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Analysis of novel pathogenesis of cancer-associated fibroblast involved in age-related stromal exosome changes

Research Project

Project/Area Number 15K06841
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor biology
Research InstitutionTokyo Medical University

Principal Investigator

Umezu Tomohiro  東京医科大学, 医学部, 講師(特任) (40385547)

Project Period (FY) 2015-04-01 – 2018-03-31
Project Status Completed (Fiscal Year 2017)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
KeywordsmiRNA / 細胞外小胞 / 骨髄間質細胞 / がん微小環境 / aging / エクソソーム / 加齢性変化 / 多発性骨髄腫 / 骨髄内微小環境 / 加齢
Outline of Final Research Achievements

Bone marrow stromal cells (BMSCs) and their exosomes are a promising area of cancer therapy; however, little is known about the age of BMSCs from which the exosomes came. Here, we investigated therapeutic effects of BMSC exosomes derived from young and elderly donors.
The exosomes were isolated from conditioned medium of BMSCs. We performed exosomal miRNA profiling, and found that the donor’s age decides senescent changes in BMSC, and exosomes derived from young BMSCs could block MM cell-induced angiogenesis in Matrigel plug. We also noted young BMSC-specific exosomal miRNA, such as miR-340. Of note is that the anti-angiogenic effect was potentiated by modifying exosomes of elderly BMSCs; exosomes are directly transfected with miR-340. Our results suggest that the BMSC exosomes is able to transfer the miRNAs, which have the ability to inhibit angiogenesis. The present study provides a new insight toward exosome-based cancer therapy by reconstruction of BMSC-derived exosomes.

Report

(4 results)
  • 2017 Annual Research Report   Final Research Report ( PDF )
  • 2016 Research-status Report
  • 2015 Research-status Report
  • Research Products

    (38 results)

All 2018 2017 2016 2015 Other

All Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 4 results,  Acknowledgement Compliant: 2 results) Presentation (26 results) (of which Int'l Joint Research: 15 results,  Invited: 3 results) Remarks (1 results)

  • [Journal Article] Extracellular vesicle (EV)- mediated cell-cell communication in hematologic neoplasms2018

    • Author(s)
      Ohyashiki JH, Umezu T, Ohyashiki K
    • Journal Title

      Philosophical Transactions of the Royal Society B: Biological Sciences

      Volume: 373 Issue: 1737 Pages: 1737-1737

    • DOI

      10.1098/rstb.2016.0484

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Replenishing exosomes from older bone marrow stromal cells with miR-340 inhibits myeloma-related angiogenesis.2017

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Kobayashi C, Yoshizawa S, Ohyashiki K, Ohyashiki JH.
    • Journal Title

      Blood Adv

      Volume: 1(13) Issue: 13 Pages: 812-823

    • DOI

      10.1182/bloodadvances.2016003251

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Teriflunomide restores 5-azacytidine sensitivity via activation of pyrimidine salvage in 5-azacytidine-resistant leukemia cells.2017

    • Author(s)
      Imanishi S, Takahashi R, Katagiri S, Kobayashi C, Umezu T, Ohyashiki K, Ohyashiki JH.
    • Journal Title

      Oncotarget

      Volume: 8(41) Issue: 41 Pages: 69906-69915

    • DOI

      10.18632/oncotarget.19436

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic variations of bone marrow mesenchymal stromal cells derived from acute leukemia and myelodysplastic syndrome by targeted deep sequencing.2017

    • Author(s)
      Azuma K, Umezu T, Imanishi S, Asano M, Yoshizawa S, Katagiri S, Ohyashiki K, Ohyashiki JH.
    • Journal Title

      Leuk Res

      Volume: 62 Pages: 23-28

    • DOI

      10.1016/j.leukres.2017.09.008

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hidden FLT3-D835Y clone in FLT3-ITD-positive acute myeloid leukemia that evolved into very late relapse with T-lymphoblastic leukemia2017

    • Author(s)
      Katagiri S, Umezu T, Asano M, Akahane D, Azuma K, Makishima H, Yoshida K, Watatani Y, Chiba K, Miyano S, Ogawa S, Ohyashiki JH, Ohyashiki K
    • Journal Title

      Leukemia and Lymphoma

      Volume: 3 Issue: 6 Pages: 1-4

    • DOI

      10.1080/10428194.2017.1382696

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Upregulated exosomal miRNA-140-3p in CML patients with musculoskeletal pain associated with discontinuation of tyrosine kinase inhibitors2017

    • Author(s)
      Asano M, Umezu T, Katagiri S, Kobayashi C, Tauchi T, Gotoh M, Ando K, Okabe S, Ohyashiki JH, Ohyashiki K
    • Journal Title

      Int J Hematol

      Volume: 105(4) Issue: 4 Pages: 419-422

    • DOI

      10.1007/s12185-017-2199-z

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Down-regulation of plasma miR-215 in chronic myeloid leukemia patients with successful imatinib discontinuation.2016

    • Author(s)
      Ohyashiki K, Umezu T, Katagiri S, Kobayashi C, Azuma K, Tauchi T, Okabe S, Fukuoka Y, Ohyashiki JH
    • Journal Title

      The International Journal of Molecular Sciences

      Volume: 17(4) Issue: 4 Pages: 570-570

    • DOI

      10.3390/ijms17040570

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Exosomes promote bone marrow angiogenesis in hematologic neoplasia: the role of hypoxia.2016

    • Author(s)
      Ohyashiki JH, Umezu T, Ohyashiki K
    • Journal Title

      Curr Opin Hematol

      Volume: 23(3) Issue: 3 Pages: 268-273

    • DOI

      10.1097/moh.0000000000000235

    • Related Report
      2015 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Treatment-free molecular remission achieved by combination therapy with imatinib and IFNα in CML with <i>BIM</i> deletion polymorphism relapsed after stop imatinib2015

    • Author(s)
      Katagiri S, Tauchi T, Umezu T, Saito Y, Suguro T, Asano M, Yoshizawa S, Kitahara T, Akahane D, Tanaka Y, Fujimoto H, Okabe S, Gotoh M, Ito Y, Ohyashiki JH, Ohyashiki K
    • Journal Title

      Rinsho Ketsueki

      Volume: 56 Issue: 2 Pages: 216-219

    • DOI

      10.11406/rinketsu.56.216

    • NAID

      130004920704

    • ISSN
      0485-1439, 1882-0824
    • Related Report
      2015 Research-status Report
  • [Journal Article] エクソソームと腫瘍血管2015

    • Author(s)
      梅津知宏、大屋敷純子
    • Journal Title

      血管医学

      Volume: 16(2) Pages: 19-24

    • Related Report
      2015 Research-status Report
  • [Journal Article] 造血器腫瘍におけるエクソソームを介した細胞間シグナル伝達機構:多発性骨髄腫を中心に2015

    • Author(s)
      梅津知宏、大屋敷純子、大屋敷一馬
    • Journal Title

      血液内科

      Volume: 71(3) Pages: 396-400

    • NAID

      40020613758

    • Related Report
      2015 Research-status Report
  • [Presentation] Replenishing exosomes from older bone marrow stromal cells by miR-340 inhibits myeloma-related angiogenesis2017

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Kobayashi C, Yoshizawa S, Ohyashiki K, Ohyashiki JH
    • Organizer
      RoyalSociety2017 「Extracellular cvesicles and tumor microenvironment」
    • Place of Presentation
      London
    • Year and Date
      2017-01-23
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Extracellular vesicles (EVs) released by bone marrow stromal cells show a distinct miRNA profile in high-risk MDS patients.2017

    • Author(s)
      Ohyashiki K, Saitoh Y, Imanishi S, Umezu T, Yoshizawa S, Asano M, Fujimoto H, Akahane D, Kobayashi C, Ohyashiki JH
    • Organizer
      The 14th International Symposium on Myelodysplastic Syndromes (MDS2017)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A role of exosomal miR-10a in bone marrow stromal cells obtained from patients with multiple myeloma.2017

    • Author(s)
      Umezu T, Imanishi S, Yoshizawa S, Ohyashiki K, Ohyashiki JH:
    • Organizer
      6th Annual Meeting of International Society for Extracellular Vesicles (ISEV2017)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] miRNA profiling of circulating extracellular vesicles in CML patients with musculoskeletal pain associated with discontinuation of tyrosine kinase inhibitors.2017

    • Author(s)
      Ohyashiki K, Asano M, Umezu T, Katagiri S, Kobayashi C, Tauchi T, Gotoh M, Ando K, Okabe S, Ohyashiki JH
    • Organizer
      22nd Congress of European Hematology Association (EHA2017)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Inhibition of extracellular vesicle secretion induces apoptosis of bone marrow stromal cells: Towards soil-targeted therapy in multiple myeloma.2017

    • Author(s)
      Umezu T, Imanishi S, Yoshizawa S, Ohyahsiki K, Ohyashiki JH:
    • Organizer
      22nd Congress of European Hematology Association (EHA2017)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] A statistical integrative analysis method for small size expression data of microRNAs and genes.2017

    • Author(s)
      Ohki T, Umezu T, Ohyahsiki JH, Fukuoka Y
    • Organizer
      39th International Conference of the IEEE Engineering in Medicine and Biology Society (IEEE EMBC2017)
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Cross-talk mediated by bone marrow stromal cells-derived extracellular vesicles.2017

    • Author(s)
      Umezu T, Imanishi S, Yoshizawa S, Ohyashiki K, Ohyashiki JH
    • Organizer
      Tokyo Medical University, Institute of Medical Science, 1st International Symposium “Role of Aging and Cancer”
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Inhibition of extracellular vesicle secretion induces apoptosis of bone marrow stromal cells derived from multiple myeloma patients.2017

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH
    • Organizer
      The 76th Annual Meeting of Japanese Cancer Association (JCA2017)
    • Related Report
      2017 Annual Research Report
  • [Presentation] Altered exosomal miRNA expression of late onset acute graft-versus-host disease in allogenic hematopoietic stem cell transplantation.2017

    • Author(s)
      Yoshizawa S, Umezu T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, Ohyashiki JH, Ohyashiki K
    • Organizer
      The 79th Annual Meeting of Japanese Society of Hematology (JSH2017)
    • Related Report
      2017 Annual Research Report
  • [Presentation] 多発性骨髄腫における骨髄内微小環境でのエクソソームの役割2016

    • Author(s)
      梅津知宏、大屋敷一馬、大屋敷純子
    • Organizer
      第19回癌と骨病変研究会
    • Place of Presentation
      東京
    • Year and Date
      2016-11-11
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] Anti-angiogenic effect of normal bone marrow stromal cell-derived exosomes rejuvenated by miR-3402016

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH
    • Organizer
      The 78th Annual Meeting of Japanese Society of Hematology (JSH2016)
    • Place of Presentation
      横浜
    • Year and Date
      2016-10-13
    • Related Report
      2016 Research-status Report
  • [Presentation] がん環境を標的とした治療戦略:骨髄間質細胞由来エクソソームおよびその内包型miRNAの役割2016

    • Author(s)
      梅津知宏、大屋敷一馬、大屋敷純子
    • Organizer
      第8回日本RNAi研究会・第3回日本細胞外小胞学会
    • Place of Presentation
      広島
    • Year and Date
      2016-08-31
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] 多発性骨髄腫における骨髄内微小環境でのエクソソームの役割2016

    • Author(s)
      梅津知宏、大屋敷一馬、大屋敷純子
    • Organizer
      第41回日本骨髄腫学会学術集会
    • Place of Presentation
      徳島
    • Year and Date
      2016-05-28
    • Related Report
      2016 Research-status Report
    • Invited
  • [Presentation] Clinical relevance of plasma miR-215 level in CML patients treated with imatinib2016

    • Author(s)
      Katagiri S, Umezu T, Kobayashi C, Azuma K, Tauchi T, Okabe S, Ohyashiki JH, Ohyashiki K
    • Organizer
      7th JSH International Symposium 2016
    • Place of Presentation
      Awaji
    • Year and Date
      2016-05-13
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Towards exosome-based cancer therapy: rejuvenation of exosomes derived from normal bone marrow stromal cells2016

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Kobayashi C, Ohyashiki K, Ohyashiki JH
    • Organizer
      ISEV2016 (5th Annual Meeting of International Society for Extracellular Vesicles)
    • Place of Presentation
      Rotterdam
    • Year and Date
      2016-05-04
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] miRNAとmRNAの統合解析における発現変化の閾値の最適化2016

    • Author(s)
      大木拓也、福岡 豊、大屋敷純子、梅津知宏
    • Organizer
      第55回日本生体医工学会大会
    • Place of Presentation
      富山
    • Year and Date
      2016-04-26
    • Related Report
      2016 Research-status Report
  • [Presentation] Bone marrow stromal cells from young healthy donors secrete exosomes that inhibit in vivo angiogenesis in multiple myeloma.2016

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Kobayashi C, Ohyashiki K, Ohyashiki JH
    • Organizer
      10th AACR-JCA Joint Conference
    • Place of Presentation
      Maui, Hawaii
    • Year and Date
      2016-02-16
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Down-regulation of plasma miR-215 in chronic myeloid leukemia patients with successful imatinib discontinuation.2016

    • Author(s)
      Ohyashiki K, Umezu T, Katagiri S, Kobayashi C, Azuma K, Tauchi T, Okabe S, Fukuoka Y, Ohyashiki JH
    • Organizer
      10th AACR-JCA Joint Conference
    • Place of Presentation
      Maui, Hawaii
    • Year and Date
      2016-02-16
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Exosomal miRNA signature of late onset acute graft-versus-host disease in allogenic hematopoietic stem cell transplantation.2015

    • Author(s)
      Yoshizawa S, Umezu T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, Ohyashiki JH, Ohyashiki K
    • Organizer
      第77回日本血液学会学術集会学術集会
    • Place of Presentation
      金沢
    • Year and Date
      2015-10-16
    • Related Report
      2015 Research-status Report
  • [Presentation] Exosomal miRNA signature of bone marrow mesenchymal stromal cells derived from MDS patients.2015

    • Author(s)
      Saitoh Y, Imanishi S, Umezu T, Yoshizawa S, Asano M, Fujimoto H, Akahane D, Yamamoto Y, Kobayashi C, Ohyashiki JH, Ohyashiki K
    • Organizer
      第77回日本血液学会学術集会学術集会
    • Place of Presentation
      金沢
    • Year and Date
      2015-10-16
    • Related Report
      2015 Research-status Report
  • [Presentation] Exosome-based therapeutic approach using exosomal miRNAs derived from bone marrow mesenchymal stromal cells2015

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH
    • 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
    • Related Report
      2015 Research-status Report
  • [Presentation] Establishment and characterization of a novel chronic hypoxia-resistant multiple myeloma cell lines, IM-9-HR.2015

    • Author(s)
      Azuma K, Takeuchi K, Umezu T, Ohyashiki K, Ohyashiki JH
    • 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
    • Related Report
      2015 Research-status Report
  • [Presentation] Leukemia cells under persistent hypoxia secrete exosomes enhancing angiogenesis in mice.2015

    • Author(s)
      Ohyashiki K, Umezu T, Imanishi S, Ohyashiki JH
    • Organizer
      ISEH 44th Annual Scientific Meeting
    • Place of Presentation
      京都
    • Year and Date
      2015-09-17
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Bone marrow mesenchymal stromal cells from healthy donors secrete exosomes that inhibit in vivo tumor growth and angiogenesis in multiple myeloma.2015

    • Author(s)
      Umezu T, Imanishi S, Azuma K, Yoshizawa S, Ohyashiki K, Ohyashiki JH
    • Organizer
      20th Congress of European Hematology Association (EHA)
    • Place of Presentation
      Vienna, Austria
    • Year and Date
      2015-06-11
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Distinct exosomal miRNA expression of late onset graft-versus-host disease in allogeneic hematopoietic stem cell transplantation.2015

    • Author(s)
      Yoshizawa S, Umezu T, Saitoh Y, Gotoh M, Akahane D, Kobayashi C, Ohyashiki JH, Ohyashiki K
    • Organizer
      20th Congress of European Hematology Association (EHA)
    • Place of Presentation
      Vienna, Austria
    • Year and Date
      2015-06-11
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Presentation] Age-related alterations in exosomal miRNAs derived from bone marrow mesenchymal stromal cells.2015

    • Author(s)
      Umezu T, Imanishi S, Yoshizawa S, Saitoh Y, Yamamoto Y, Ohyashiki K, Ohyashiki JH
    • Organizer
      6th JSH International Symposium 2015
    • Place of Presentation
      軽井沢
    • Year and Date
      2015-05-22
    • Related Report
      2015 Research-status Report
    • Int'l Joint Research
  • [Remarks] 東京医科大学 医学総合研究所 分子腫瘍研究部門

    • URL

      http://team.tokyo-med.ac.jp/ims_onc/index.html

    • Related Report
      2015 Research-status Report

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Published: 2015-04-16   Modified: 2019-03-29  

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