Development of precision medicine to control the microenvironment in glioma stem cells.

• Project/Area Number: 18K08998
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Saga University
• Principal Investigator: Abe Tatsuya 佐賀大学, 医学部, 教授 (40281216)
• Co-Investigator(Kenkyū-buntansha): 増岡 淳 佐賀大学, 医学部, 准教授 (50359949) ; 中原 由紀子 佐賀大学, 医学部, 講師 (50380770)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 脳腫瘍 / 遺伝子 / 治療 / 微小環境制御 / 幹細胞 / precision medicine / 非対称分裂 / NDRG1 / 分子標的治療 / 腫瘍幹細胞 / 分子標的薬 / 微小環境

Outline of Final Research Achievements

Malignant glioma showed treatment resistance due to various factors including hypoxic microenvironment and glioma stem cells. We isolated glioma stem cells in patients with glioblastoma (GBM) and examined the genetic changes under hypoxic condition. We found the gaining diversity under microenvironment and possible novel mechanism to utilize microenvironment in glioma stem cells. Above all, we examined both molecular mechanism of asymmetric cell division in glioma stem cells and NDRG1-dependent antitumor effects, suggesting the clinical benefits of NDRG1-targeted therapeutics against GBM.

Academic Significance and Societal Importance of the Research Achievements

悪性脳腫瘍は予後不良な疾患である。これまで様々な治療が行われてきたが、極めて治療抵抗性である。そこで、我々は腫瘍幹細胞株を単離・樹立していく過程で、NDRG1遺伝子に着目し研究を推進させた。この遺伝子は膠芽腫の予後を左右する因子でありこれまでにない切り口での治療法開発に結び付く可能性を見出せたことは、将来の治療発展に新展開をもたらすことが期待でき、学術的意義は極めて高いと考えられる。

Research Products

• [Journal Article] Bidirectional Regulation between NDRG1 and GSK3β Controls Tumor Growth and Is Targeted by Differentiation Inducing Factor-1 in Glioblastoma (2020)
  • Author(s): Ito Hiroshi、Watari Kosuke、Shibata Tomohiro、Miyamoto Tomofumi、Murakami Yuichi、Nakahara Yukiko、Izumi Hiroto、Wakimoto Hiroaki、Kuwano Michihiko、Abe Tatsuya、Ono Mayumi
  • Journal Title: Cancer Research Volume: 80 Issue: 2 Pages: 234-248
  • DOI: 10.1158/0008-5472.can-19-0438
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BMP4 induces asymmetric cell division in human glioma stem-like cells (2020)
  • Author(s): Koguchi Motofumi、Nakahara Yukiko、Ito Hiroshi、Wakamiya Tomihiro、Yoshioka Fumitaka、Ogata Atsushi、Inoue Kohei、Masuoka Jun、Izumi Hideki、Abe Tatsuya
  • Journal Title: Oncology Letters Volume: 19 Pages: 1247-1254
  • DOI: 10.3892/ol.2019.11231
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic analysis in patients with newly diagnosed glioblastomas treated with interferon-beta plus temozolomide in comparison with temozolomide alone (2020)
  • Author(s): Natsume A, Nagane M, Wakabayashi T, et al.
  • Journal Title: J Neurooncol Volume: May 4 Issue: 1 Pages: 17-27
  • DOI: 10.1007/s11060-020-03505-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Boron Neutron Capture Therapy and Photodynamic Therapy for High-Grade Meningiomas (2020)
  • Author(s): Nakahara Y, Ito H, Masuoka J, Abe T
  • Journal Title: Cancers (Basel) Volume: 12 Issue: 5 Pages: 1334-1334
  • DOI: 10.3390/cancers12051334
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between Pericytes in Intraplaque Neovessels and Magnetic Resonance Angiography Findings (2020)
  • Author(s): Ogata A, Wakamiya T, Nishihara M, Tanaka T, Mizokami T, Masuoka J, Momozaki N, Sakata S, Irie H, Abe T
  • Journal Title: Int. J. Mol. Sci Volume: 21 Issue: 6 Pages: 1980-1980
  • DOI: 10.3390/ijms21061980
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between extracranial internal carotid artery tortuosity and thromboembolic complications during coil embolization of anterior circulation ruptured aneurysms (2019)
  • Author(s): Ogata Atsushi、Suzuyama Kenji、Ebashi Ryo、Takase Yukinori、Inoue Kohei、Masuoka Jun、Yoshioka Fumitaka、Nakahara Yukiko、Abe Tatsuya
  • Journal Title: Acta Neurochirurgica Volume: 161 Issue: 6 Pages: 1175-1181
  • DOI: 10.1007/s00701-019-03903-7
  • Peer Reviewed / Open Access
• [Journal Article] Stabilization of vulnerable carotid plaques with proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab (2019)
  • Author(s): Ogata Atsushi、Oho Kazuhiko、Matsumoto Noriaki、Masuoka Jun、Inoue Kohei、Koguchi Motofumi、Yoshioka Fumitaka、Abe Tatsuya
  • Journal Title: Acta Neurochirurgica Volume: 161 Issue: 3 Pages: 597-600
  • DOI: 10.1007/s00701-019-03825-4
  • Peer Reviewed
• [Journal Article] Significance of simulated conventional images on dual energy CT after endovascular treatment for ischemic stroke (2019)
  • Author(s): Ebashi Ryo、Ogata Atsushi、Nishihara Masashi、Inoue Kohei、Yoshioka Fumitaka、Takase Yukinori、Masuoka Jun、Yakushiji Yusuke、Irie Hiroyuki、Hara Hideo、Abe Tatsuya
  • Journal Title: Journal of NeuroInterventional Surgery Volume: 印刷中 Issue: 9 Pages: 898-902
  • DOI: 10.1136/neurintsurg-2018-014486
  • Peer Reviewed
• [Journal Article] Status epilepticus induced by treatment with dopamine agonist therapy for giant prolactinoma: a case report (2019)
  • Author(s): Koguchi Motofumi、Nakahara Yukiko、Ebashi Ryo、Ogata Atsushi、Shimokawa Shoko、Masuoka Jun、Abe Tatsuya
  • Journal Title: Journal of Medical Case Reports Volume: 13 Issue: 1 Pages: 18-18
  • DOI: 10.1186/s13256-018-1939-x
  • Peer Reviewed / Open Access
• [Journal Article] Cushing’s Syndrome and Psychosis (2018)
  • Author(s): Fujii Yuka、Mizoguchi Yoshito、Masuoka Jun、Matsuda Yayoi、Abe Tatsuya、Anzai Keizo、Kunitake Yutaka、Tateishi Hiroshi、Inaba Takayoshi、Murakawa Toru、Kato Takahiro A.、Monji Akira
  • Journal Title: The Primary Care Companion For CNS Disorders Volume: 20 Issue: 5
  • DOI: 10.4088/pcc.18br02279
  • Peer Reviewed
• [Journal Article] Extensive spinal epidural immature teratoma in an infant: case report (2018)
  • Author(s): Yoshioka Fumitaka、Shimokawa Shoko、Masuoka Jun、Izaki Tomoko、Nakahara Yukiko、Kawashima Masatou、Sakata Shuji、Abe Tatsuya
  • Journal Title: Journal of Neurosurgery: Pediatrics Volume: 22 Issue: 4 Pages: 411-415
  • DOI: 10.3171/2018.4.peds17676
  • Peer Reviewed
• [Journal Article] Possible involvement of pericytes in intraplaque hemorrhage of carotid artery stenosis (2018)
  • Author(s): Tanaka Tatsuya、Ogata Atsushi、Masuoka Jun、Mizokami Taichiro、Wakamiya Tomihiro、Nakahara Yukiko、Inoue Kohei、Shimokawa Shoko、Yoshioka Fumitaka、Momozaki Nobuaki、Sakata Shuji、Abe Tatsuya
  • Journal Title: Journal of Neurosurgery Volume: 印刷中 Issue: 6 Pages: 1-7
  • DOI: 10.3171/2018.1.jns171942
  • Peer Reviewed
• [Journal Article] Effects of Surgery With Salvage Stereotactic Radiosurgery Versus Surgery With Whole-Brain Radiation Therapy in Patients With One to Four Brain Metastases (JCOG0504): A Phase III, Noninferiority, Randomized Controlled Trial (2018)
  • Author(s): Kayama Takamasa、Sato Shinya、Sakurada Kaori、et al
  • Journal Title: Journal of Clinical Oncology Volume: 36 Issue: 33 Pages: 3282-3289
  • DOI: 10.1200/jco.2018.78.6186
  • Peer Reviewed / Open Access
• [Journal Article] Elevation of autoantibody level against PDCD11 in patients with transient ischemic attack (2017)
  • Author(s): Yoshida Y, Wang H, Hiwasa T, Machida T, Takiguchi M, Iwadate Y, et al.
  • Journal Title: Oncotarget Volume: 9 Issue: 3 Pages: 8836-8848
  • DOI: 10.1007/s11060-018-2831-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Novel malleable forcipes for endoscopic assisted technique in pediatric brain tumors. (2020)
  • Author(s): Nakahara Y, Ito H, Yoshioka F, Inoue K, Ogata A, Masuoka J, Abe T
  • Organizer: The 19th International Symposium on Pediatric Neuro-Oncology,
  • Int'l Joint Research
• [Presentation] 阿部 竜也：遺伝子プロファイルと神経機能コネクトミクスに基づいた脳腫瘍手術戦略 (2020)
  • Author(s): 阿部 竜也
  • Organizer: 第38回日本脳腫瘍学会学術集会
• [Presentation] 運動機能のreorganizationにより摘出が可能であった中心前回の神経膠腫 (2020)
  • Author(s): 中原 由紀子,伊藤 寛,高口 素史,井上 浩平,増岡 淳,阿部 竜也
  • Organizer: 第25回日本脳腫瘍の外科学会
• [Presentation] Unruptured cerebral aneurysm and mortality in neurologically healthy adults: 8.7 years follow-up in the Kashima Scan Study. (2020)
  • Author(s): Ogata A, Yakushiji Y, Suzuyama K, Nishihara M, Nakajima J, Hirotsu T, Eriguchi M, Noguchi , Abe T, Hara H
  • Organizer: ESO-WSO
  • Int'l Joint Research
• [Presentation] 運動機能のreorganizationにより摘出が可能であった中心前回の神経膠腫． (2020)
  • Author(s): 中原 由紀子,伊藤 寛,高口 素史,井上 浩平,増岡 淳,阿部 竜也
  • Organizer: 第18回日本Awake Surgery学会
• [Presentation] BMP4 induces asymmetric cell division in human glioma stem-like cells (2019)
  • Author(s): Koguchi Motofumi、Nakahara Yukiko、Ito Hiroshi、Wakamiya Tomihiro、Yoshioka Fumitaka、Ogata Atsushi、Inoue Kohei、Masuoka Jun、Izumi Hideki、Abe Tatsuya
  • Organizer: Society of Neurooncology
  • Int'l Joint Research
• [Presentation] Hypoxic Microenvironment Detected by FRP-170 PET May Induce the Expression of Drug Resistance Genes in the Patient with Glioblastoma． (2018)
  • Author(s): Abe T.１）, Morisaki I.2), Momii Y2), Fudaba H.2), Fujiki M.2), Koguchi M.１), Ito H１),Wakamiya T.１),Wakimoto H.3) Nakahara Y.１）
  • Organizer: 23rd ANNUAL SCIENTIFIC MEETING AND EDUCATION DAY OF THE SOCIETY FOR NEURO-ONCOLOGY
  • Int'l Joint Research
• [Presentation] The efficacies and indication of direct carotid artery puncture for endovascular thrombectomy (2018)
  • Author(s): 劉 軒(Xuan Liu),田中 達也,桃﨑 宣明,緒方 敦之,増岡 淳,阿部 竜也
  • Organizer: 日中脳神経外科連盟第２回学術集会（第10回日中友好脳神経外科学会）
  • Int'l Joint Research
• [Presentation] NDRG1 を標的としたグリオブラストーマのGSK3β/AKT/S6 活性制御による新規治療研究 (2018)
  • Author(s): 伊藤 寛1、渡 公佑2、村上 雄一2,3、柴田 智博2、阿部 竜也1、小野 眞弓2
  • Organizer: 第22回日本がん分子標的治療学会学術集会
• [Presentation] NDRG1 を標的としたGSK3β/AKT/S6シグナル阻害を介するグリオブラストーマ治療研究 (2018)
  • Author(s): 伊藤 寛1,2,渡 公佑2,村上 雄一2,3,柴田 智博2,桑野 信彦3,阿部 竜也1,小野 眞弓2
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] BMP4 signaling はGlioma stem-like cell の非対称分裂を誘導し幹細胞性を阻害する (2018)
  • Author(s): 高口 素史1,泉 秀樹2,伊藤 寛1,吉岡 史隆1,井上 浩平1,緒方 敦之1,高瀬 幸徳1,下川 尚子1,中原 由紀子1,増岡 淳1,阿部 竜也1
  • Organizer: 第36回日本脳腫瘍学会学術集会
• [Presentation] 頸動脈プラーク内新生血管のペリサイトと放射線学的プラーク診断の関連性 (2018)
  • Author(s): 緒方 敦之1,若宮 富浩1,西原 正志2,田中 達也1,3,溝上 泰一朗4,増岡 淳1,中原 由紀子1,下川 尚子1,高瀬 幸徳1,井上 浩平1,吉岡 史隆1,桃﨑 宣明1,坂田 修治4,阿部 竜也1
  • Organizer: 第5回日本心血管脳卒中学会学術集会