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Estashment of peritoneal dissumination model and clinical application.

Research Project

Project/Area Number 09671291
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Digestive surgery
Research InstitutionKanazawa University

Principal Investigator

YONEMURA Yutaka (1998)  University Hospital, Kanazawa University, Assistant Professor, 医学部・附属病院, 講師 (20167042)

藤村 隆 (1997)  金沢大学, 医学部・附属病院, 助手 (50262580)

Co-Investigator(Kenkyū-buntansha) YODHIO Endou  Kanazawa University, Deoartmebt of experimetal theraapentis Cancer Research cebt, 助手 (30211783)
米村 豊  金沢大学, 医学部・附属病院, 講師 (20167042)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1998: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1997: ¥1,500,000 (Direct Cost: ¥1,500,000)
KeywordsMMP-7 / MKN-45-P / MMP-11 / c-met / AMFredepter / integrinalpha2alpha3 / Integrin. / urokinase / VEGF / antisense oligo / MMP-1 / integrin / IL-8 / IL-6 / TIMP-2 / VLA-2 / VLA-3 / MTI-MMP
Research Abstract

To clarify the molecular mechanisms of the formation of peritoneal dissemination, a highly metastatic cell line, named MKN-45-P was established from gastric cancer cell line of MKN-45 by repeat intraperitoneal inoculation of free cancer cells in ascites. Intraperitoneal inoculation of 1O^7 cells of this cell line can reproduce peritoneal dissemination with bloody ascites. Screening of metastasis related genes, which are expressed from this cell line was performed using specific primers. Among more than 30 metastasis related genes, MKN-45-P expressed MMP-7, MMP-l1, urokinase type plasminogen activator, and its receptor, MTl-MMP, integrin alpha2, alpha3, betal, c-erbB-2 , c-met, mst-l, autoctine motility factor and its receptor. Among these gene products. MMP-7, integrin alpha2, alpha3, beta1, and c-erbB-2 are expressed in a large amount, as the metastatic potential increases. In the in vitro experiments, anti integrin antibodies against integrin alpha2, alpha3, beta1 inhibited the adhes … More ion and invasion abilities of this cell line. Furthermore, when 1O^7 cells of this cell line after treatment of anti-integrin monoclonal antibody for 48 hours were intraperitoneally inoculated in nude mice, the survival of mice of Mab treated group was significantly longer than that of non treated group.
Antisense oligonucleotides of 16 mer DNA containing initiation codon of AUG of c-met, and AMFR mRNA completely suppressed the invasion ability of MKN-45-P through Matrigel coated chamber. Furthermore, antisense oligonucleotides against MMP-7 was tried whether this S-oligo. can inhibit the invasion and proliferation activity of MKN-45-P or not. Even by treating 10 muM of the antisense DNA for 48 hours, proliferative activity of MKN-45-P was not suppressed. In contrast, invasion ability of MKN-45-P was completely blocked by this antisense DNA.However, antisense DNA against MMP-7 did not improve the survival of nude mice bearing MKN-45-P, inoculated intraperitoneally.
MKN-45-P also expressed c-ets -l gene, and this gene product (Ets-l) is a transcription factor of several metastasis associated genes, such as MMP-l, -3, -9, MTl-MMP, urokinase, integrin subunites, and c-erbB-2. By treatment of MKN-45-P with antisense DNA against c-ets -l mRNA, expressions of urokinase, MMP-l , integrin a2, cx.3 and MMP-7 were dramatically reduced. As a results, adhesion and invasion ability of MKN-45-P were completely inhibited after treatment of antisense DNA agains c-ets -l mRNA.
In addition, the antisense DNA improved the survival of nude mice bearing intraperitoneal MKN45-P.From these results, this highly metastatic cell line acquires the overexpression of multiple metastasis related genes, such as adhesion molecules, motility factors and matrix digesting enzymes. The control of c-ets-1 gene may suppress several metastasis related genes simultaneously , and the strategy to control c-ets-I mRNA may be a hopeful one to treat peritoneal dissemination. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Yonemura,Y.,Nojima,N.,et al.: "E-cadherin and c-met expression as a aprognostic factor in gastric cancer." Oncology Reports. 4. 743-748 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yonemura,Y.,Endou,Y.,et al.: "A possible fole of cytokines in the formation of peritoneal dissemination." Int J Oncol. 11. 349-358 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Taniguchi,K.,Yonemura,Y.,et al.: "The relation between the growth patterns of gastric carcinoma and the expression of hepalocyte growth factor receptor (c-met),autocrine motility factor receptor,and urokinase-type plasminogen activator recepter." Cancer. 82. 362-365 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tsugawa,K.,Yonemura,Y.,et al.: "Amplification of the c-met,c-erbB-2 and epidermal growth factor receptor gene in human gastric cancers:Correlation to clinical features." Oncology. 55. 475-481 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yonemura,Y.,Ninomiya,I.,et al.: "Prognostic significance of c-erbB-2 gene expression in the poorly differrentiated type of adenocarcinoma of the stomach." Cancer petection and Preventionr. 22. 139-146 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yonemura,Y.: "Preitoneal Dissemination" Maeda shoten Co.,Ltd, 301 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yonemuraa, Y., Nojima, N., etal.: "E-cadherin and c-met expression as a aprognosic factor in gastric cancer" Oncology Reports. 4. 743-748 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yonemura, Y., Endou, Y., etal.: "A possible role of cytokines in the formation of peritoneal dissemination." Int J Oncol. 11. 349-358 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Taniguchi, K., Yonemura, Y., etal.: "the relation between the growth patterns of gastricc carcinoma and the expresssion of hepatocyte growth factor receptor (c-met), autocrine motiltity factor receptor, and urokinase-type Plasminogen activator recepter." Cancer. 82. 362-365 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Tsugawa, K., Yonemura, Y., etal.: "Amplification of the c-met, c-erbB-2 and epidermal growth factor recepter gene in human gastric cancers : Correlation to clinical features." Oncology. 55. 475-481 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yonemura, Y., Ninomiya, I., etal.: "Prognostic significance of c-erbaB-2 gene expresion in the poorly differrentiated type of adenocarcinoma of the stomach." Cancer petection and Preventionr. 22. 139-146 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yonemura, Y.: Preitoneal Dissemination. Maeda Shoten co., Ltd, 301 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Yonemura, Y., Nojima, N., etal.: "E-cadherin and c-met expression as a aprognostic factor in gastric cancer." Oncology Reports. 4. 743-748 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yonemura, Y., Endou, Y., etal.: "A possible role of cytokines in the formation of peritoneal dissemination." Int J Oncol. 11. 349-358 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Taniguchi, K., Yonemura Y., etal.: "The relation between the growth patterns of gastric carcinoma and the expression of hepatocyte growth factor receptor(c-met), autocrine motility factor receptor, and urokinase-type plasminogen activator recepter." Cancer. 82. 362-365 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tsugawa, K., Yonemura, Y., etal.: "Amplification of the c-met, c-erbB-2 and epidermal growth factor receptor gene in human gastric cancers:Correlation to clinical features." Oncology. 55. 475-481 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yonemura, Y., Ninoiya, I., etal.: "Prognostic significance of c-erbB-2 gene expression in the poorly differrentiated type of adenocarcinoma of the stomach." Cancer petection and Preventionr. 22. 139-146 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Yonemura, Y.: "Preitoneal Dissemination" Maeda Shoten Co., Ltd, 301 (1997)

    • Related Report
      1998 Annual Research Report
  • [Publications] Takashi Fujimura: "E-cadherin and c-met expression as a prognostic factor in gastric cancer" Oncology report. 4. 743-748 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Takashi Fujimura: "Participation of c-met in the progression of human gastric cancers anti-c-met oligonucleotides inhibit proliferation or invasveness of gastric cance cells" Cancer Gene Ther. 3. 393-404 (1996)

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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