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Development of dual targeting therapy for cancer stem cells and niche

Research Project

Project/Area Number 21591213
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionSapporo Medical University

Principal Investigator

KOBUNE Masayoshi  札幌医科大学, 医学部, 准教授 (90336389)

Co-Investigator(Kenkyū-buntansha) KIKUCHI Shohei  札幌医科大学, 医学部, 研究員 (80515792)
IYAMA Satoshi  札幌医科大学, 医学部, 助教 (50398319)
TAKIMOTO Rishu  札幌医科大学, 医学部, 講師 (10336399)
Project Period (FY) 2009 – 2011
Project Status Completed (Fiscal Year 2011)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2011: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2010: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywords癌 / 内科 / シグナル伝達 / 臨床 / 発現制御
Research Abstract

Aberrant reactivation of Hedgehog(Hh) signaling has been described in a wide variety of human cancers including cancer stem cells. However, involvement of Hh signaling system in bone marrow(BM) microenvironment in the development of myeloid neoplasm has remained unclear. In this study, we assessed the expression of Hh related proteins in normal human CD34+cells, CD34+leukemic/dysplastic cells and BM stromal cells. Both Indian hedgehog(Ihh) and its signal transducer, SMO were expressed in CD34+acute myeloid leukemia(AML) and myelodysplastic syndrome(MDS) derived cells, suggesting that Ihh could effect in autocrine manner. Remarkably, the intrinsic Hh signaling inhibitor, human hedgehog-interacting protein(HHIP) expression in AML/MDS-associated stromal cells was drastically lower than that in healthy donor derived stromal cells. Moreover, the HHIP expression level in BM stromal cells highly correlated with supporting activity of SMO+leukemic cells. Demethylating agent 5-aza-dC rescued the HHIP expression via demethylation of HHIP gene and reduced the leukemia-supporting activity of AML/MDS-associated stromal cells. This effect of 5-aza-dC could be negated by HHIP shRNA transfer into stromal cells. Interestingly, HHIP-reduced stromal cells preferentially migrated toward Ihh-releasing leukemic cells. These results indicate that suppression of stromal HHIP expression could be involved in the progression of AML/MDS.

Report

(4 results)
  • 2011 Annual Research Report   Final Research Report ( PDF )
  • 2010 Annual Research Report
  • 2009 Annual Research Report
  • Research Products

    (35 results)

All 2012 2011 2010 2009

All Journal Article (17 results) (of which Peer Reviewed: 16 results) Presentation (10 results) Book (8 results)

  • [Journal Article] Prognostic significance of serum ferritin level at diagnosis in myelodysplastic syndrome2012

    • Author(s)
      Kobune M
    • Journal Title

      Int J Hematol

      Volume: 95 Pages: 527-534

    • NAID

      10030633185

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Prognostic significance of serum-ferritin level at diagnosis in myelodysplastic syndrome2012

    • Author(s)
      Kobune M, et al. 2^<nd>
    • Journal Title

      Int J Hematol

      Volume: (In press) Issue: 5 Pages: 527-534

    • DOI

      10.1007/s12185-012-1048-3

    • NAID

      10030633185

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Establishment of a simple test for iron absorption from the gastrointestinal tract2011

    • Author(s)
      Kobune M
    • Journal Title

      Int J Hematol

      Volume: 93 Pages: 715-719

    • NAID

      10029535427

    • Related Report
      2011 Annual Research Report 2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Novel missense mutation in the TMPRSS6 gene in a Japanese female with iron-refractory iron deficiency anemia2011

    • Author(s)
      Sato T, Takimoto R, Kato J
    • Journal Title

      Int J Hematol

      Volume: 94 Issue: 1 Pages: 101-103

    • DOI

      10.1007/s12185-011-0881-0

    • NAID

      10029536603

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Endoscopic findings of enteropathy-type T-cell lymphoma by double-balloon enteroscopy and capsule endoscopy2010

    • Author(s)
      Sato Y, Kobune M
    • Journal Title

      Dig Endosc

      Volume: 22 Pages: 243-245

    • NAID

      10028187103

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Pure red cell aplasia associated with Good's syndrome accompanied by decreased stem cell factor production in the bone marrow2010

    • Author(s)
      Kuribayashi K, Kobune M
    • Journal Title

      Intern Med

      Volume: 49 Pages: 377-382

    • NAID

      130000251680

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Pure red cell aplasia associated with Good's syndrome accompanied by decreased stem cell factor production in the bone marrow.2010

    • Author(s)
      Kuribayashi K, Kobune M, et al.
    • Journal Title

      Intern Med.

      Volume: 49 Pages: 377-382

    • NAID

      130000251680

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Endoscopic findings of enteropathy-type T-cell lymphoma by double-balloon enteroscopy and capsule endoscopy.2010

    • Author(s)
      Sato Y, Kobune M, et al.
    • Journal Title

      Dig Endosc.

      Volume: 22 Pages: 243-245

    • NAID

      10028187103

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Phase II study of S-1, docetaxel and cisplatin combination chemotherapy in patients with unresectable metastatic gastric cancer. Cancer Chemother Pharmacol.2010

    • Author(s)
      Sato Y, Kobune M, et al.
    • Journal Title

      Cancer Chemother Pharmacol.

      Volume: 66 Pages: 721-728

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] De novo follicular regeneration of the skin by wingless int 3 and bone morphogenetic protein 2 genes introduced into dermal fibroblasts and fibroblast growth factor-2 protein2009

    • Author(s)
      Ono I, Kobune M
    • Journal Title

      Wound Rep Reg

      Volume: 17 Pages: 436-446

    • NAID

      10031181580

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Late onset neutropenia and immunoglobulin suppression of the patientswith malignant lymphoma following autologous stem cell transplantation with rituximab2009

    • Author(s)
      Hirayama Y, Kobune M
    • Journal Title

      Intern Med

      Volume: 48 Pages: 57-60

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Drug resistance is dramatically restored by hedgehog inhibitors in CD34+leukemic cells2009

    • Author(s)
      Kobune M
    • Journal Title

      Cancer Sci

      Volume: 100 Pages: 948-955

    • NAID

      10025145994

    • Related Report
      2011 Final Research Report
    • Peer Reviewed
  • [Journal Article] Drug resistance is dramatically restored by hedgehog inhibitors in CD34+ leukemic cells2009

    • Author(s)
      Kobune M, et al
    • Journal Title

      Cancer Sci 100

      Pages: 948-955

    • NAID

      10025145994

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Suppressive effect of sulindac on branch duct-intraductal papillary mucinous neoplasms2009

    • Author(s)
      Hayashi T, Kobune M, et al
    • Journal Title

      J Gastroenterol 44

      Pages: 964-975

    • NAID

      10025581446

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Late onset neutropenia and immunoglobulin suppression of the patients with malignant lymphoma following autologous stem cell transplantation with rituximab2009

    • Author(s)
      Hirayama Y, Kobune M, et al
    • Journal Title

      Intern Med 48

      Pages: 57-60

    • NAID

      130000080003

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article] De novo follicular regeneration of the skin by wingless int 3 and bone morphogenetic protein 2 genes introduced into dermal fibroblasts and fibroblast growth factor-2 protein2009

    • Author(s)
      Ono I, Kobune M, et al
    • Journal Title

      Wound Rep Reg 17

      Pages: 436-446

    • NAID

      10031181580

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Journal Article]2009

    • Author(s)
      小船雅義, 加藤淳二
    • Journal Title

      血液疾患アプローチのための解剖生理. 病気と薬パーフェクトBOOK2009(南山堂)

      Pages: 1202-1205

    • Related Report
      2009 Annual Research Report
  • [Presentation] Long-Term Production System of Red Blood Cells Using Human Cord Blood and Stromal Cells2010

    • Author(s)
      Kobune M, et al.
    • Organizer
      52nd American society of Hematology Annual Meeting 2010
    • Place of Presentation
      Orlando, U.S.A.
    • Year and Date
      2010-12-05
    • Related Report
      2010 Annual Research Report
  • [Presentation] Long-Term ex vivo Production of Mature Erthroblasts from Umbilical Cord Blood Using a Coculture Systeme with Telomerized Human Stromal Cells2010

    • Author(s)
      Kobune M, et al.
    • Organizer
      JSH International Symposium 2010
    • Place of Presentation
      Akita, Japan.
    • Year and Date
      2010-07-16
    • Related Report
      2010 Annual Research Report
  • [Presentation] SMO阻害剤は急性骨髄性白血病細胞の薬剤耐性を解除する(ワークショップ)2010

    • Author(s)
      小船雅義
    • Organizer
      第14回日本がん分子標的治療学会学術集会
    • Place of Presentation
      東京
    • Year and Date
      2010-07-06
    • Related Report
      2010 Annual Research Report
  • [Presentation] 鉄過剰症と鉄キレート療法の最新2010

    • Author(s)
      小船雅義
    • Organizer
      第58回日本輸血・細胞治療学会総会
    • Place of Presentation
      名古屋(招待講演)
    • Year and Date
      2010-05-29
    • Related Report
      2010 Annual Research Report
  • [Presentation] Expression of DNA Repair Factor DDB2 Predicts Chemoresistance in Various Cancer Cell Lines2010

    • Author(s)
      Miyanishi K, Kobune M, et al
    • Organizer
      AACR 101st Annual Meeting 2010
    • Place of Presentation
      Washington DC, U.S.A.
    • Year and Date
      2010-04-18
    • Related Report
      2010 Annual Research Report
  • [Presentation] Long-Term Production System of Red Blood Cells Using Human Cord Blood and Stromal Cells2010

    • Author(s)
      Kobune M
    • Organizer
      52nd American society of Hematology Annual Meeting
    • Place of Presentation
      Orlando, U. S. A.
    • Related Report
      2011 Final Research Report
  • [Presentation] Long-Term ex vivo Production of Mature Erthroblasts from Umbilical Cord Blood Using a Coculture Systeme with Telomerized Human Stromal Cells2010

    • Author(s)
      Kobune M
    • Organizer
      JSH International Symposium
    • Place of Presentation
      Akita, Japan
    • Related Report
      2011 Final Research Report
  • [Presentation] SMO阻害剤は急性骨髄性白血病細胞の薬剤耐性を解除する2010

    • Author(s)
      小船雅義, 村瀬和幸, 井山諭, 佐藤勉, 瀧本理修, 菊地尚平, 宮西浩嗣, 佐藤康史, 加藤淳二
    • Organizer
      第14回日本がん分子標的治療学会学術集会
    • Place of Presentation
      東京
    • Related Report
      2011 Final Research Report
  • [Presentation] Cyclopamine induced apoptosis in primary CD34+ acute leukemic cells2009

    • Author(s)
      Kobune M, et al
    • Organizer
      American Society of Hematology
    • Place of Presentation
      New Orleans, USA
    • Year and Date
      2009-12-07
    • Related Report
      2009 Annual Research Report
  • [Presentation] Cyclopamine induced apoptosis in primary CD34+acute leukemic cells2009

    • Author(s)
      Kobune M
    • Organizer
      American Society of Hematology
    • Place of Presentation
      New Orleans, USA.
    • Related Report
      2011 Final Research Report
  • [Book] 血液疾患アプローチのための解剖生理.病気と薬パーフェクトガイド増刊号2011

    • Author(s)
      小船雅義, 加藤淳二
    • Publisher
      南山堂
    • Related Report
      2011 Annual Research Report 2011 Final Research Report
  • [Book] 主な血液疾患用薬剤の作用機序と適応.鉄剤・ビタミンB122011

    • Author(s)
      小船雅義、加藤淳二
    • Publisher
      南江堂
    • Related Report
      2011 Annual Research Report
  • [Book] 感染・血液診療エキスパート-貧血-炎症に伴う貧血2010

    • Author(s)
      小船雅義、加藤淳二
    • Publisher
      中外医学社
    • Related Report
      2011 Final Research Report
  • [Book] 主な血液疾患用薬剤の作用機序と適応鉄剤・ビタミン2010

    • Author(s)
      小船雅義、加藤淳二
    • Publisher
      南江堂
    • Related Report
      2011 Final Research Report
  • [Book] 血液疾患アプローチのための解剖生理病気と薬パーフェクトBOOK20102010

    • Author(s)
      小船雅義
    • Publisher
      南山堂
    • Related Report
      2010 Annual Research Report
  • [Book] 主な血液疾患用薬剤の作用機序と適応鉄剤・ビタミンB122010

    • Author(s)
      小船雅義
    • Publisher
      南江堂
    • Related Report
      2010 Annual Research Report
  • [Book] 感染・血液診療エキスパート貧血-炎症に伴う貧血2010

    • Author(s)
      小船雅義
    • Publisher
      中外医学社
    • Related Report
      2010 Annual Research Report
  • [Book] 血液疾患アプローチのための解剖生理.病気と薬パーフェクトBOOK20092009

    • Author(s)
      小船雅義, 加藤淳二
    • Publisher
      南山堂
    • Related Report
      2011 Final Research Report

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Published: 2009-04-01   Modified: 2016-04-21  

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