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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

具有内皮开窗的肿瘤微血管作为透明细胞肾细胞癌抗 VEGF 治疗的有效预测标记和靶点

基本信息

批准号：
18591751
负责人：
KAMBA Tomomi
金额：
$ 2.49万
依托单位：
Kyoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

BackgroundVEGF-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.ResultsAbundant 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.ConclusionsOur 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.

vegf靶向治疗对晚期肾细胞癌具有明显的抗肿瘤作用。目前，迫切需要各种能够成功预测肿瘤反应的替代标志物。此前，利用VEGF中和小鼠肿瘤模型的实验研究表明，在电镜下，肿瘤血管中VEGF依赖性毛细血管的特征是内皮中存在开孔。基于这些结果，我们研究了内皮开窗是否与RCC的VHL状态和肿瘤对抗vegf治疗的反应有关。结果在大多数携带VHL突变的散发性cc - rcc中发现了丰富的内皮开孔，而没有VHL突变的cc - rcc中没有内皮开孔。这一发现在小鼠异种移植模型中也得到了证实，与VHL野生WT8甚至WT8/HIF2α P531A细胞相比，VHL无pRC3细胞建立的毛细血管具有更丰富的内皮开孔。贝伐单抗治疗导致pRC3细胞的平均肿瘤大小显著降低，但后两种细胞没有显著降低。在贝伐单抗敏感的pRC3异种移植物中，治疗后观察到内皮开窗数量和微血管密度显著减少。结论散发性VHL突变rcc中存在vegf依赖的肿瘤血管，这些血管可能是抗vegf治疗的靶点。因此，内皮开窗可以作为预测rcc对该疗法敏感性的有用替代标志物。我们的研究结果还表明，VHL-/- rcc中VEGF依赖性毛细血管的增加不仅仅是由随后的VEGF过量产生和HIF2α积累引起的。