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腫瘍血管内皮細胞の幹細胞性と薬剤耐性獲得機構との関わりの解明

Research Project

Project/Area Number 23390457
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Surgical dentistry
Research InstitutionHokkaido University

Principal Investigator

樋田 京子  北海道大学, 歯学研究科(研究院), その他 (40399952)

Co-Investigator(Kenkyū-buntansha) 進藤 正信  北海道大学, 歯学研究科(研究院), 教授 (20162802)
樋田 泰浩  北海道大学, 大学病院, 講師 (30399919)
大賀 則孝  北海道大学, 歯学研究科(研究院), 特任助教 (40548202)
Project Period (FY) 2011-04-01 – 2014-03-31
Project Status Declined (Fiscal Year 2013)
Budget Amount *help
¥18,980,000 (Direct Cost: ¥14,600,000、Indirect Cost: ¥4,380,000)
Fiscal Year 2013: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2012: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2011: ¥8,060,000 (Direct Cost: ¥6,200,000、Indirect Cost: ¥1,860,000)
Keywords腫瘍血管 / 血管新生 / 幹細胞 / 薬剤耐性
Research Abstract

1)薬剤抵抗性と幹細胞性の関連解析:がん幹細胞は薬剤抵抗性をもつことはよく知られている.腫瘍血管内皮細胞には幹細胞性(CD90, Sca-1などの幹細胞マーカーの発現)や薬剤抵抗関連遺伝子,MDR1の発現が高いことがわかった.また,腫瘍培養上清により正常血管内皮においてこのトランスポーター遺伝子MDR1の発現が上昇したことから,腫瘍血管内皮細胞の薬剤抵抗性と幹細胞性との関わりについてCD90, Sca-1, CD133,MDR1発現と薬剤感受性の違いとの関係をreal time PCR,MTS assay, フローサイトメトリーによるSP分画解析などにより解析した.さらにALDHが高い腫瘍血管内皮細胞の存在をみいだし,それらが薬剤耐性をもっていることを明らかにした.また,幹細胞性をもつ腫瘍血管内皮細胞においてある細胞成長因子のシグナル経路が亢進していることなどを現在解析中である.
2)培養上清中サイトカインの解析:腫瘍培養上清により正常血管内皮における腫瘍血管内皮マーカーの発現亢進や薬剤耐性に影響を及ぼすサイトカインの解析をおこなった.悪性度の異なるがん細胞の培養上清による処理後, 細胞の抗がん剤や血管新生阻害剤への感受性の変化を増殖能, 遊走能への影響を通して比較検討した.
培養上清中のVEGFが血管内皮の薬剤耐性を亢進させることをみいだした.血管内皮においてこの受容体の阻害を行うことで薬剤耐性を回避できることを確認した.その他の培養上清中のサイトカインもいくつか見出され,現在解析中である.

Current Status of Research Progress
Reason

翌年度、交付申請を辞退するため、記入しない。

Strategy for Future Research Activity

翌年度、交付申請を辞退するため、記入しない。

Report

(2 results)
  • 2012 Annual Research Report
  • 2011 Annual Research Report
  • Research Products

    (40 results)

All 2013 2012 2011 Other

All Journal Article (17 results) (of which Peer Reviewed: 17 results) Presentation (19 results) (of which Invited: 15 results) Book (2 results) Remarks (2 results)

  • [Journal Article] Tumor endothelial cells acquire drug resistance in a tumor microenvironment2013

    • Author(s)
      Hida K.
    • Journal Title

      J Biochem

      Volume: 153(3) Pages: 243-249

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The effect of liposomal size on the targeted delivery of doxorubicin to Integrin alpha)v(beta)3-expressing tumor endothelial cells2013

    • Author(s)
      Kibria G.
    • Journal Title

      Biomaterials

      Volume: 印刷中

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Expression of parathyroid hormone-related protein confers malignant potential to mucoepidermoid carcinoma2013

    • Author(s)
      Nagamine K.
    • Journal Title

      Oncol Rep

      Volume: 印刷中

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] An approach to transgene expression in liver endothelial cells using a liposome-based gene vector coated with hyaluronic acid2013

    • Author(s)
      Yamada Y.
    • Journal Title

      J Pharm Sci

      Volume: 印刷中

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The F-prostaglandin receptor is a novel marker for tumor endothelial cells in renal cell carcinoma2013

    • Author(s)
      Akiyama K., Ohga N., Maishi N., Hida Y., Kitayama K., Kawamoto T., Osawa T., Suzuki Y., Shinohara N., Nonomura K., Shindoh M., Hida K.
    • Journal Title

      Pathol. Int.

      Volume: 63(1) Issue: 1 Pages: 37-44

    • DOI

      10.1111/pin.12031

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Development of a novel DNA aptamer ligand against primary cultured tumor endothelial cell2012

    • Author(s)
      Naznin Ara.
    • Journal Title

      PLoS ONE

      Volume: 7(12) Issue: 12 Pages: e50174-e50174

    • DOI

      10.1371/journal.pone.0050174

    • Related Report
      2012 Annual Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise foruse in drug-resistant cancer therapy,2012

    • Author(s)
      Takara K.
    • Journal Title

      J Controlled Release

      Volume: 162(1) Issue: 1 Pages: 225-232

    • DOI

      10.1016/j.jconrel.2012.06.019

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Prostacyclin receptor in tumor endothelial cells promotes angiogenesis in an autocrine manner2012

    • Author(s)
      Osawa T, Ohga N, Hida Y, Kitayama K, Akiyama K, Onodera Y, Fujie M, Shinohara N, Shindoh M, Nonomura K, Hida K
    • Journal Title

      Cancer Sci

      Volume: 103(6) Issue: 6 Pages: 1038-1044

    • DOI

      10.1111/j.1349-7006.2012.02261.x

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Tumor-Derived Microvesicles Induce Proangiogenic Phenotype in Endothelial Cells via Endocytosis2012

    • Author(s)
      T. Kawamoto, et al.
    • Journal Title

      PLoS ONE

      Volume: 7 Issue: 3 Pages: e34045-e34045

    • DOI

      10.1371/journal.pone.0034045

    • Related Report
      2012 Annual Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biglycan is a aspecific marker and an autocrine angiogenic factor of tumour endothelial cells2012

    • Author(s)
      Yamamoto K, Ohga N, Hida Y, Maishi N, Kawamoto T, Kitayama K, Akiyama K, Osawa T, Kondoh M, Matsuda K, Onodera Y, Fujie M, Kaga K, Hirano S, Shinohara N, Shindoh M, Hida K.
    • Journal Title

      Br J Cancer

      Volume: 106(6) Issue: 6 Pages: 1214-23

    • DOI

      10.1038/bjc.2012.59

    • Related Report
      2012 Annual Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CXCR7: A novel tumor endothelial marker in renal cell carcinoma2012

    • Author(s)
      Maishi N, Ohga N, Hida Y, Akiyama K, Shinohara N, Nonomura K, Shindoh M, Hida K. Kitayama K, Osawa T, Onodera Y
    • Journal Title

      Pathol Int

      Volume: 65(5) Issue: 5 Pages: 309-17

    • DOI

      10.1111/j.1440-1827.2012.02792.x

    • NAID

      10031185206

    • Related Report
      2012 Annual Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heterogeneity of Tumor Endothelial Cells : Comparison between Tumor Endothelial Cells Isolated from Highly Metastatic and Low Metastatic2012

    • Author(s)
      Ohga N
    • Journal Title

      Am J Pathol

      Volume: 180(3) Issue: 3 Pages: 1294-1307

    • DOI

      10.1016/j.ajpath.2011.11.035

    • Related Report
      2012 Annual Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Tumor endothelial cells acquire drug resistance by MDR1 upregulation via VEGF signaling in tumor microenvironment2012

    • Author(s)
      Akiyama K.
    • Journal Title

      Am J Pathol

      Volume: 180(3) Issue: 3 Pages: 1283-1293

    • DOI

      10.1016/j.ajpath.2011.11.029

    • Related Report
      2012 Annual Research Report 2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Size-controlled, dual-ligand modified liposomes that target the tumor vasculature show promise foruse in drug-resistant cancer therapy2012

    • Author(s)
      Takara K.
    • Journal Title

      J Controlled Release

      Volume: 162(1) Pages: 225-232

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cyclooxygenase-2 inhibition causes antiangiogenic effects on tumor endothelial and vascular progenitor cells2012

    • Author(s)
      Muraki C, Ohga N, Hida Y, Nishihara H, Kato Y, Tsuchiya K, Matsuda K, Totsuka Y, Shindoh M, Hida K.
    • Journal Title

      Int J Cancer

      Volume: 130(1) Issue: 1 Pages: 59-70

    • DOI

      10.1002/ijc.25976

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] HuR keeps an angiogenic switch on by stabilizing mRNA of VEGF and COX-2 in tumor endothelium2011

    • Author(s)
      Kurosu T.
    • Journal Title

      Br J Cancer

      Volume: 104(5) Issue: 5 Pages: 819-829

    • DOI

      10.1038/bjc.2011.20

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Dual-ligand modification of PEGylated liposomes shows better cell selectivity and efficient gene delivery2011

    • Author(s)
      Kibria G.
    • Journal Title

      J Controlled Release

      Volume: 153(2) Pages: 141-148

    • Related Report
      2011 Annual Research Report
    • Peer Reviewed
  • [Presentation] Heterogeneity of Tumor Endothelial Cells.2012

    • Author(s)
      Hida K.
    • Organizer
      The 43rd International Symposium of The Princess Takamatsu Cancer Research Fund“Cancer Heterogeneity: Impact on Carcinogenesis, Cancer Stem Cell, Microenvironment, Diagnosis and Treatment”
    • Place of Presentation
      ホテルグランドパレス(東京都)
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] Altered phenotype in endothelial cells in tumor microenvironment.2012

    • Author(s)
      Hida K.
    • Organizer
      The 2nd International Symposium by JSPS Core-to-Core Program“Cooperative International Framework in TGF-β Family Signaling”
    • Place of Presentation
      昭和薬科大学(東京都)
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] がん微小環境と血管新生2012

    • Author(s)
      樋田京子
    • Organizer
      第57回日本口腔外科学会総会・学術大会ワークショップ「がん治療戦略を目指した先端的がん研究」
    • Place of Presentation
      パシフィコ横浜(横浜市)
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] 血管を標的とした新規抗がん剤の開発を目指して2012

    • Author(s)
      樋田京子
    • Organizer
      第43回PFA国際歯学会日本部会年次大会-ピエールフォーシャルアカデミー国際歯学会日本部会
    • Place of Presentation
      ホテルオークラ札幌(札幌市)
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] Crosstalk between tumor endothelial cells and tumor cells.2012

    • Author(s)
      Hida K.
    • Organizer
      The 71st Annual Meeting of the Japanese Cancer Association
    • Place of Presentation
      ホテルさっぽろ芸文館(札幌市)
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] がんの浸潤転移と血管新生2012

    • Author(s)
      樋田京子
    • Organizer
      第28回日本DDS学会学術集会
    • Place of Presentation
      札幌コンベンションセンター
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] 腫瘍血管内皮細胞の異常性と転移との関連2012

    • Author(s)
      樋田京子
    • Organizer
      第101回日本病理学会総会コンパニオンミーティング7「口腔癌の悪性形質の発現に関する橋渡し研究と分子標的治療への応用」
    • Place of Presentation
      京王プラザホテル(東京都)
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] Characterization of stem-like tumor endothelial cells, The 20th annual Meeting of the Japanese Vascular Biology and MedicineOrganization2012

    • Author(s)
      Hida K.
    • Organizer
      The 10th Korea-Japan Joint Symposium on Vascular Biology
    • Place of Presentation
      あわぎんホール(徳島市)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Tumor endothelial cell s acquire drug resistance by MDR1 upregulation2012

    • Author(s)
      Hida K.
    • Organizer
      the 17th International Vascular Biology Meeting
    • Place of Presentation
      Rein-Main-Hallen(Wiesbaden, Germany)
    • Related Report
      2012 Annual Research Report
  • [Presentation] 腫瘍血管の多様性とがんの転移2011

    • Author(s)
      樋田京子
    • Organizer
      Recent Advance in Tumor Angiogenesis 2011
    • Place of Presentation
      グランドホテル浜松(浜松市)
    • Related Report
      2011 Annual Research Report
    • Invited
  • [Presentation] 腫瘍血管新生阻害療法における新たな局面-Lesson from Basic research2011

    • Author(s)
      樋田京子
    • Organizer
      函館Basic Cancer Forum
    • Place of Presentation
      ベルクラシック函館(函館市)
    • Related Report
      2011 Annual Research Report
    • Invited
  • [Presentation] 腫瘍血管内皮細胞の異常性がもたらすがん治療への影響2011

    • Author(s)
      樋田京子
    • Organizer
      平成23年度遺伝子病制御研究所共同研究集会,「がん細胞・組織の多様性の出現・維持に関わる微小環境因子」
    • Place of Presentation
      北海道大学医学部フラテ会館(札幌市)
    • Related Report
      2011 Annual Research Report
    • Invited
  • [Presentation] 腫瘍血管特異性の解明と新たな血管新生阻害療法への応用2011

    • Author(s)
      樋田京子
    • Organizer
      大阪歯科大学大学院50周年記念講演会
    • Place of Presentation
      大阪歯科大学楠葉学舎(大阪府枚方市)
    • Related Report
      2011 Annual Research Report
    • Invited
  • [Presentation] A New Insights into Tumor endothelial cell2011

    • Author(s)
      Kyoko Hida
    • Organizer
      The 5th Meeting of Asian Society of Oral and Maxillofacial Pathology
    • Place of Presentation
      九州大学医学部百年講堂(福岡市)
    • Related Report
      2011 Annual Research Report
    • Invited
  • [Presentation] 腫瘍血管内皮細胞の特異性とその制御2011

    • Author(s)
      樋田京子
    • Organizer
      ACCEL in Hokkaido~NSCLCに対するアバスチンの治療戦略~
    • Place of Presentation
      アートホテルズ札幌(札幌市)
    • Related Report
      2011 Annual Research Report
    • Invited
  • [Presentation] 腫瘍血管内皮細胞の多様な生物像2011

    • Author(s)
      樋田京子
    • Organizer
      第27回日本DDS学会学術集会
    • Place of Presentation
      東京大学本郷キャンパス(東京都)
    • Related Report
      2011 Annual Research Report
    • Invited
  • [Presentation] 癌間質の異常,とくに腫瘍血管の特性と浸潤との関連性2011

    • Author(s)
      樋田京子
    • Organizer
      第100回日本病理学会総会コンパニオンミーティング4「口腔癌の浸潤:外科病理と分子病理の架け橋」(震災のため中止,誌上発表)
    • Place of Presentation
      東京大学本郷キャンパス(東京都)
    • Related Report
      2011 Annual Research Report
    • Invited
  • [Presentation] Analysis of interaction between tumor endothelial cells and tumor cells2011

    • Author(s)
      Nako Maishi
    • Organizer
      AACR 102nd ANNUAL MEETING 2011
    • Place of Presentation
      Orange County Convention Center(Orlando, Florida, USA)
    • Related Report
      2011 Annual Research Report
  • [Presentation] Gene expression analysis of circulating endothelial cells in cancer patients2011

    • Author(s)
      Miyako Kondoh
    • Organizer
      AACR 102nd ANNUAL MEETING 2011
    • Place of Presentation
      Orange County Convention Center(Orlando, Florida, USA)
    • Related Report
      2011 Annual Research Report
  • [Book] 佐藤靖史,髙倉伸幸編,血管新生研究の最先端2013

    • Author(s)
      樋田京子(分担執筆)
    • Total Pages
      331
    • Publisher
      医薬ジャーナル社
    • Related Report
      2012 Annual Research Report
  • [Book] 日本血管生物医学会編「血管生物医学事典」2011

    • Author(s)
      樋田京子(分担執筆)
    • Total Pages
      350
    • Publisher
      朝倉書店
    • Related Report
      2011 Annual Research Report
  • [Remarks] 北海道大学大学院 歯学研究科 血管生物学教室

    • URL

      http://www.den.hokudai.ac.jp/vascular-biology/

    • Related Report
      2012 Annual Research Report
  • [Remarks] 北海道大学大学院 歯学研究科 血管生物学教室

    • URL

      http://www.den.hokudai.ac.jp/vascular-biology/

    • Related Report
      2011 Annual Research Report

URL: 

Published: 2011-04-06   Modified: 2019-07-29  

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