Identification of novel therapeutic targets to block crosstalk of Wnt/Shh/Hypoxia-pathway feedforward loops in glioblastoma stem cells
| Project/Area Number |
16K08722
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | Kyoto Pharmaceutical University |
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Principal Investigator |
Nakata Susumu 京都薬科大学, 薬学部, 准教授 (80590695)
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| Co-Investigator(Kenkyū-buntansha) |
藤田 貢 近畿大学, 医学部, 准教授 (40609997)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | 膠芽腫幹細胞 / Wnt経路 / 低酸素応答シグナル / Shh経路 / シグナル間クロストーク / 膠芽腫 / 幹細胞 / がん幹細胞 / 膠芽種幹細胞 / 低酸素 / Wntシグナル / Shhシグナル / マウス発がんモデル |
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| Outline of Final Research Achievements |
Stat5b has been identified as a candidate for a novel therapeutic target, which is regulated by both Wnt and hypoxia responsible signaling pathways as a hub-gene in glioblastoma stem cells derived from a transposon-induced mouse model. On the other hand, it has also been clarified that the activity of the Shh pathway, which is maintained by Gli2 expression, forms a feedforward loop that activates Wnt pathway, by the signal crosstalk, in the shTP53/NRasG12V/EGFRvIII-driven glioblastoma stem cells, thereby promotes expansion of the glioblastoma stem cell population. The upregulation of Gli2 is maintained by a novel factor that regulates homeostasis of redox metabolism. These findings would be usuful for a development of a novel strategy targeting Stat5b or Gli2 to improve treatment for patients with glioblastoma.
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| Academic Significance and Societal Importance of the Research Achievements |
成人に最も多い脳腫瘍である膠芽腫は極めて予後不良な疾患であり、このような難治性癌は現在も深刻な問題として取り残されている。特に膠芽腫癌幹細胞を制御する因子や経路等の相互関係性や、特に階層性については不明な点が多いのが現状である。本研究により、複数の幹細胞制御機構のシグナルが集中するハブ遺伝子としての性質を有する新規治療標的分子の候補として、Stat5bおよびGli2を見出した。これらの因子を阻害することができれば、Wnt経路、Shh経路、低酸素応答シグナル等を一度に阻害することが出来ることが期待でき、より効率的に膠芽腫幹細胞を阻害できる、これまでにない新しい治療戦略に繋がる可能性がある。
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Report
(4 results)
Research Products
(39 results)
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[Journal Article] Bone-marrow-derived microglia-like cells ameliorate brain amyloid pathology and cognitive impairment in a mouse model of Alzheimer's disease.2018
Author(s)
Kawanishi S., Takata K., Itezono S., Nagayama H., Konoya S., Chisaki Y., Toda Y., Nakata S., Yano Y., Kitamura Y., Ashihara E.
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Journal Title
J. Alzheimer’s Dis.
Volume: 64
Issue: 2
Pages: 563-585
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A real time near-infrared imaging method for the detection of oral cancers in mice using an indocyanine green-labeled podoplanin antibody2018
Author(s)
Akihiro Ito, Mitsuhiko Ohta, Yukinari Kato, Shunko Inada, Toshio Kato, Susumu Nakata, Yasushi Yatabe, Mitsuo Goto, Norio Kaneda, Kenichi Kurita, Hayao Nakanishi, and Kenji Yoshida
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Journal Title
Technology in Cancer Research & Treatments
Volume: 17
Pages: 1-11
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A Novel Prodrug of a γ-Glutamylcyclotransferase Inhibitor Suppresses Cancer Cell Proliferation in vitro and Inhibits Tumor Growth in a Xenograft Mouse Model of Prostate Cancer.2018
Author(s)
Ii H, Yoshiya T, Nakata S, Taniguchi K, Hidaka K, Tsuda S, Mochizuki M, Nishiuchi Y, Tsuda Y, Ito K, Kageyama S, Yoshiki T.
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Journal Title
ChemMedChem.
Volume: 13
Issue: 2
Pages: 155-163
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] CG13250, a novel bromodomain inhibitor, suppresses proliferation of multiple myeloma cells in an orthotopic mouse model.2017
Author(s)
Natsuki Imaysohi, Makoto Yoshioka, Jay Chauhan, Susumu Nakata, Yuki Toda, Steven Fletcher, Jeffrey Strovel, Kazuyuki Takata, and Eishi Ashihara.
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Journal Title
Biochem. Biophys. Res. Commun.
Volume: 484
Issue: 2
Pages: 262-268
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] A novel prodrug of γ-glutamylcyclotransferase inhibitor has anti-proliferative activity in vitro and anti-cancer activity in vivo.2018
Author(s)
Hiromi Ii, Taku Yoshiya, Susumu Nakata, Keiko Taniguchi, Koushi Hidaka, Shugo Tsuda, Masayoshi Mochizuki, Yuji Nishiuchi, Yuko Tsuda, Kosei Ito, Susumu Kageyama, Tatsuhiro Yoshiki
Organizer
20th international conference on medicinal chemistry & rational drugs
Related Report
Int'l Joint Research
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