Project/Area Number |
18591751
|
Research Category |
Grant-in-Aid for Scientific Research (C)
|
Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Urology
|
Research Institution | Kyoto 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)
|
Keywords | endothelial 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.
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