Development of therapeutic methods targeting proliferation / metastasis induction by interaction between sarcoma and platelets and its molecular mechanism

• Project/Area Number: 18K09060
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: University of Yamanashi
• Principal Investigator: Ichikawa Jiro 山梨大学, 大学院総合研究部, 講師 (00456469)
• Co-Investigator(Kenkyū-buntansha): 波呂 浩孝 山梨大学, 大学院総合研究部, 教授 (10313264)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2019: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 骨軟部肉腫 / 血小板 / 転移 / 骨肉腫

Outline of Final Research Achievements

The purpose of this study is to elucidate the role of P2Y12 in the aggregation and activation of platelets due to osteosarcoma, and to connect it to treatment. Specifically, (1) the effect of a P2Y12 inhibitor (ticagrelor) on the aggregation and activation of osteosarcoma and platelets, (2) the effect of platelet activation on the growth, migration, and EMT of osteosarcoma, and (3) the possibility of new treatment with a P2Y12 inhibitor. Was examined. In (1), ticagrelor was found to have an inhibitory effect on osteosarcoma aggregation. (2) By adding ticagrelor to platelets. Suppression of cytokine release was observed when co-cultured with osteosarcoma. (3) The suppression of metastasis of osteosarcoma by ticagrelor was examined in a mouse model, but the suppression of metastasis could not be confirmed.

Academic Significance and Societal Importance of the Research Achievements

今回の実験では骨肉腫細胞を用いて行うが、一般に骨軟部肉腫は50種類以上の異なる疾患の総称で、各々の分子細胞学的特徴は異なる。ただ、ほとんどの症例で予後決定因子は肺転移の有無である。この点から転移における血小板の役割を解明することは肉腫治療全体への応用が可能と考えられた。更に、P2Y12阻害薬はすでに心筋梗塞や血栓症への治療薬として承認されている。すなわち、我々の仮説が証明されれば、実臨床への還元の可能性が非常に高く、停滞して肉腫治療を大きく変えられると考えていた。結果からはP2Y12はターゲットとならなかったが、それ以外にも血小板活性化機構は存在するため今後更なる検討を行って行きたい。

Research Products

• [Journal Article] Role of Platelet C-Type Lectin-Like Receptor 2 in Promoting Lung Metastasis in Osteosarcoma (2020)
  • Author(s): Jiro Ichikawa, Takashi Ando, Tomonori Kawasaki, Tomoyuki Sasaki, Toshiaki Shirai, Nagaharu Tsukiji, Yujiro Kimura, Kaoru Aoki, Keiko Hayakawa, Katsue Suzuki-Inoue, Masao Saitoh, Hirotaka Haro
  • Journal Title: Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research Volume: in press Issue: 9 Pages: 1738-1750
  • DOI: 10.1002/jbmr.4045
  • Peer Reviewed
• [Journal Article] Gemcitabine and Rapamycin Exhibit Additive Effect against Osteosarcoma by Targeting Autophagy and Apoptosis (2020)
  • Author(s): Ando Takashi、Ichikawa Jiro、Fujimaki Taro、Taniguchi Naofumi、Takayama Yoshihiro、Haro Hirotaka
  • Journal Title: Cancers Volume: 12 Issue: 11 Pages: 3097-3097
  • DOI: 10.3390/cancers12113097
  • Peer Reviewed / Open Access