Elucidation of molecular mechanisms of cancer progression by mechanical unloading

• Project/Area Number: 19K22719
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 57:Oral science and related fields
• Research Institution: The University of Tokushima
• Principal Investigator: HIASA Masahiro 徳島大学, 大学院医歯薬学研究部(歯学域), 講師 (90511337)
• Project Period (FY): 2019-06-28 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2019: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
• Keywords: 免荷 / 破骨細胞 / メカニカルストレス / がん / 廃用性萎縮 / 骨

Outline of Research at the Start

乳がん、肺がんや多発性骨髄腫は、高頻度で骨転移と骨破壊病変がみられる難治性疾患である。これらのがんの骨破壊病変は骨痛や神経障害、骨折を生じ寝たきりを引き起こすが、寝たきりによる不動は廃用性筋萎縮や骨萎縮、易感染性の原因となり、がんの進展と生存率低下に関与する。故に、寝たきりを如何に防ぐか、寝たきりとなったとしてもがんの進展に直結しないための治療法や機能回復法が望まれる。本研究は、不動（寝たきり）による免荷が骨転移がんの進展・再発を加速化するメカニズムを、免荷による骨髄微小環境の変化と薬剤耐性休眠期がん細胞との関連を中心に解明し、治療法を確立することを目的とする。

Outline of Final Research Achievements

Breast cancer, lung cancer, and multiple myeloma are intractable diseases that frequently develop bone metastasis and osteolytic lesions. Osteolytic lesions of these cancers can cause bone pain, nerve damage, and fractures, which can leave patients bedridden. Furthermore, immobility due to bedridden status causes disuse muscle atrophy, bone atrophy, and increased susceptibility to infection, all of which contribute to cancer progression and poor prognosis. Therefore, it is desired for therapeutic strategies to prevent bedridden patients from directly leading to the progression of cancer. This study elucidated that the mechanism by which immobilization accelerates the progression of bone metastatic cancer involves the activation of osteoclasts, and demonstrated the efficacy of TAK-Pim signaling inhibitors as therapeutic agents targeting for this mechanism.

Academic Significance and Societal Importance of the Research Achievements

本研究は不動（寝たきり）による免荷で生じる骨髄微小環境の変化が、破骨細胞依存的にがん細胞の形質を転換させ、骨転移がんの進展を加速化するメカニズムを解明した。さらに、本研究で開発したTAK-Pimシグナル阻害薬は抗腫瘍作用を有する上に骨形成誘導作用を併せ持ち、転移をも克服することができ難治性のがん治療に光明をもたらす可能性がある。

Research Products

• [Int'l Joint Research] Indiana University School of Medicine(米国)
• [Journal Article] TGF‐β‐activated kinase‐1 inhibitor LL‐Z1640‐2 reduces joint inflammation and bone destruction in mouse models of rheumatoid arthritis by inhibiting NLRP3 inflammasome, TACE, TNF‐α and RANKL expression (2022)
  • Author(s): Tenshin H, Teramachi J, Ashtar M, Hiasa M, Inoue Y, Oda A, Tanimoto K, Shimizu S, Higa Yi, Harada T, Oura M, Sogabe K, Hara T, Sumitani R, Maruhashi T, Sebe M, Tsutsumi R, Sakaue H, Endo I, Matsumoto T, Tanaka E, Abe M
  • Journal Title: Clinical & Translational Immunology Volume: 11 Issue: 1
  • DOI: 10.1002/cti2.1371
  • Peer Reviewed / Open Access
• [Journal Article] Mechanical unloading aggravates bone destruction and tumor expansion in myeloma (2022)
  • Author(s): Tanimoto K, Hiasa M, Tenshin H, Teramachi J, Oda A, Harada T, Higa Y, Sogabe K, Oura M, Sumitani R, Hara T, Endo I, Matsumoto T, Tanaka E, Abe M
  • Journal Title: Haematologica Volume: 107 Issue: 3 Pages: 744-749
  • DOI: 10.3324/haematol.2021.278295
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenesis and treatment of multiple myeloma bone disease (2021)
  • Author(s): 2. Hiasa M, Harada T, Tanaka E, Abe M
  • Journal Title: Jpn Dent Sci Rev Volume: 57 Pages: 164-173
  • DOI: 10.1016/j.jdsr.2021.08.006
  • NAID: 210000172895
  • Peer Reviewed / Open Access
• [Journal Article] Sensory nerves: A driver of the vicious cycle in bone metastasis? (2021)
  • Author(s): Yoneda T、Hiasa M、Okui T、Hata K
  • Journal Title: Journal of Bone Oncology Volume: 30 Pages: 100387-100387
  • DOI: 10.1016/j.jbo.2021.100387
  • Peer Reviewed / Open Access
• [Journal Article] Myeloma-Bone Interaction: A Vicious Cycle via TAK1-PIM2 Signaling (2021)
  • Author(s): 1. Harada T, Hiasa M, Teramachi J, Abe M
  • Journal Title: Cancers Volume: 13 Issue: 17 Pages: 4441-4441
  • DOI: 10.3390/cancers13174441
  • Peer Reviewed / Open Access
• [Journal Article] The HMGB1/RAGE axis induces bone pain associated with colonization of 4T1 mouse breast cancer in bone (2021)
  • Author(s): Okui Tatsuo、Hiasa Masahiro、Ryumon Shoji、Ono Kisho、Kunisada Yuki、Ibaragi Soichiro、Sasaki Akira、Roodman G. David、White Fletcher A.、Yoneda Toshiyuki
  • Journal Title: Journal of Bone Oncology Volume: 26 Pages: 100330-100330
  • DOI: 10.1016/j.jbo.2020.100330
  • NAID: 120007032763
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reveromycin A, a novel acid-seeking agent, ameliorates bone destruction and tumor growth in multiple myeloma. (2020)
  • Author(s): Keiichiro Watanabe、Ariunzaya Bat-Erdene、Hirofumi Tenshin、Qu Cui、Jumpei Teramachi、Masahiro Hiasa、Asuka Oda、Takeshi Harada、Hirokazu Miki、Kimiko Sogabe、Masahiro Oura、Ryohei Sumitani、Yukari Mitsui、Itsuro Endo、Eiji Tanaka、Makoto Kawatani、Hiroyuki Osada、Toshio Matsumoto、Masahiro Abe
  • Journal Title: Haematologica Volume: 106 Issue: 4 Pages: 1172-1177
  • DOI: 10.3324/haematol.2019.244418
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Roles of ROS Generation in RANKL-Induced Osteoclastogenesis: Suppressive Effects of Febuxostat. (2020)
  • Author(s): 1. Ashtar M, Tenshin H, Teramachi J, Bat-Erdene A, Hiasa M, Oda A, Tanimoto K, Shimizu S, Higa Y, Harada T, Oura M, Sogabe K, Nakamura S, Fujii S, Sumitani R, Miki H, Udaka K, Takahashi M, Kagawa K, Endo I, Tanaka E, Matsumoto T, Abe M.
  • Journal Title: Cancers (Basel) Volume: 12 Issue: 4 Pages: 929-929
  • DOI: 10.3390/cancers12040929
  • NAID: 120006894611
  • Peer Reviewed / Open Access
• [Journal Article] TAK1 is a pivotal therapeutic target for tumor progression and bone destruction in myeloma. (2020)
  • Author(s): 2. Teramachi J, Tenshin H, Hiasa M, Oda A, Bat-Erdene A, Harada T, Nakamura S, Ashtar M, Shimizu S, Iwasa M, Sogabe K, Oura M, Fujii S, Kagawa K, Miki H, Endo I, Haneji T, Matsumoto T, Abe M.
  • Journal Title: Haematologica Volume: haematol.2019 Issue: 5 Pages: 1401-1413
  • DOI: 10.3324/haematol.2019.234476
  • NAID: 120007180361
  • Peer Reviewed / Open Access
• [Presentation] Immobilization accelerates bone loss and myeloma tumor expansion. (2020)
  • Author(s): Tanimoto K, Hiasa M, Tenshin H, Abe M, Tanaka E.
  • Organizer: 9th IOC
  • Int'l Joint Research
• [Presentation] Evaluation of the effects of age on root resorption caused by orthodontic treatment. (2020)
  • Author(s): Takahashi F, Hiasa M, Horiuchi S, Honda E, Tanaka E.
  • Organizer: 9th IOC
  • Int'l Joint Research
• [Presentation] 徳島大学病院矯正歯科における口唇裂口蓋裂患者の診療動向調査． (2020)
  • Author(s): 中上絵美子、天真寛文、森 浩喜、渡邉佳一郎、日浅雅博、堀内信也、岩本 勉、橋本一郎、田中栄二
  • Organizer: 第44回日本口蓋裂学会総会・学術集会
• [Presentation] ソトス症候群に貴院する交叉咬合を伴う骨格性下顎前突 (2020)
  • Author(s): 吉永薫、塩屋園玲子、伊藤彩実、松木佑太、谷本幸多朗、渡邉佳一郎、日浅雅博、田中栄二
  • Organizer: 第63回中・四国矯正歯科学会大会
• [Presentation] 抗腫瘍薬が誘導するROSは破骨細胞分化を促進する：Xanthine oxidase阻害剤febuxostatの治療効果 (2020)
  • Author(s): 天真寛文、Mohannad Ashtar、寺町順平、日浅雅博、谷本幸多朗、清水宗、比嘉佳基、 原田武志、大浦雅博、曽我部公子、中村信元、三木浩和、遠藤逸朗、田中栄二、松本俊夫、安倍正博
  • Organizer: 第38回日本骨代謝学会学術集会
• [Presentation] 不動は骨吸収と骨髄腫進展を促進させる (2020)
  • Author(s): 谷本幸多朗、日浅雅博、天真寛文、Mohannad Ashter、清水宗、比嘉佳基、寺町順平、原田武志、中村信元、三木浩和、遠藤逸朗、田中栄二、松本俊夫、安倍正博
  • Organizer: 第38回日本骨代謝学会学術集会
• [Presentation] 骨髄腫細胞のPP2A阻害因子CIP2A発現誘導を介するTAK1活性化増強機構 (2020)
  • Author(s): 清水宗、寺町順平、原田武志、小田明日香、天真寛文、日浅雅博、谷本幸多朗、比嘉佳基、田中栄二、松本俊夫、安倍正博
  • Organizer: 第38回日本骨代謝学会学術集会
• [Presentation] TAK1 upregulates the PP2A inhibitor CIP2A to potentiate survival signaling pathways in myeloma cells. (2020)
  • Author(s): 清水宗、寺町順平、原田武志、天真寛文、小田明日香、日浅雅博、遠藤逸朗、松本俊夫、田中栄二、安倍正博
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 口唇口蓋裂治療における医科歯科連携を考える (2020)
  • Author(s): 日浅雅博
  • Organizer: 第44回日本口蓋裂学会総会・学術集会
• [Presentation] Critical roles of TACE-TIMP-3 system in skewed osteoclast vs. dendritic cell differentiation in MM (2020)
  • Author(s): 日浅雅博、谷本幸多朗、比嘉佳基、天真寛文、曾我部公子、大浦雅博、原田武志、中村信元、三木浩和、遠藤逸朗、松本俊夫、安倍正博
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Versatile anti-myeloma effects by elotuzumab: impact on gamma delta T cells and osteoclasts (2020)
  • Author(s): T Harada, Y Inoue, H Tenshin, A Oda, M Oura, K Sogabe, R Sumitani, S Fujii, S Nakamura, H Miki, K Kagawa, M Hiasa, J Teramachi, M Abe
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Resumption of myeloma cell sensitivity to proteasome inhibitors by PIM and Akt inhibition (2020)
  • Author(s): 曽我部公子、原田武志、中村信元、三木浩和、小田明日香、井上雄介、住谷龍平、丸橋朋子、大浦雅博、藤井志朗、賀川久美子、天眞寛文、日浅雅博、寺町順平、安倍正博
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] Mechanical unloading aggravates bone destruction and tumor expansion in myeloma (2020)
  • Author(s): K Tanimoto，M Hiasa，H Tenshin， A Mohannad，Y Higa，S Shimizu，A Oda， T Harada，K Sogabe，M Oura，I Endo，T Matsumoto，M Abe
  • Organizer: 第82回日本血液学会学術集会
• [Presentation] 不動性骨吸収の亢進は骨髄内の骨髄腫進展を促進させる (2019)
  • Author(s): 谷本 幸太朗, 日浅 雅博, 天眞 寛文, 寺町 順平, ASHTAR MOHANNAD, 岩佐 昌美, 小田 明日香, 曽我部 公子, 大浦 雅博, 原田 武志, 中村 信元, 三木 浩和, 遠藤 逸朗, 田中 栄二, 松本 俊夫, 安倍 正博
  • Organizer: 第37回日本骨代謝学会学術集会
• [Presentation] Mechanical unloading accelerates myeloma tumor expansion. (2019)
  • Author(s): Kotaro Tanimoto, Masahiro Hiasa, Hirohumi Tenshin, Junpei Teramachi, Mohannad Ashtar, Ariunzaya Baterdene, Masami Iwasa, Kimiko Sogabe, Masahiro Oura, Takeshi Harada, Shingen Nakamura, Kazuhiro Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto, Masahiro Abe
  • Organizer: 29th ANZBMS Annual Scientific Meeting
  • Int'l Joint Research
• [Presentation] Immobilization promotes bone resorption and tumor expansion in myeloma (2019)
  • Author(s): Kotaro Tanimoto, Masahiro Hiasa, Hirohumi Tenshin, Junpei Teramachi, Mohannad Ashtar, Asuka Oda, Masami Iwasa, Kimiko Sogabe, Masahiro Oura, Takeshi Harada, Shingen Nakamura, Kazuhiro Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto, Masahiro Abe
  • Organizer: 第81回日本血液学会学術集会
• [Presentation] 不動は骨吸収と骨髄腫進展を促進させる (2019)
  • Author(s): 谷本 幸太朗, 日浅 雅博, 天眞 寛文, 寺町 順平, ASHTAR MOHANNAD, 岩佐 昌美, 小田 明日香, 曽我部 公子, 大浦 雅博, 原田 武志, 中村 信元, 三木 浩和, 遠藤 逸朗, 田中 栄二, 松本 俊夫, 安倍 正博
  • Organizer: 第44回日本骨髄腫学会学術集会
• [Book] Encyclopedia of Bone Biology (2020)
  • Author(s): Toshiyuki Yoneda, Masahiro Hiasa, TatsuoOkui
  • Total Pages: 2374
  • Publisher: Elsevier Inc.
  • ISBN: 9780128140826