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腫瘍関連ムチンのがん診断治療への応用

Research Project

Project/Area Number 06282250
Research Category

Grant-in-Aid for Scientific Research on Priority Areas

Allocation TypeSingle-year Grants
Research InstitutionSapporo Medical University

Principal Investigator

今井 浩三  札幌医科大学, 医学部, 教授 (60117603)

Co-Investigator(Kenkyū-buntansha) 日野田 裕治  札幌医科大学, 医学部, 助教授 (10165128)
牧口 祐介  札幌医科大学, 医学部, 助手 (40274922)
高橋 徹  札幌医科大学, 医学部, 助手 (70253995)
今井 浩三 (高橋 徹)  札幌医科大学, 医学部, 教授 (60117603)
高橋 徹  札幌医科大学, 医学部, 助手 (30188031)
Project Period (FY) 1994 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥20,500,000 (Direct Cost: ¥20,500,000)
Fiscal Year 1996: ¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 1995: ¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1994: ¥7,000,000 (Direct Cost: ¥7,000,000)
Keywordsムチン抗原 / MUC1 / モノクローナル抗体 / 抗ムチン抗体 / CTL / 脱糖鎖 / 腫瘍関連ムチン / MUC-1
Research Abstract

腫瘍細胞におけるムチンは、腫瘍細胞の細胞生物学的な機能に深く関与する重要な分子であることが示唆されるため、MUC1を中心とするムチン分子の、腫瘍細胞における種々の機能を解析し、以下の諸点を明らかにした。
1.ヒト腫瘍細胞株やマウス腺維芽細胞株にMUC1遺伝子を導入した細胞株を各種作製し、細胞生物学的側面から転移能や増殖能につき検討を加えた。MUC1は細胞凝集の抑制にはたらくとともに、in vivo、in vitroにおいて細胞増殖の抑制に作用した。線維芽細胞株に対するボンベシンの効果や、コラーゲン、フィブロネクチンをコートしたdish上での細胞増殖刺激効果がMUC1遺伝子導入により阻害され、MUC1が細胞表面レセプターと各刺激因子との相互作用を抑制する可能性が考えられた。
2.脱糖鎖した胃のムチンを免疫原として新たなモノクローナル抗体(MoAb)A3D4を作製した。MoAbA3D4は正常消化器では大腸と胆嚢のみに陽性であるが、正常胃上皮とは反応せず胃癌と高率に反応した。正常大腸のlysateを用いたウエスタンブロットでは高分子量のスメア様のバンドが認められ、MoAbA3D4は既報のムチンコア蛋白とは異なる新たムチン分子を認識する可能性が示唆された。
3.多発性骨髄腫患者の骨髄液中のリンパ球からCTLラインTSとKYを作製した。これらのCTLは骨髄腫細胞株や乳癌細胞株を幅広く障害した。MUC1トランスフェクタントを用いた実験等により、CTLは腫瘍細胞上のMUC1をHLA非拘束性にTCRを用いて認識することが示された。またMUC1を発現する腫瘍細胞の脱糖鎖により、細胞障害性は著しく増強され、MUC1上のCTLエピトープの発現にはMUC1の脱糖鎖が重要であると考えられた。

Report

(3 results)
  • 1996 Annual Research Report
  • 1995 Annual Research Report
  • 1994 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Takahashi,T.: "Reactivity of Autologous CD4^+ T Lymphocytes Against Human Melanoma : Evidence for a Shared Melanoma Antigen Presented by HLA-DR15." J.Immunol.154. 772-779 (1995)

    • Related Report
      1996 Annual Research Report
  • [Publications] Katayose,Y.,Imai,K.: "MUC-1 specific targeting immunotherapy with bispecific antibodies." Cancer Res.56. 4205-4212 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yamamoto,H.,Imai,K.: "Inverse association of cell adhesion regulator messenger RNA expression with metastasis in human colorectal cancer." Cancer Res.56. 3605-3609 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Makiguchi,Y.: "Effect of MUC1 mucin,an anti-adhesion molecule,on tumor cell growth." Jap.J.Cancer Res.87. 505-511 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Toyota,M.,Imai,K.: "A rat genetic map constructed by representational differenceanalysis : suitability for large scale typing." Proc.Natl.Acad.Sci.USA. 93. 394-399 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Adachi,M.,Imai,K.: "Mammalian SH2-containing protein tyrosine phosphatases." Cell. 85. 15 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Adachi,M.,Imai,K.: "Interleukin-2 (IL-2) upregulates BAG-1 gene expression through serine-rich region within IL-2 receptor b chain." Blood. 88. 4118-4123 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Noto,H.,Takahashi,T.: "Cytotoxic T lymphocytes derived from bone marrow mononuclear cells of multiple myeloma patients recognize underglycosylated form of MUC1 mucin." Int.Immunol.(印刷中). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Adachi,M.,Imai,K.: "Interleukin-2 induces tyrosine phophorylation of SHP-2 through IL-2 receptor β chain." Oncogene. (印刷中). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yamamoto,H.,Imai,K.: "Relation of enhanced secretion of active matrix metalloproteinases with tumor spread in human hepatocellular carcinoma." Gastroenterol.(印刷中). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Tanaka,K.,Hinoda,Y.: "Decreased expression of biliary glycoprotein in hepatocellular carcinomas." Int.J.Cancer. (印刷中). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Makiguchi,Y., Imai,K., et al.: "Effect of MUC1 mucin, an anti-adhesion molecule,on tumor cell growth.21GC01:Jpn.J.Cancer Res." (in press). (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takahashi,T., Chapman,PB.,et al.: "Reactivity of autologous CD4^+ T lymphocytes against human melanoma:Evidence for a shared melanoma antigen presented by HLA-DR15." J.Immunol.156. 772-779 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Hinoda,Y., Imai,K., et al.: "Internal image-bearing anti-idiotypic monoclonal antibodies." Tumor Biol.16. 48-55 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Takahashi,T.,Imai,K.et al.: "Expression of MUC1 on myeloma cells and induction of HLA-unrestricted cytotoxic T lymphocytes from a multiple meyloma patient." J.Immunol.153. 2102-2109 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Toyota,M.,Imai,K.et al.: "cDNAcloning and characterization of truncated form of c-kit in human colon carcinoma cells." Cancer Res.54. 272-275 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Ohe,T.,Imai,K.et al.: "Expression of sulfated carbohydrate chains detected by monoclonal antibody 91.9H in human gastric cancer tissues." Jpn.J.Cancer Res.85. 400-408 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kakiuchi,H.,Imai,K.et al.: "Specific 5′-GGGA-3′ to5′-GGA-3′mutation of the APC genein rat colon tumors induced by 2 amino 1 methy1 6 phenylimidazo[4-5b]pyridine." Proc.Natl.Acad.Sci.USA. (in press).

    • Related Report
      1994 Annual Research Report
  • [Publications] Isobe.M.,Imai,K.et al.: "Chromosomal localization of an SH2 containing tyrosine phosphatase (SH-PTP3) gene to chromosome 12q24." Oncogene. 9. 1751-1753 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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