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Tumor microvasculature with endothelial fenestrations as a potent predictive marker and target of anti-VEGF therapy in clear cell renal cell carcinoma

Research Project

Project/Area Number 18591751
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Urology
Research InstitutionKyoto University

Principal Investigator

KAMBA Tomomi  Kyoto University, Graduate school of medicine, assistant professor (20402836)

Co-Investigator(Kenkyū-buntansha) OGAWA Osamu  Kytot University, Graduate school of medicine, professor (90260611)
KAMOTO Toshiyuki  Kytot University, Graduate school of medicine, associate professor (00281098)
NAKAMURA Eijiro  Kytot University, Graduate school of medicine, associate professor (90293878)
伊藤 哲之  京都大学, 医学研究科, 講師 (70343225)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsendothelial fenestration / renal cell carcinoma / anti-VEGF therapy / VHL gene / 腫瘍血管 / 抗血管新生療法 / fenestration
Research Abstract

Background
VEGF-targeted therapy show substantial anti-tumor effects for advanced renal cell carcinomas. Now, kinds of surrogate markers which successfully predict the tumor response are highly required. Previously, experimental studies using VEGF neutralization in mice tumor model showed that VEGF-dependent capillaries in tumor vessels were characterized by the existence of fenestrations in endothelium on electron microscopy study. Based on those results, we examined if endothelial fenestrations were associated with VHL status and tumor responses to anti-VEGF therapy in RCC.
Results
Abundant endothelial fenestrations were found in a majority of sporadic CC-RCCs with VHL mutation but not those without. This finding was also confirmed in mice xenograft models in that capillaries established from VHL null pRC3 cells harbored more abundant endothelial fenestrations compared to those from VHL wild WT8 or even WT8/HIF2α P531A cells. Treatment with Bevacizumab resulted in the significant decrease in the mean tumor size of pRC3 but not the latter two cells. In Bevacizumab sensitive pRC3 xenografts, a significant reduction of the number of endothelial fenestrations and microvessel density was observed after the treatment.
Conclusions
Our results suggest that sporadic RCCs with VHL mutation harbor VEGF-dependent tumor vessels and those capillaries are possible target for anti-VEGF therapy. Therefore, endothelial fenestration could be a useful surrogate marker in predicting susceptibilities of RCCs to that therapy. Our results also indicated that an increase of VEGF dependent capillaries in VHL-/-RCC is not merely caused by the subsequent VEGF overproduction followed by HIF2α accumulation.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (14 results)

All 2008 2007 2006

All Journal Article (3 results) (of which Peer Reviewed: 2 results) Presentation (11 results)

  • [Journal Article] Mechanisms of adverse effects of anti-VEGF therapy for cancer.2007

    • Author(s)
      Kamba T, MacDonald DM
    • Journal Title

      Br J Cancer 96

      Pages: 1788-1795

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature2006

    • Author(s)
      Kamba T, MacDonald DM, et al
    • Journal Title

      Am J Physiol Heart Circ Physiol 290

      Pages: 560-576

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] VEGF-dependent plasticity of fenestrated capillaries in the normal adult microvasculature.2006

    • Author(s)
      Kamba T, Tarn BY, Hashizume H, Haskell A, Sennino B, Mancuso MR, Norberg SM, O'brien SM, Davis RB, Gowen LC, Anderson KD, Thurston G, Joho S, Springer ML, Kuo CJ, McDonald DM
    • Journal Title

      Am J Physiol Heart Circ Physiol. 290

      Pages: 560-576

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 腎細胞癌の腫瘍血管微細構造に着目した抗血管新生療法感受性に関する研究2008

    • Author(s)
      山崎俊成, 神波大己, 中村英二郎, 寒野徹, 賀本敏行, 小川修
    • Organizer
      第96回日本泌尿器科学会総会
    • Place of Presentation
      横浜
    • Year and Date
      2008-04-25
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Endothelial fenestration as a predictive factor of anti-VEGF therapy in clear cell renal cell carcinoma2008

    • Author(s)
      Toshinari Yamasaki, Tomomi Kamba, Eijiro Nakamura, Toru Kanno, Toshiyuki Kamoto, Osamu Ogawa
    • Organizer
      96th annual meeting of the Japanese Urological Association
    • Place of Presentation
      Yokohama, Japan
    • Year and Date
      2008-04-25
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Endothelial fenestration as a predictive factor of anti-VEGF therapy in clear cell renal cell carcinoma2008

    • Author(s)
      Toshinari Yamasaki, Tomomi Kamba, Eijiro Nakamura, Toru Kanno, Toshiyuki Kamoto, Osamu Ogawa
    • Organizer
      第23回ヨーロッパ泌尿器科学会
    • Place of Presentation
      イタリア、ミラノ
    • Year and Date
      2008-03-26
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Endothelial fenestration as a predictive factor of anti-VEGF therapy in clear cell renal cell carcinoma2008

    • Author(s)
      Toshinari Yamasaki, Tomomi Kamba, Eijiro Nakamura, Toru Kanno, Toshiyuki Kamoto, Osamu Ogawa
    • Organizer
      第23回EAU
    • Place of Presentation
      イタリア ミラノ
    • Year and Date
      2008-03-26
    • Related Report
      2007 Annual Research Report
  • [Presentation] Endothelial fenestration as a predictive factor of anti-VEGF therapy in clear cell renal cell carcinoma2008

    • Author(s)
      Toshinari Yamasaki, Tomomi Kamba, Eijiro Nakamura, Toru Kanno, Toshiyuki Kamoto, Osamu Ogawa
    • Organizer
      23th annual meeting of the European Urological Association
    • Place of Presentation
      Milan, Itary
    • Year and Date
      2008-03-23
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Endothelial fenestration as a predictive factor of anti-VEGF therapy in clear cell renal cell carcinoma2007

    • Author(s)
      山崎俊成, 神波大己, 中村英二郎, 寒野徹, 賀本敏行, 小川修
    • Organizer
      第66回日本癌学会学術総会
    • Place of Presentation
      横浜
    • Year and Date
      2007-10-13
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Endothelial fenestration as a predictive factor of anti-VEGF therapy in clear cell renal cell carcinoma2007

    • Author(s)
      Toshinari Yamasaki, Tomomi Kamba, Eijiro Nakamura, Toru Kanno, Toshiyuki Kamoto, Osamu Ogawa
    • Organizer
      66th annual meeting of the Japanese Cancer Association
    • Place of Presentation
      Yokohama, Japan
    • Year and Date
      2007-10-13
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 腎細胞癌の腫瘍血管微細構造に着目した抗血管新生療法感受性に関する研究2007

    • Author(s)
      山崎 俊成
    • Organizer
      第95回日本泌尿器科学会総会
    • Place of Presentation
      神戸
    • Year and Date
      2007-04-14
    • Related Report
      2007 Annual Research Report
  • [Presentation] Endothelial fenestration as a predictive factor of anti-VEGF therapy in clear cell renal cell carcinoma2007

    • Author(s)
      Tomomi Kamba, Toshinari Yamasaki, Eijiro Nakamura, Osamu Ogawa
    • Organizer
      第29回国際泌尿器科学会
    • Place of Presentation
      フランス、パリ
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Endothelial fenestration as a predictive factor of anti-VEGF therapy in clear cell renal cell carcinoma2007

    • Author(s)
      Tomomi Kamba, Toshinari Yamasaki, Eijiro Nakamura, Osamu Ogawa
    • Organizer
      29th SIU
    • Place of Presentation
      Paris, France
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Endothelial fenestration as a predictive factor of anti-VEGF therapy in clear cell renal cell carcinoma2007

    • Author(s)
      Tomomi Kamba, Toshinari Yamasaki, Eijiro Nakamura, Osamu Ogawa
    • Organizer
      第29回SIU
    • Place of Presentation
      フランス パリ
    • Related Report
      2007 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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