Osteosarcoma therapeutic strategy targeting anticancer drug resistance by mitochondrial transfer
Project/Area Number |
20K21659
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Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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Allocation Type | Multi-year Fund |
Review Section |
Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
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Research Institution | Nara Medical University |
Principal Investigator |
國安 弘基 奈良県立医科大学, 医学部, 教授 (00253055)
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Co-Investigator(Kenkyū-buntansha) |
谷 里奈 奈良県立医科大学, 医学部, 講師 (20783872)
岸 真五 奈良県立医科大学, 医学部附属病院, 研究員 (50790341)
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Project Period (FY) |
2020-07-30 – 2024-03-31
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Project Status |
Completed (Fiscal Year 2023)
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Budget Amount *help |
¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2022: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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Keywords | 骨肉腫 / ミトトランスファー / 薬剤耐性 / 幹細胞性 / NFkBシグナル / HKGB1 / ミトコンドリア / ミトコンドリアトランスファー / HMGB1 / がん細胞 / ミトコンドリア移行 / 化学療法 / 間葉系幹細胞 |
Outline of Research at the Start |
本研究では、抗がん剤処理を受けた骨肉腫細胞が間葉系幹細胞からミトコンドリア移行を受けることで、細胞死から免れ薬剤耐性を獲得するという現象の機序を解明し、その阻害法を発見することによりより有効な骨肉腫治療を可能にする。骨肉腫は、化学療法や分子標的治療の選択肢は未だに乏しく、手術的病変摘出への根治性の高い要求から機能温存に高いハードルが存在する。化学療法の奏効性を高めることは、骨肉腫に罹患する多くの若年者の身体機能の保全を可能にし、将来の社会的活動を担保することにつながると期待される。
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Outline of Annual Research Achievements |
本年度は、ヒト骨肉腫細胞を用いて、ミトトランスファーについて検討を行った。HMGB1は核内タンパクであるが、細胞障害に伴い酸化されて放出され、損傷組織での炎症、組織修復に関与する。悪性腫瘍においても抗がん剤治療後のがん組織にMSCを誘引し癌細胞の生存に寄与することが報告されているがその機序は明らかでない。Doxorubicin(DOX)およびCisplatin(CDDP)によって腫瘍細胞から放出される酸化型のHMGB1が、間葉系幹細胞(MSC)から骨肉腫細胞へのmitochondria移行(mitochondria transfer、MT)を誘導し耐性に寄与することを見出した。ヒト骨肉腫細胞SaOS2, U2OSとMSCを共培養し、DXR,CDDPで処理したところMTがcontrolに比べ、優位に誘導された。この時腫瘍内のmitochondria由来活性酸素は減少し、腫瘍細胞の耐性化がみられた。次にHMGB1抗体を作成した。SaOS2, U2OS骨肉腫細胞株を用いてこの抗体がHMGB1を中和するか検討した。骨肉腫細胞株をDOXで処理したところ上清のHMGB1濃度が上昇し、抗体を低下したことからDOX(1μM)によってHMGB1が放出され、抗体で中和されていると考えられた。この抗HMGB1抗体は抗がん剤処理時のMTの誘導を著しく抑制した。またこの際、MSCによるROSの減少、抗がん剤耐性が解除された。Mitochondria transferはdonor細胞のMiro1, Cx43の発現量と相関した。最後にMSCを還元型HMGB1及び酸化型HMGB1で処理したところ酸化型HMGB1でのみMT関連遺伝子の発現上昇が確認された。今回の結果から化学療法時の障害で放出される酸化型HMGB1が、MSCによるMTを誘導し抗がん剤抵抗性に寄与すると考えられた。
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Report
(4 results)
Research Products
(61 results)
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[Journal Article] Short telomere lesions with dysplastic metaplasia histology may represent precancerous lesions of Helicobacter pylori-positive gastric mucosa2023
Author(s)
Fujiwara-Tani R, Takagi T, Mori S, Kishi S, Nishiguchi Y, Sasaki T, Ikeda M, Nagai K, Bhawal UK, Ohmori H, Fujii K, Kuniyasu H
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Journal Title
International Journal of Molecular Sciences
Volume: 24(4)
Issue: 4
Pages: 3182-3182
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Role of creatine shuttle in colorectal cancer cells2023
Author(s)
Kita Mayu、Fujiwara-Tani Rina、Kishi Shingo、Mori Shiori、Ohmori Hitoshi、Nakashima Chie、Goto Kei、Sasaki Takamitsu、Fujii Kiyomu、Kawahara Isao、Bhawal Ujjal Kumar、Luo Yi、Kuniyasu Hiroki
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Journal Title
Oncotarget
Volume: 14
Issue: 1
Pages: 485-501
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Role of Glycated High Mobility Group Box-1 in Gastric Cancer2021
Author(s)
Kishi Shingo、Nishiguchi Yukiko、Honoki Kanya、Mori Shiori、Fujiwara-Tani Rina、Sasaki Takamitsu、Fujii Kiyomu、Kawahara Isao、Goto Kei、Nakashima Chie、Kido Akira、Tanaka Yasuhito、Luo Yi、Kuniyasu Hiroki
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Journal Title
International Journal of Molecular Sciences
Volume: 22
Issue: 10
Pages: 5185-5185
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Safety and efficacy of an anti-claudin-5 monoclonal antibody to increase blood-brain barrier permeability for drug delivery to the brain in a non-human primate2021
Author(s)
Tachibana K, Hashimoto Y, Shirakura K, Okada Y, Hirayama R, Iwashita Y, Nishino I, Ago Y, Takeda H, Kuniyasu H, Kondoh M
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Journal Title
Journal of Controlled Release
Volume: 336
Pages: 105-111
DOI
Related Report
Peer Reviewed
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[Journal Article] BRAF Mutation Is Associated with Hyperplastic Polyp-Associated Gastric Cancer2021
Author(s)
Fujiwara-Tani Rina、Okamoto Ayaka、Katsuragawa Hiroyuki、Ohmori Hitoshi、Fujii Kiyomu、Mori Shiori、Kishi Shingo、Sasaki Takamitsu、Nakashima Chie、Kawahara Isao、Hojo Yudai、Nishiguchi Yukiko、Mori Takuya、Mizumoto Takeshi、Nagai Kenta、Luo Yi、Kuniyasu Hiroki
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Journal Title
International Journal of Molecular Sciences
Volume: 22
Issue: 23
Pages: 12724-12724
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Anti-stem cell property of pterostilbene in gastrointestinal cancer cells.2020
Author(s)
Mori S, Kishi S, Honoki K, Fujiwara-Tani R, Moriguchi T, Sasaki T, Fujii K, Tsukamoto S, Fujii H, Kido A, Tanaka Y, Luo Y, Kuniyasu H.
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Journal Title
Int J Mol Sci.
Volume: 21
Issue: 24
Pages: 9347-9347
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Effect of Proton Pump Inhibitors on Colorectal Cancer2020
Author(s)
Sasaki Takamitsu、Mori Shiori、Kishi Shingo、Fujiwara-Tani Rina、Ohmori Hitoshi、Nishiguchi Yukiko、Hojo Yudai、Kawahara Isao、Nakashima Chie、Fujii Kiyomu、Luo Yi、Kuniyasu Hiroki
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Journal Title
International Journal of Molecular Sciences
Volume: 21
Issue: 11
Pages: 3877-3877
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Role of Nuclear Claudin-4 in Renal Cell Carcinoma2020
Author(s)
Owari Takuya、Sasaki Takamitsu、Fujii Kiyomu、Fujiwara-Tani Rina、Kishi Shingo、Mori Shiori、Mori Takuya、Goto Kei、Kawahara Isao、Nakai Yasushi、Miyake Makito、Luo Yi、Tanaka Nobumichi、Kondoh Masuo、Fujimoto Kiyohide、Kuniyasu Hiroki
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Journal Title
International Journal of Molecular Sciences
Volume: 21
Issue: 21
Pages: 8340-8340
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Malic enzyme 1 is associated with tumor budding in oral squamous cell carcinomas.2020
Author(s)
Nakashima C, Kirita T, Yamamoto K, Mori S, Luo Y, Sasaki T, Fujii K, Ohmori H, Kawahara I, Mori T, Goto K, Kishi S, Fujiwara-Tani R, Kuniyasu H
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Journal Title
Int J Mol Sci
Volume: 21
Issue: 19
Pages: 7149-7149
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Clostridium perfringens enterotoxin induced claudin-4 to activate YAP in oral squamous cell carcinomas.2020
Author(s)
Nakashima C, Yamamoto K, Kishi S, Sasaki T, Ohmori H, Fujiwara-Tani R Mori S, Kawahara I, Nishiguchi Y, Mori T, Kondoh M, Luo Y, Kirita T, Kuniyasu H
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Journal Title
Oncotarget
Volume: 11
Issue: 4
Pages: 309-321
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Safety assessment of modifying the blood-brain barrier by targeting claudin-5 in a cynomolgus monkey model.2023
Author(s)
Kuzu T, Hashimoto Y, Wakayama E, Nishino I, Tachibana K, Okada Y, Hirayama R, Kuniyasu H, Kondoh M
Organizer
Society of Toxicology (SOT) 62nd Annual Meeting and ToxExpo, Nashville, Tennessee, USA, 2023.3.19-23
Related Report
Int'l Joint Research
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[Presentation] Caprylic acid alleviates cachexia-induced myocardial damage by inhibiting HMGB1 via ketone body.2023
Author(s)
Nukaga S, Rina Fujiwara-Tani R, Miyagawa Y, Kawahara I, Nishida R, Mori T, Goto K, Kishi S, Mori S, Fujii K, Ohmori H, Kuniyasu H
Organizer
MASCC 2023 Annual Meeting, Nara, Japan, 2023.6.22-24
Related Report
Int'l Joint Research
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[Presentation] Lovastatin induces novel cell death due to impaired mitochondria iron utilization specifically in osteosarcoma cells.2023
Author(s)
Kishi S, Mori S, Honoki K, Fujii H, Tsukamoto S, Sasagawa S, Nakagawa H, Kuniyasu H, Tanaka Y
Organizer
Annual Meeting of Connective Tissue Oncology Society, Dublin, Ireland, 2023.11.1-4
Related Report
Int'l Joint Research
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[Presentation] The creatine kinase is a metabolic vulnerability in Osteosarcoma.2020
Author(s)
Kishi S, Mori S, Fujiwara-Tani R, Hojo Y, Owar T, Mori T, Nukaga S, Kita M, Sasaki R, Honoki K, Kuniyasu H
Organizer
79th Annual Meeting of Japanese Association for Cancer
Related Report
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[Presentation] Effects of medium-chain fatty acids on cancer-derived myocardial atrophy2020
Author(s)
Nukaga S, Mori T, Luo Y, Kawahara I, Miyagawa Y, Goto K, Fujiwara-Tani R, Kishi S, Mori S, Ohmori H, Kuniyasu H
Organizer
79th Annual Meeting of Japanese Association for Cancer
Related Report
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