s): Hayashi Chikako、Suzuki Nobuharu、Mabuchi Yo、Kikura Naomi、Hosoda Yukina、de Vega Susana、Akazawa Chihiro
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 523 Issue: 1 Pages: 171-176
  • DOI: 10.1016/j.bbrc.2019.12.002
  • Peer Reviewed / Open Access
• [Journal Article] Expression and Characterization of Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization: HYBID, Alias KIAA1199 and CEMIP. (2020)
  • Author(s): de Vega S, Yoshida H, Okada Y
  • Journal Title: Methods Mol Biol Volume: 2132 Pages: 129-138
  • DOI: 10.1007/978-1-0716-0430-4_1
  • ISBN: 9781071604298, 9781071604304
• [Journal Article] Fibulin-7 is overexpressed in glioblastomas and modulates glioblastoma neovascularization through interaction with angiopoietin-1 (2019)
  • Author(s): Susana de Vega, Akihide Kondo, MarioSuzuki, Hajime Arai, Shabierjiang Jiapaer, Hemragul Sabit, Mitsutoshi Nakada, Tomoko Ikeuchi, Muneaki Ishijima, Eri Arikawa-Hirasawa, Yoshihiko Yamada and Yasunori Okada
  • Journal Title: International Journal of Cancer Volume: xx Issue: 8 Pages: 2157-2169
  • DOI: 10.1002/ijc.32306
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The transcription factor AmeloD stimulates epithelial cell motility essential for tooth morphology. (2019)
  • Author(s): Chiba Y, He B, Yoshizaki K, Rhodes C, Ishijima M, Bleck CKE, Stempinski E, Chu EY, Nakamura T, Iwamoto T, de Vega S, Saito K, Fukumoto S, Yamada Y
  • Journal Title: J Biol Chem Volume: 294(10) Issue: 10 Pages: 3406-3418
  • DOI: 10.1074/jbc.ra118.005298
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Extracellular Protein Fibulin-7 and Its C-Terminal Fragment Have In Vivo Antiangiogenic Activity (2018)
  • Author(s): Ikeuchi Tomoko、de Vega Susana、Forcinito Patricia、Doyle Andrew D.、Amaral Juan、Rodriguez Ignacio R.、Arikawa-Hirasawa Eri、Yamada Yoshihiko
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 17654-17654
  • DOI: 10.1038/s41598-018-36182-w
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Identification of the Novel Tooth-Specific Transcription Factor AmeloD (2018)
  • Author(s): He B.、Chiba Y.、Li H.、de Vega S.、Tanaka K.、Yoshizaki K.、Ishijima M.、Yuasa K.、Ishikawa M.、Rhodes C.、Sakai K.、Zhang P.、Fukumoto S.、Zhou X.、Yamada Y.
  • Journal Title: Journal of Dental Research Volume: 98 Issue: 2 Pages: 234-241
  • DOI: 10.1177/0022034518808254
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cell adhesion protein fibulin-7 and its C-terminal fragment negatively regulate monocyte and macrophage migration and functions in vitro and in vivo. (2018)
  • Author(s): Sarangi PP, Chakraborty P, Dash SP, Ikeuchi T, de Vega S, Ambatipudi K, Wahl L, Yamada Y.
  • Journal Title: FASEB J Volume: In press Issue: 9 Pages: 0000-0000
  • DOI: 10.1096/fj.201700686rrr
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Epiprofin Regulates Enamel Formation and Tooth Morphogenesis by Controlling Epithelial-Mesenchymal Interactions During Tooth Development. (2017)
  • Author(s): Nakamura T, Jimenez-Rojo L, Koyama E, Pacifici M, de Vega S, Iwamoto M, Fukumoto S, Unda F, Yamada Y.
  • Journal Title: J Bone Miner Res. Volume: 32 Issue: 3 Pages: 601-610
  • DOI: 10.1002/jbmr.3024
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] Role of the matricellular protein Fibulin-7 in glioblastoma vascularization (2019)
  • Author(s): Susana de Vega, Akihide Kondo, Mario Suzuki, Hajime Arai, Shabierjiang Jiapaer, Hemragul Sabit, Mitsutoshi Nakada, Tomoko Ikeuchi, Muneaki Ishijima, Eri Arikawa-Hirasawa, Yoshihiko Yamada and Yasunori Okada
  • Organizer: The Matricellular Proteins in Tissue Remodeling and Inflammation Conference
  • Int'l Joint Research
• [Presentation] Fibulin-7 modulates glioblastoma neovascularization via regulation of the Ang1/Ang2-Tie2 system (2019)
  • Author(s): Susana de Vega, Mitsutoshi Nakada, and Yasunori Okada
  • Organizer: 第78回 日本癌学会学術総会
• [Presentation] Understanding the Challenges in Glioblastoma Treatment (2019)
  • Author(s): Susana de Vega, Yasunori Okada
  • Organizer: Ⅱ Encuentro de ACE Japon (II Meeting of Spanish Researchers in Japan
• [Presentation] Fibulin-7 overproduction contributes to glioma vascularization via interaction with angiopoietin-1 (2018)
  • Author(s): Susana de Vega, Akihide Kondo, Mario Suzuki, Eri Arikawa-Hirasawa and Yasunori Okada
  • Organizer: 第107回日本病理学会総会
  • Int'l Joint Research
• [Presentation] Overexpression of Fibulin-7 Modulates the Ang1-Tie2 System and Contributes to the Aberrant Vasculature in Glioblastoma (2018)
  • Author(s): Susana de Vega, Akihide Kondo, Mario Suzuki, Eri Arikawa-Hirasawa, Yasunori Okada
  • Organizer: Matrix Biology Europe
  • Int'l Joint Research
• [Presentation] Fibulin-7, a non-elastogenic short fibulin, modulates the abnormal vascularization in glioblastoma brain tumo (2018)
  • Author(s): Susana de Vega
  • Organizer: 第２回エラスチン・関連分子研究会学術集会出張報告書
  • Invited
• [Presentation] Analysis of the expression and prospective role of Fibulin-7 in aberrant blood vessel formation in glioblastoma (2017)
  • Author(s): Susana de Vega, Akihide Kondo, Mario Suzuki, Eri Arikawa-Hirasawa and Yasunori Okada
  • Organizer: 第49回日本結合組織学会学術大会抄録