Identification of molecules that suppressed osteoclastgenesis in extracellular vesicles derived from osteosarcoma cells
| Project/Area Number |
19K18529
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 56020:Orthopedics-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
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| Keywords | 骨肉腫 / 破骨細胞 / エクソソーム / マイクロRNA / 転移 / 骨微小環境の変化 / TRAF6 / miRNA146a-5p / 弾性線維関連蛋白 / NFATc1 / NFκB / IκBα / リン酸化抑制 / 血管新生 / 肺転移 / 骨肉腫由来エクソソーム |
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| Outline of Research at the Start |
骨髄環境の恒常性を維持している破骨細胞は骨肉腫細胞の存在下にその分化が抑制されて数が減少し、さらにその状況下に肺転移が促進されていることが報告されている。一方、骨肉腫など希少がんの腫瘍細胞がエクソソームの分泌を介してどのように生体内の細胞と情報伝達しているかについてはほとんど知られていない。そこで、骨肉腫細胞由来エクソソームが、骨髄環境の恒常性維持のために働いている破骨細胞にどのような分子や機序を通じてがん細胞の進展・環境形成に寄与しているかを解明することで、破骨細胞の分化を維持し、肺転移の抑制につながる骨肉腫の新たな治療戦略の可能性を探索する。
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| Outline of Final Research Achievements |
In an orthotopic implantation study, we found that osteosarcoma-derived SEVs had the potential to enhance metastases and angiogenesis. In addition, osteosarcoma derived SEVs decreased the number of mature osteoclasts in vivo. In vitro osteoclastogenesis studies revealed that the inhibition of osteoclast maturation by osteosarcoma‐derived SEVs was mediated by suppressing the NFκB signal pathway. MicroRNA analysis of SEVs from different malignant human osteosarcomas revealed that miR-146a-5p was involved in the inhibition of osteoclastogenesis. In osteosarcoma patients, lower numbers of osteoclasts in biopsy specimens were correlated with higher malignancy. These findings indicated that osteosarcoma-derived SEVs enhance distant metastasis of osteosarcomas by inhibiting osteoclast maturation, which may be a useful prognostic marker. This diagnostic method may enable to predict malignancy at early stage, and help to provide optimal care to patients with risk of high malignancy.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究により，骨肉腫の進展に細胞外小胞が深く関与しており，その産生を抑えることで，腫瘍の浸潤・転移を抑えることができる可能性が示されました。今後，骨肉腫の早期発見や予後診断，新たな治療法の開発へと研究が発展することが期待されます。
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Report
(3 results)
Research Products
(8 results)
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[Journal Article] Osteosarcoma-Derived Small Extracellular Vesicles Enhance Tumor Metastasis and Suppress Osteoclastogenesis by miR-146a-5p2021
Author(s)
Yoshihiro Araki, Hisaki Aiba, Takeshi Yoshida, Norio Yamamoto, Katsuhiro Hayashi, Akihiko Takeuchi, Shinji Miwa, Kentaro Igarashi, Tuan D. Nguyen, Kiyo-aki Ishii, Takayuki Nojima, Satoru Takahashi, Hideki Murakami, Hiroyuki Tsuchiya and Rikinari Hanayama
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Journal Title
Frontiers in Oncology
Volume: 11
Pages: 667109-667109
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Presentation] Molecular mechanism for suppression of osteoclastogenesis by osteosarcoma cell-derived extracellular vesicles2021
Author(s)
Yoshihiro Araki, Norio Yamamoto, Katsuhiro Hayashi, Akihiko Takeuchi, Shinji Miwa, Kentaro Igarashi, Takashi Higuchi, Kensaku Abe, Yuta Taniguchi, Hirotaka Yonezawa, Sei Morinaga, Yohei Asano, Hiroyuki Tsuchiya
Organizer
13th Asia Pacific Musculoskeletal Tumor Society
Related Report
Int'l Joint Research
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