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ガラクトース型C型レクチンによる消化器癌転移の制御とその診断への応用

Research Project

Project/Area Number 18013016
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Review Section Biological Sciences
Research InstitutionThe University of Tokyo

Principal Investigator

入村 達郎  The University of Tokyo, 大学院・薬学系研究科, 教授 (80092146)

Co-Investigator(Kenkyū-buntansha) 中森 正二  国立病院機構大阪医療センター, 臨床研究部・分子医療室, 室長 (70294080)
奥村 明彦  愛知医科大学, 医学部, 講師 (70288512)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥13,400,000 (Direct Cost: ¥13,400,000)
Fiscal Year 2007: ¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 2006: ¥6,600,000 (Direct Cost: ¥6,600,000)
Keywords大腸癌 / 胃癌 / 肝転移 / レクチン / ASGPR
Research Abstract

本研究ではヒト及びマウス胃癌及び大腸癌細胞において、肝実質細胞に発現するC型レクチンASGRの機能が転移形成に重要であることを分子レベルで検証すること及びこれを肝転移の治療に役立てることを目的とした。具体的には、ASGRと結合する責任分子を同定してその分子機能を明らかにすることによりカウンターレセプターとして確立する、その発現及び構造変化(グリコフォーム等)と癌の進行及び悪性挙動との関係を究明する、このレクチンの低分子リガンドであるガラクトースを用いてマウスにおいて転移形成の抑制を試み治療薬としての可能性を実験的に検証する、などであった。2年間の研究期間及び6ヶ月の延長期間に以下の結果を得た。
ASGPR遺伝子を欠損させたマウスにおいて、大腸癌の実験的肝転移が有意に低下すること、ASGPRの競合阻害物質であるガラクトースの投与によって、肝転移が抑制されることを示し、マウス実験モデルにおいてASGPRとの相互作用が転移促進因子であることを証明した。またこれがASGPRを介する細胞接着による細胞増殖の促進によることを示した。ASGRを介して接着した状態ではヒト大腸癌細胞が複数の抗癌剤に対する耐性が上昇していることを示す実験結果を得た。ヒト胃癌細胞株を用いて表面へのASGPR結合性によって細胞選別を行いASGPR高結合細胞と低結合細胞とを得た。高結合性細胞はヌードマウスに於ける実験的な肝転移性が低結合性細胞より著しく高かった。即ち胃癌の肝転移機構についても、ASGPRの重要性が示された。胃癌細胞表面のASGR結合分子をASGRアフィニティークロマトグラフィーによって精製し、プロテオミックス解析によって、主要な画分がラミニン5:1:1:であることを明らかにした。この分子の発現がヒト胃癌の悪性挙動と関係することは既に推定されていたが、ASGRとの相互作用に介在するというメカニズムが初めて明らかになった。パラフィン包埋ヒト大腸癌組織及び胃癌組織に於いて、リコンビナントASGRの結合性が組織学的に検出され、上記の相互作用の重要性を臨床的に示す基盤が築かれた。

Report

(2 results)
  • 2008 Annual Research Report
  • 2006 Annual Research Report
  • Research Products

    (22 results)

All 2008 2007 2006 Other

All Journal Article (20 results) (of which Peer Reviewed: 8 results) Presentation (2 results)

  • [Journal Article] A lectin recognizes differential arrangements of 0-glycans on mucin repeats.2008

    • Author(s)
      Kato K, et. al.
    • Journal Title

      Biochem Biophys Res Commun 371(4)

      Pages: 698-701

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] MUC4 interacts with ErbB2 in human gallbladder carcinoma : potential pathobiological implications.2008

    • Author(s)
      Miyahara N, et. al.
    • Journal Title

      Eur J Cancer 44(7)

      Pages: 1048-56

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Heparanase expression in B16 melanoma cells and peripheral blood neutrophils before and after extravasation detected by novel anti-mouse heparanase monoclonal antibodies2008

    • Author(s)
      Komatsu N, et. al.
    • Journal Title

      J Immunol Meth. 331(1-2)

      Pages: 82-93

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Differential effector mechanisms induced by vaccination with MUC1 DNA in the rejection of colon carcinoma growth at orthotopic sites and metastases.2008

    • Author(s)
      Sugiura D, et. al.
    • Journal Title

      Cancer Sci. (in press)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Human colon carcinoma cell growth is enhanced by immobilized hepatic asialoglycoprotein receptor 1.2008

    • Author(s)
      Fang JB, et. al.
    • Journal Title

      Oncol Res. (in press)

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biological and therapeutic significance of MUC1 with sialoglycans in clear cell adenocarcinoma of the ovary.2007

    • Author(s)
      Tamada Y, et. I.
    • Journal Title

      Cancer Sci. 98(10)

      Pages: 1586-1591

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Expression of NEU3 (plasma membrane-associated sialidase) in dear cell ade nocarcinoma of the ovary : its relationship with T factor of pTNM classification.2007

    • Author(s)
      Nomura H, et. al.
    • Journal Title

      Oncol Res. 16(6)

      Pages: 289-297

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification and expression of human epiglycanin/MUC21 : a novel transmembrane mucin.2007

    • Author(s)
      Itoh Y, et. al.
    • Journal Title

      Glycobiology 18(1)

      Pages: 74-83

    • Related Report
      2008 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Properties of blocking and non-blocking monoclonal antibodies specific for human macrophage galactose-type C-type lectin (MGL/ClecSF1OA/CD301).2007

    • Author(s)
      Sano Y, et al.
    • Journal Title

      J Biochem 1093・10

      Pages: 127-136

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Involvement of ribonucleotide reductase M1 subunit overexpression in gemcitabine resistance of human pancreatic cancer.2007

    • Author(s)
      Nakahira S, et al.
    • Journal Title

      Int J Cancer 120 (6)

      Pages: 1355-1363

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Molecular cloning and characterization of a novel 3'-phosphoadenosine 5'-phosphosulfate transporter, Part2. JBC, published online, 20062006

    • Author(s)
      Kamiyama S, et al.
    • Journal Title

      J Biol Chem 281

      Pages: 10945-10953

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Tyro3 family-mediated cell entry of Ebola and Marburg viruses.2006

    • Author(s)
      Shimojima M, et al.
    • Journal Title

      J Virol 80・20

      Pages: 10109-10116

    • Related Report
      2006 Annual Research Report
  • [Journal Article] The dermal microenvironment induces the expression of alternative activation markers in mononuclear phagocytes independent of IL-4/IL-13 signaling.2006

    • Author(s)
      Marcel Dupasquier, et al.
    • Journal Title

      J Leukocyte Biol 80

      Pages: 838-849

    • Related Report
      2006 Annual Research Report
  • [Journal Article] The SHAP-hyaluronan complex in serum from patients with chronic liver diseases caused by hepatitis virus infection.2006

    • Author(s)
      Shen L.et al.
    • Journal Title

      Hepatology Research 34

      Pages: 178-186

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Alteration of serum cytokine balances among differentphase of chronic hepatitis B virus infection.2006

    • Author(s)
      Ayada M. et al.
    • Journal Title

      Hepatology Research 34

      Pages: 214-221

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Expression pattern of angiogenic factors and prognosis after hepatic resection in hepatocellular carcinoma : importance of angiopoietin-2 and hypoxia-induced factor-1a2006

    • Author(s)
      Wada H, et al.
    • Journal Title

      Liver Int. 26 (4)

      Pages: 414-423

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Expression of type I interferon receptor as a predictor of clinical response to interferon- alpha therapy of gastrointestinal cancers.2006

    • Author(s)
      Ota H, et al.
    • Journal Title

      Oncol Rep 16 (2)

      Pages: 249-255

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Hepatoma-derived growth factor is a novel prognostic factor for patients with pancreatic cancer.2006

    • Author(s)
      Uyama H, et al.
    • Journal Title

      Clin Cancer Res 12

      Pages: 6043-6048

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Effect of vitamin K2 on the recurrence in patients with heaptocellular carcinoma.

    • Author(s)
      Hotta N. et al.
    • Journal Title

      Hepato-gastroenterology (in press)

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Expression of Toll-like receptors in chronic hepatitis C virus infection.

    • Author(s)
      Sato K.et al.
    • Journal Title

      Journal of gastroenterology and Hepatology (in press)

    • Related Report
      2006 Annual Research Report
  • [Presentation] Involvement of asialoglycoprotein receptor in liver metastasis of colon carcinomas.2008

    • Author(s)
      Ueno S, et. al.
    • Organizer
      Metastasis Research Society(MRS) - the American Association for Cancer(AACR) Joint Conference on Metastasis
    • Place of Presentation
      Vancouver, BC, Canada
    • Year and Date
      2008-08-06
    • Related Report
      2008 Annual Research Report
  • [Presentation] A Novel Transmembrane Mucin MUC21.2007

    • Author(s)
      Irimura T, et. al.
    • Organizer
      The 27th Sapporo Cancer Seminar International Synposium
    • Place of Presentation
      Sapporo, Japan
    • Year and Date
      2007-07-12
    • Related Report
      2008 Annual Research Report

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Published: 2006-04-01   Modified: 2018-03-28  

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