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Mechanisms of myeloma growth in bone marrow microenvironment and development of novel therapeutic options for myeloma

Research Project

Project/Area Number 26461422
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Hematology
Research InstitutionThe University of Tokushima

Principal Investigator

ABE Masahiro  徳島大学, 大学院医歯薬学研究部(医学系), 教授 (80263812)

Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywords骨髄腫 / 骨破壊病変 / 酸環境 / 骨形成 / 骨病変 / TRPV1 / Pim-2 / TAK-1 / 酸性環境 / 骨髄微小環境
Outline of Final Research Achievements

Acid activates the TRPV1-PI3K-Akt survival signaling in MM cells, which further upregulates the pH sensor TRPV1 while inducing HDAC-mediated gene repression, suggesting a positive feedback loop between acid sensing and the PI3K-Akt signaling. Cocultures of MM cells with bone marrow stromal cells (BMSCs) or osteoclasts (OCs) activate the TGF-β-activated kinase-1 (TAK-1)-Pim-2 pathway in these cells to enhance MM tumor progression and bone destruction. TAK-1 inhibition not only directly suppressed MM cell growth but also impaired MM cell adhesion to BMSCs to reduce BMSC support for MM cell growth. In addition, TAK-1 inhibition was able to restore osteoblastogenesis suppressed by MM cells and abolish RANKL-induced osteoclastogenesis. Thus, TAK1 may become an efficacious therapeutic target in MM to suppress tumor burden while restoring bone.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Research-status Report
  • 2014 Research-status Report
  • Research Products

    (13 results)

All 2017 2016 2015 2014

All Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Acknowledgement Compliant: 5 results,  Open Access: 5 results) Presentation (5 results) (of which Invited: 3 results)

  • [Journal Article] Expansion of Th1-like Vγ9Vδ2T cells by new generation IMiDs, lenalidomide and pomalidomide, in combination with zoledronic acid.2017

    • Author(s)
      2. Harada T, Miki H, Cui Q, Oda A, Amachi R, Teramachi J, Bat-Erdene A, Sogabe K, Iwasa M, Fujii S, Nakamura S, Kagawa K, Yoshida S, Endo I, Aihara K, Ozaki S, Matsumoto T, Abe M.
    • Journal Title

      Leukemia

      Volume: 31 Issue: 1 Pages: 258-262

    • DOI

      10.1038/leu.2016.273

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Synergistic targeting of Sp1, a critical transcription factor for myeloma cell growth and survival, by panobinostat and proteasome inhibitors2016

    • Author(s)
      Bat-Erdene A, Miki H, Oda A, Nakamura S, Teramachi J, Amachi R, Tenshin H, Hiasa M, Iwasa M, Harada T, Fujii S, Sogabe K, Kagawa K, Yoshida S, Endo I, Aihara K, Abe M.
    • Journal Title

      Oncotarget

      Volume: 7 Issue: 48 Pages: 79064-79075

    • DOI

      10.18632/oncotarget.12594

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A vicious cycle between acid sensing and survival signaling in myeloma cells: acid-induced epigenetic alteration.2016

    • Author(s)
      Amachi R, Hiasa M, Teramachi J, Harada T, Oda A, Nakamura S, Hanson D, Watanabe K, Fujii S, Miki H, Kagawa K, Iwasa M, Endo I, Kondo T, Yoshida S, Aihara KI, Kurahashi K, Kuroda Y, Horikawa H, Tanaka E, Matsumoto T, Abe M
    • Journal Title

      Oncotarget

      Volume: 7 Issue: 43 Pages: 70447-70461

    • DOI

      10.18632/oncotarget.11927

    • NAID

      120006576954

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Susceptibility to bendamustine considerably varies among myeloma cells, but is enhanced in acidic conditions2016

    • Author(s)
      Nakamura S , Miki H, Oda A, Amachi R, Teramachi J, Sogabe K, Fujino H, Maruhashi T, Fujii S, Kagawa K , Abe M.
    • Journal Title

      International Journal of Myeloma

      Volume: 6 Pages: 7-11

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Effective impairment of myeloma cells and their progenitors by blockade of monocarboxylate transportation2015

    • Author(s)
      6. Hanson DJ, Nakamura S, Amachi R, Hiasa M, Oda A, Tsuji D, Itoh K, Harada T, Horikawa K, Teramachi J, Miki H, Matsumoto T, Abe M.
    • Journal Title

      Oncotarget

      Volume: 6 Issue: 32 Pages: 33568-33586

    • DOI

      10.18632/oncotarget.5598

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma2015

    • Author(s)
      Hiasa M, Jumpei T, Oda A, Amachi R, Harada T, Nakamura S, Miki H, Fujii S, Kagawa K, Watanabe K, Endo I, Kuroda Y, Yoneda T, Tsuji D, Nakao M, Tanaka E, Hamada K, Sano S, Itoh K, Matsumoto T, Abe M
    • Journal Title

      Leukemia

      Volume: 29 Pages: 207-217

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Induction of endoplasmic reticulum stress by bortezomib sensitizes myeloma cells to DR5-mediated cell death2015

    • Author(s)
      Miki H, Nakamura S, Oda A, Amachi R, Watanabe K, Hanson D, Teramachi J, Hiasa M, Yagi H, Sogabe K, Takahashi M, Maruhashi T, Udaka K, Harada T, Fujii S, Nakano A, Kagawa K, Ri M, Iida S, Ozaki S, Matsumoto T, Abe M
    • Journal Title

      International Journal of Myeloma

      Volume: 5 Pages: 1-7

    • Related Report
      2014 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Risk factors for early-onset peripheral neuropathy caused by vincristine in patients with a first administration of R-CHOP or R-CHOP-like chemotherapy2014

    • Author(s)
      Okada N, Hanafusa T, Sakurada T, Kawazoe K, Teraoka K, Kujime T, Abe M, Shinohara Y, Minakuchi K
    • Journal Title

      J Clin Med Res

      Volume: 6 Pages: 252-260

    • DOI

      10.14740/jocmr1856w

    • Related Report
      2014 Research-status Report
    • Peer Reviewed
  • [Presentation] 多発性骨髄腫:QoLの改善に向けた治療の進歩2016

    • Author(s)
      安倍正博
    • Organizer
      第78回日本血液学会学術集会
    • Place of Presentation
      パシフィコ横浜(神奈川県・横浜市)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] Pivotal role of TAK-1 in tumor growth and bone destruction in myeloma: therapeutic impact of TAK-1 inhibition2015

    • Author(s)
      Jumpei Teramachi, Masahiro Hiasa, Asuka Oda, Hirofumi Tenshin, Ryota Amachi, Takeshi Harada, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Tatsuji Haneji, Toshio Matsumoto and Masahiro Abe
    • Organizer
      American Society for Bone and Mineral Research Annual Meeting
    • Place of Presentation
      Seattle (USA)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Research-status Report
  • [Presentation] Up-regulation of the pH sensor TRPV1 in myeloma cells and their adaption to an acidic microenvironment2015

    • Author(s)
      Ryota Amachi, Masahiro Hiasa, Jumpei Teramachi, Asuka Oda, Keiichiro Watanabe, Shingen Nakamura, Hirokazu Miki, Itsuro Endo, Eiji Tanaka, Toshio Matsumoto, Masahiro Abe
    • Organizer
      American Society for Bone and Mineral Research Annual Meeting
    • Place of Presentation
      Seattle (USA)
    • Year and Date
      2015-10-08
    • Related Report
      2015 Research-status Report
  • [Presentation] 骨髄腫骨病変の管理:ゾレドロン酸かデノスマブか2014

    • Author(s)
      安倍正博
    • Organizer
      第76回血液学会学学術集会
    • Place of Presentation
      大阪国際会議場(大阪府大阪市)
    • Year and Date
      2014-10-31
    • Related Report
      2014 Research-status Report
    • Invited
  • [Presentation] 骨微小環境と骨髄腫の進展2014

    • Author(s)
      安倍正博
    • Organizer
      第32回日本骨代謝学会学術集会
    • Place of Presentation
      大阪国際会議場(大阪府大阪市)
    • Year and Date
      2014-07-24
    • Related Report
      2014 Research-status Report
    • Invited

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Published: 2014-04-04   Modified: 2018-03-22  

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