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Development of a new molecular target therapy for ovarian carcinoma based on the analyses of mechanisms for its peritoneal dissemination

Research Project

Project/Area Number 15390502
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Obstetrics and gynecology
Research InstitutionShinshu University

Principal Investigator

KONISHI Ikuo  Shinshu University, School of Medicine, Professor, 医学部, 教授 (90192062)

Co-Investigator(Kenkyū-buntansha) NIKAIDO Toshio  Shinshu University, School of Medicine, Professor, 医学部, 教授 (50180568)
HIRIUCHI Akiko  Shinshu University, School of Medicine, Assistant, 医学部, 助手 (80334895)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥16,900,000 (Direct Cost: ¥16,900,000)
Fiscal Year 2004: ¥6,500,000 (Direct Cost: ¥6,500,000)
Fiscal Year 2003: ¥10,400,000 (Direct Cost: ¥10,400,000)
KeywordsOvarian cancer / Peritoneal dissemination / Molecular target therapy / Microenvironment / Hypoxia / E-cadherin / SNAIL / Rho / LPA
Research Abstract

Ovarian carcinoma is the leading cause of gynecological cancer death. The poor prognosis for patients with ovarian cancer is related with peritoneal dissemination ; a metastatic process in which cancer cells detach from the primary tumor, attach to the peritoneum, and re-grow at the site. The objective of this study is to develop a new molecular target therapy, based on the analyses of the molecular mechanisms of peritoneal dissemination of ovarian cancer cells.
In the metastatic process, since cancer cells become independent from the blood supply and exposed to hypoxia, we focused on the hypoxic environment and. Ovarian cancer cells in the tip of papillary projection actually expressed HIF-1 alpha, being associated with reduced expression of E-cadherin. In vitro experiment indicated that hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL that is a repressor of E-cadherin promotor, and also increases the invasive capacity. These findings suggest that hypoxia play … More s an important role in the dissemination of ovarian cancer cells in the primary lesion.
In the metastaic sites, we focused on the small GTPase RhoA, that is the candidate of common pathway from various growth signals from the ascites. The expression of RhoA was significantly higher in the peritoneal dissemination than in the primary lesion. Up-regulation and activation of Rho by treatment with lysophospahtidic acid (LPA) increased the invasiveness of cancer cells, and treatment with C3 exoenzyme, a specific inhibitor of Rho, reversed the effect of LPA treatment. Ex vivo model using nude mice showed that peritoneal dissemination was more prominent in ovarian cancer cells expressing Rho constitutively. In addition, our preliminary study showed that oral administration of statins, potential inhibitor of Rho activation, suppressed the peritoneal dissemination of ovarian cancer cells. These findings indicate that RhoA is a good molecular target in the new therapy for peritoneal dissemination of ovarian carcinoma. Less

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (18 results)

All 2005 2004 2003 2002 Other

All Journal Article (13 results) Book (2 results) Publications (3 results)

  • [Journal Article] Elevated expression of E-cadherin, alpha-, beta-, and gamma-catenins in metastatic lesions compared with primary epithelial ovarian carcinomas.2004

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

      Human Pathology 36

      Pages: 1469-1476

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of BRCA1 protein in benign, borderline, and malignant epithelial ovarian neoplasms and its relationship to methylation and alleic loss of the BRCA1 gene.2004

    • Author(s)
      Wang C, et al.
    • Journal Title

      Journal of Pathology 202

      Pages: 215-223

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Elevated expression of E-cadherin, alpha-, beta-, and gamma-catenins in metastatic lesions compared with primary epithelial ovarian carcinomas.2004

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

      Hum Pathol 35

      Pages: 1469-1476

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of BRCA1 protein in benign, borderline, and malignant epithelial ovarian neoplasms and its relationship to methylation and alleic loss of the BRCA1 gene.2004

    • Author(s)
      Wang C, et al.
    • Journal Title

      J Pathol 202

      Pages: 215-223

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Elevated expression of E-cadherin, alpha-, beta-, and gamma-catenins in metastatic lesions compared with primary epithelial ovarian carcinomas.2004

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

      Human Pathology 35

      Pages: 1469-1476

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells.2003

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

      American Journal of Pathology 163

      Pages: 1437-1447

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Up-regulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma.2003

    • Author(s)
      Horiuchi A, et al.
    • Journal Title

      Laboratory Investigation 83

      Pages: 861-870

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Toward understanding the natural history of ovarian carcinoma development : a clinicopathological approach.2003

    • Author(s)
      Horiuchi A, et al.
    • Journal Title

      Gynecologic Oncology 88

      Pages: 309-317

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Hypoxia attenuates the expression of E-cadherin via up-regulation of SNAIL in ovarian carcinoma cells.2003

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

      Am J Pathol 163

      Pages: 1347-1447

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Up-regulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma.2003

    • Author(s)
      Horiuchi A, et al.
    • Journal Title

      Lab Invest 83

      Pages: 861-870

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Toward understanding natural history of ovarian carcinoma development : a clinicopathological approach.2003

    • Author(s)
      Horiuchi A, et al.
    • Journal Title

      Gynecol Oncol 88

      Pages: 309-317

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hypoxia-induced changes in the expression of VEGF, HIF-1alpha, and cell cycle-related molecules in ovarian carcinoma cells.2002

    • Author(s)
      Horiuchi A, et al.
    • Journal Title

      Anticancer Research 22

      Pages: 2697-2702

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hypoxia-induced changes in the expression of VEGF, HIF-1 alpha and cell cycle-related molecules in ovarian cancer cells.2002

    • Author(s)
      Horiuchi A, et al.
    • Journal Title

      Anticancer Res 22

      Pages: 2697-2702

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] Trends in Ovarian Cancer Research2005

    • Author(s)
      Horiuchi A, Konishi I
    • Total Pages
      20
    • Publisher
      Nova Publishers
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Book] Trends in Ovarian cancer Research.2005

    • Author(s)
      Horiuchi A, Konishi I
    • Publisher
      Nova Publishers
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Horiuchi A, et al.: "Up-regulation of small GTPases, Rho A and Rho C, is associated"Lab Invest. 83. 861-870 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Horiuchi A, et al.: "Toward understanding the natural history of ovarian carcinoma"Gynecol Oncol. 88. 309-317 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Imai T, Horiuchi A, et al.: "Hypoxia attenuates the expression of E-cadherin via"Am J Pathol. 163. 1437-1447 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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