Investigation of the molecular mechanisms underlying therapeutic resistance in osteosarcoma metastasis

• Project/Area Number: 15K06845
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Hoshi University
• Principal Investigator: SHIMIZU TAKATSUNE 星薬科大学, 薬学部, 准教授 (40407101)
• Research Collaborator: SAYA Hideyuki 慶應義塾大学, 医学部・先端医科学研究所・遺伝子制御研究部門, 教授 ; SOGA Tomoyoshi 慶應義塾大学, 先端生命科学研究所, 教授
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 骨肉腫 / 転移 / 治療抵抗性 / 転移巣 / がん微小環境 / 癌微小環境

Outline of Final Research Achievements

The elucidation of molecular mechanisms underlying therapeutic resistance in metastasis of osteosarcoma (OS) and development of novel therapies are urgently needed.
The changes of gene expression caused by chemotherapy suggested that macrophages or thrombosis might be involved in the therapeutic resistance in lung metastasis.
Through the screening of drugs, simvastatin and calcitriol were found to inhibit anchorage-independent growth, an important property for the establishment of metastasis. Simvastatin induced apoptosis in a manner dependent on inhibition of the mevalonate synthetic pathway. Combination of simvastatin and a fat-free diet exerted a significant antitumor effect. Calcitriol induced cell cycle arrest by activating the ER stress response. A single dose of calcitriol was sufficient to inhibit tumor growth. These findings indicated the potential of both drugs as novel therapeutic options for OS metastasis although further refinement of the optimal conditions is required.

Research Products

• [Journal Article] Activation of ventral tegmental area dopaminergic neurons reverses pathological allodynia resulting from nerve injury or bone cancer (2018)
  • Author(s): Watanabe Moe、Narita Michiko、Hamada Yusuke、Yamashita Akira、Tamura Hideki、Ikegami Daigo、Kondo Takashige、Shinzato Tatsuto、Shimizu Takatsune、Fukuchi Yumi、Muto Akihiro、Okano Hideyuki、Yamanaka Akihiro、Tawfik Vivianne L、Kuzumaki Naoko、Navratilova Edita、Porreca Frank、Narita Minoru
  • Journal Title: Molecular Pain Volume: 14 Pages: 1-10
  • DOI: 10.1177/1744806918756406
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ：Calcitriol exerts an anti-tumor effect in osteosarcoma by inducing the endoplasmic reticulum stress response. (2017)
  • Author(s): Shimizu T, Kamel WA, Yamaguchi-Iwai S, Fukuchi Y, Muto A, Saya H.
  • Journal Title: Cancer Science Volume: 108 Issue: 9 Pages: 1793-1802
  • DOI: 10.1111/cas.13304
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Robotic crowd biology with Maholo LabDroids. (2017)
  • Author(s): Yachie N; Robotic Biology Consortium (inc. Masaki Matsumoto)., Natsume T.
  • Journal Title: Nature Biotechnology Volume: 35 Issue: 4 Pages: 310-312
  • DOI: 10.1038/nbt.3758
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Simvastatin-Induced Apoptosis in Osteosarcoma Cells: A Key Role of RhoA-AMPK/p38 MAPK Signaling in Antitumor Activity. (2017)
  • Author(s): Kamel WA, Sugihara E, Nobusue H, Yamaguchi-Iwai S, Onishi N, Maki K, Fukuchi Y, Matsuo K, Muto A, Saya H, Shimizu T.
  • Journal Title: Molecular Cancer Therapeutics Volume: 16 Issue: 1 Pages: 182-192
  • DOI: 10.1158/1535-7163.mct-16-0499
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Synergistic antiproliferative effect of imatinib and adriamycin in platelet-derived growth factor receptor-expressing osteosarcoma cells. (2015)
  • Author(s): Yamaguchi SI, Ueki A, Sugihara E, Onishi N, Yaguchi T, Kawakami Y, Horiuchi K, Morioka H, Matsumoto M, Nakamura M, Muto A, Toyama Y, Saya H, Shimizu T.
  • Journal Title: Cancer Sci. Volume: 106 Issue: 7 Pages: 875-882
  • DOI: 10.1111/cas.12686
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] カルシトリオールは小胞体ストレス反応を誘導することにより骨肉腫に抗腫瘍効果を示す (2017)
  • Author(s): 清水孝恒、山口さやか、武藤章弘、佐谷秀行
  • Organizer: 第76回 日本癌学会学術総会
• [Presentation] LivinはFas発現回復によるリンパ腫抑制バリアに対する抵抗性を付与する (2017)
  • Author(s): 杉原英志、橋本典諭、大須賀覚、植野さやか、清水孝恒、佐谷秀行
  • Organizer: 第76回 日本癌学会学術総会
• [Presentation] マウス骨肉腫幹細胞と疾患克服への挑戦 (2017)
  • Author(s): 清水孝恒
  • Organizer: 日本薬学会東海支部特別講演会
  • Place of Presentation: 名古屋
  • Invited
• [Presentation] スタチン系薬剤はメバロン酸合成経路を阻害し、AMPK、p38MAPKの活性化を介して骨肉腫に抗腫瘍効果を発揮する (2016)
  • Author(s): カメル・ワリード、杉原英志、山口さやか、信末博行、大西伸幸、武藤章弘、佐谷秀行、清水孝恒
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Statins induce apoptosis in osteosarcoma cells by activation of Ampk and p38 via suppression of mevalonate pathway (2016)
  • Author(s): Kamel AW, Sugihara E, Yamaguchi S, Nobusue H, Maki K, Muto A, Saya H, Shimizu T
  • Organizer: American Association for Cancer Research Annual Meeting 2016
  • Place of Presentation: New Orleans, USA
  • Year and Date: 2016-04-16
  • Int'l Joint Research
• [Presentation] Novel therapeutic approach with statins for lethal osteosarcoma (2016)
  • Author(s): 槇健太、清水孝恒、福地由美、武藤章弘
  • Organizer: 第89回日本薬理学会年会
  • Place of Presentation: 横浜
  • Year and Date: 2016-03-09
• [Presentation] 新規B 細胞リンパ腫モデルを用いたリンパ腫発症及び維持におけるFas の抑制制御 (2015)
  • Author(s): 杉原英志、橋本典諭、植野さやか、清水孝恒、佐谷秀行
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] アクチン細胞骨格動態に基づく脂肪分化制御による骨肉腫幹細胞の治療戦略 (2015)
  • Author(s): 信末博行、大西伸幸、清水孝恒、杉原英志、沖嘉尚、千代田達幸、高橋信博、赤司浩一、加野浩一郎、佐谷秀行
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] ROCK 阻害剤は骨肉腫幹細胞の脂肪細胞への終末分化を誘導する (2015)
  • Author(s): 高橋信博、信末博行、清水孝恒、大西伸幸、杉原英志、佐谷秀行
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Presentation] イマチニブとアドリアマイシンの併用は、PDGFR を発現する骨肉腫に対し、相乗的な抗腫瘍効果を呈する (2015)
  • Author(s): 山口さやか、杉原英志、大西伸幸、菊田一貴、堀内圭輔、森岡秀夫、佐谷秀行、清水孝恒
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-08
• [Book] 分子病態薬理学Ⅲ (2017)
  • Author(s): 成田年、加藤良規、清水孝恒、鳥越一宏
  • Total Pages: 326
  • Publisher: 京都廣川書店
  • ISBN: 9784909197160
• [Remarks] 清水孝恒 - 研究者 - researchmap
  • URL: https://researchmap.jp/shimizutakatsune/
• [Remarks] 清水 孝恒 - 慶應義塾大学 医学部 先端医科学研究所
  • URL: http://www.genereg.jp/html2/html/staff/NInst/Shimizu/
• [Remarks] 星薬科大学ホームページ
  • URL: http://www.hoshi.ac.jp/site/kyoiku/kyoushitsuhgaid/15kyoushitsu.byoutai.php
• [Remarks] 慶應義塾大学医学部・先端医科学研究所・遺伝子制御研究部門ホームページ
  • URL: http://www.genereg.jp/html2/html/staff/NInst/Shimizu/
• [Remarks] Research Map
  • URL: http://researchmap.jp/shimizutakatsune/
• [Remarks] 清水孝恒 研究者 researchmap
  • URL: http://researchmap.jp/shimizutakatsune/
• [Remarks] 星薬科大学 薬学部 病態生理学教室
  • URL: http://www.hoshi.ac.jp/site/kyoiku/kyoushitsuhgaid/15kyoushitsu.byoutai.php
• [Remarks] 慶應義塾大学 医学部 先端医科学研究所 遺伝子制御研究部門
  • URL: http://www.genereg.jp/html/staff/NInst/Shimizu/