Anti-angiogenic therapy for glioma beyond VEGF inhibition based on tumor microenvironment

• Project/Area Number: 24390339
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cerebral neurosurgery
• Research Institution: University of Tsukuba
• Principal Investigator: TAKANO Shingo 筑波大学, 附属病院, 病院講師 (50292553)
• Co-Investigator(Kenkyū-buntansha): KUBOTA YOshinori 慶應義塾大学, 医学部, 教授 (50348687) ; YAMASHITA Toshiharu 筑波大学, 医学医療系, 助教 (50400677) ; EMA Masatsugu 滋賀医科大学, 動物生命科学研究センター, 教授 (60359578) ; 加藤 幸成 山形大学, 医学部, 准教授 (00571811)
• Project Period (FY): 2012-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000); Fiscal Year 2014: ¥6,110,000 (Direct Cost: ¥4,700,000、Indirect Cost: ¥1,410,000); Fiscal Year 2013: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2012: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 神経膠腫 / 血管新生 / 微小環境 / 周皮細胞 / RANTES / VEGF / 神経血管ワイアリング / SDF1 / グリオーマ / 内皮細胞 / 管腔形成 / 血管密度 / 予後因子 / 脳腫瘍 / 血管新生抑制 / ペプチド療法 / 間葉系幹細胞 / 腫瘍幹細胞 / IDH1 / 微小血管内皮細胞 / 悪性脳腫瘍 / 膠芽種 / 遺伝子発現

Outline of Final Research Achievements

Crosstalk between tumor cells and cells composed of tumor microenvironment as well as endothelial cells is important for glioma angiogenesis. Glioma angiogenesis evaluated by endothelial cell tube formation induced by glioma conditioned medium. Glioma tube formation was stimulated by tumor stem cell, mesenchymal stem cell and pericyte. The target molecules for stimulation of tube formation were determined RANTES, but not SDF-1. Further studies, such as RANTES targeted animal study and new crosstalk molecule, neurovascular wiring molecule are needed for clinical use of these molecules as antiangiogenic agent.

Research Products

• [Journal Article] Diagnostic advantage of double immunohistochemistry using two mutation-specific anti-IDH antibodies (HMab-1 and MsMab-1) in gliomas. (2015)
  • Author(s): Takano S, Kato Y, Yamamoto T, Liu X, Ishikawa E, Kaneko MK, Ogasawara S, Matsuda M, Noguchi M, Matsumura A.
  • Journal Title: Brain Tumor Pathol. Volume: 32 Issue: 3 Pages: 169-175
  • DOI: 10.1007/s10014-015-0214-8
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Improvement of long-term results with neoadjuvant chemotherapy and radiotherapy for central nervous system germinoma (2015)
  • Author(s): Takano S, Yamamoto T, Ishikawa E, Akutsu H, Nakai K, Matsuda M, Muroi A, Shibata Y, Mizumoto M, Tsuboi K, Matsumura A
  • Journal Title: World Neurosurgery Volume: 84 Issue: 3 Pages: 846-854
  • DOI: 10.1016/j.wneu.2015.06.029
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neuroendoscopy followed by radiotherapy in cystic craniopharyngiomas-a long-term follow-up (2015)
  • Author(s): Takano S, Akutsu H, Mizumoto M, Yamamoto T, Tsuboi K, Matsumura A
  • Journal Title: World Neurosurgery Volume: 84 Issue: 5 Pages: 1305-1315
  • DOI: 10.1016/j.wneu.2015.06.022
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A high-sensitive HMab-2 specifically detects IDH1-R132H, the most common IDH mutation in gliomas (2015)
  • Author(s): Fujii Y, Ogasawara S, Oki H, Liu X, Kaneko MK, Takano S, Kato Y
  • Journal Title: Biochem Biophys Res Commun. Volume: 466 Issue: 4 Pages: 733-739
  • DOI: 10.1016/j.bbrc.2015.09.070
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Diagnostic advantage of double immunohistochemistry using two mutation-specific anti-IDH antibodies (HMab-1 and MsMab-1) in gliomas (2015)
  • Author(s): Takano S, Kato Y, Yamamoto T, Liu X, Ishikawa E, Kaneko MK, Ogasawara S, Matsuda M, Noguchi M, Matsumura A
  • Journal Title: Brain Tumor Pathol 2015 Feb 5. [Epub ahead of print] Volume: 2
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Interferon-β inhibits glioma angiogenesis through downregulation of vascular endothelial growth factor and upregulation of interferon inducible protein 10 (2014)
  • Author(s): 1.Takano S, Ishikawa E, Matsuda M, Yamamoto T, Matsumura A
  • Journal Title: Int J Oncol Volume: 45 Issue: 5 Pages: 1837-1846
  • DOI: 10.3892/ijo.2014.2620
  • NAID: 120007136594
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Bevacizumab in Japanese Patients with Malignant Glioma from Basic Research to Clinical Trial (2014)
  • Author(s): Takano S, Ishikawa E, Nakai K, Matsuda M, Masumoto T, Yamamoto T, Matsumura A
  • Journal Title: OncoTargets Ther 7: 1551-1562, 2014 Volume: 7 Pages: 1551-1562
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Correlations of vascular architecture and angiogenesis with pituitary adenoma histotype (2014)
  • Author(s): Takano S, Akutsu H, Hara T, Yamamoto T, Matsumura A
  • Journal Title: Int J Endocrinol vol. 2014, Article ID 989574, 12 pages, 2014. Volume: 1 Pages: 1-12
  • DOI: 10.1155/2014/989574
  • NAID: 120007136544
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] CXCL12 secreted from glioma stem cells regulates their proliferation (2014)
  • Author(s): Uemae Y, Ishikawa E, Osuka S, Matsuda M, Sakamoto N, Takano S, Nakai K, Yamamoto T, Matsumura A
  • Journal Title: J Neurooncol Volume: 117 Pages: 43-51
  • Peer Reviewed
• [Journal Article] Umbilical cord blood-derived mesenchymal stem cells inhibit, but adipose tissue-derived mesenchymal stem cells promote, glioblastoma multiforme proliferation (2013)
  • Author(s): Akimoto K, Kimura K, Nagano M, Takano S, To'a Salazar G, Yamashita T, Ohneda O.
  • Journal Title: Stem Cells Dev Volume: 22 Issue: 9 Pages: 1370-1386
  • DOI: 10.1089/scd.2012.0486
  • Peer Reviewed
• [Journal Article] Establishment of novel monoclonalantibodies KMab-1 and MMab-1 specificfor IDH2 mutations (2013)
  • Author(s): Kaneko MK, MoritaS, Tsujimoto Y, Yanagiya R, Nasu K,Sasaki H, Hozumi Y, Goto K, Natsume A,Watanabe M, Kumabe T, Takano S, KatoY
  • Journal Title: Biochem Biophys Res Commun Volume: 1;432(1) Issue: 1 Pages: 40-5
  • DOI: 10.1016/j.bbrc.2013.01.088
  • Peer Reviewed
• [Journal Article] IGF1 Receptor Signaling Regulates Adaptive Radioprotection in Glioma Stem Cells (2013)
  • Author(s): Osuka S, Sampetrean O, Shimizu T, Saga I, Onishi N, Sugihara E, Okubo J, Fujita S, Takano S, Matsumura A, Saya H
  • Journal Title: Stem Cells. 2013 Jan 17. 8. [Epub ahead of print] PMID: 23335250 Volume: 31 Issue: 9 Pages: 627-640
  • DOI: 10.1002/stem.132
  • Peer Reviewed
• [Journal Article] Decrease in the apparent diffusion coefficient in peritumoral edema for the assessment of recurrent glioblastoma treated by bevacizumab (2013)
  • Author(s): Takano S, Kimu H, Tsuda K, Osuka S, Nakai K, Yamamoto T, Ishikawa E, Akutsu H, Matsuda M, Matsumura A
  • Journal Title: Acta Neurochir Suppl Volume: 118 Pages: 185-189
  • DOI: 10.1007/978-3-7091-1434-6_34
  • ISBN: 9783709114339, 9783709114346
  • Peer Reviewed
• [Presentation] 悪性神経膠腫におけるポドプラニン発現・IDH変異・Aktシグナルによる予後解析 (2015)
  • Author(s): 高野晋吾、石川栄一、松田真秀、加藤幸成、山本哲哉、松村 明
  • Organizer: 第33回日本脳腫瘍学会
  • Place of Presentation: グランドプリンスホテル京都（京都府京都市）
  • Year and Date: 2015-12-06
• [Presentation] 血管内皮増殖因子（VEGF）/低酸素誘導因子（HIF1）発現はIDH変異とは独立したグリオーマの予後因子である (2015)
  • Author(s): 高野晋吾、石川栄一、松田真秀、中井 啓、阿久津博義、山本哲哉、加藤幸成、松村 明
  • Organizer: 第74回日本脳神経外科学会総会
  • Place of Presentation: ロイトン札幌（北海道札幌市）
  • Year and Date: 2015-10-14
• [Presentation] Podoplanin expression combined with IDH mutation as a prognostic factor with high grade gliomas (2015)
  • Author(s): 高野晋吾、石川栄一、松田真秀、金子美華、加藤幸成
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-08
• [Presentation] 悪性神経膠腫におけるポドプラニン発現・IDH変異・Aktシグナルによる予後解析 (2015)
  • Author(s): 高野晋吾、石川栄一、松田真秀、加藤幸成、山本哲哉、松村 明
  • Organizer: 第16回分子脳神経外科学会
  • Place of Presentation: アクアシテイ浜松コングレスセンター（静岡県浜松市）
  • Year and Date: 2015-08-29
• [Presentation] 分子診断によるgrade IIIグリオーマの予後解析 (2015)
  • Author(s): 高野晋吾、山本哲哉、石川栄一、坂本則影、松田真秀、中井 啓、阿久津博義、加藤幸成、松村 明
  • Organizer: 第33回日本脳腫瘍病理学会
  • Place of Presentation: JRホテルクレメント高松（香川県高松市）
  • Year and Date: 2015-05-29
• [Presentation] Improvement of long term results with adjuvant chemoradiation therapy for central nervous system germinoma (2015)
  • Author(s): Shingo Takano, Tetsuya Yamamoto, Eiichi Ishikawa, Hiroyoshi Akutsu, Kei Nakai, Masahide Matsuda, Ai Muroi, Yasushi Shibata, Masashi Mizumoto, Koji Tsuboi, Akira Matsumura
  • Organizer: The 4th International CNS Germ Cell Tumour Symposium
  • Place of Presentation: 八芳園（東京都港区）
  • Year and Date: 2015-04-12
  • Int'l Joint Research
• [Presentation] 下垂体腺種の組織型による血管新生と血管構築の関係 (2015)
  • Author(s): 高野晋吾、阿久津博義、原 拓真、山本哲哉、松村 明:
  • Organizer: 第25回間脳下垂体学会
  • Place of Presentation: 京都
  • Year and Date: 2015-02-27
• [Presentation] グリオーマにおける可溶性VEGFレセプター（sFlt-1）の役割 (2014)
  • Author(s): 高野晋吾、石川栄一、松田真秀、山本哲哉、松村 明
  • Organizer: 第32回日本脳腫瘍学会
  • Place of Presentation: 舞浜
  • Year and Date: 2014-11-30
• [Presentation] ベバシズマブにより予後改善する膠芽腫 (2014)
  • Author(s): 高野晋吾、中井 啓、石川栄一、松田真秀、室井 愛、増本智彦、山本哲哉、松村 明
  • Organizer: 第73回脳神経外科学会総会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-10
• [Presentation] Cnetral neurocytomaの血管新生能 (2014)
  • Author(s): 杉井成志、高野晋吾、山本哲哉、石川栄一、阿久津博義、松田眞秀、坂本規影、増本智彦、松村 明
  • Organizer: 第32回脳腫瘍病理学会
  • Place of Presentation: 徳島
  • Year and Date: 2014-05-23