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

背景VEGF靶向治疗对晚期肾癌有显著的抗肿瘤作用。目前，人们迫切需要能够成功预测肿瘤反应的替代标志物。此前，在小鼠肿瘤模型中使用VEGF中和的实验研究表明，电子显微镜研究显示，肿瘤血管中VEGF依赖性毛细血管的特征是内皮细胞中存在穿孔。基于这些结果，我们研究了是否内皮开窗与VHL状态和肿瘤的反应，抗VEGF治疗RCC.ResultsAbundant内皮开窗被发现在大多数散发性CC-RCCs与VHL突变，但不是那些没有。这一发现也在小鼠异种移植模型中得到证实，因为与VHL野生型WT 8或甚至WT 8/HIF 2 α P531 A细胞相比，由VHL null pRC 3细胞建立的毛细血管具有更丰富的内皮开窗。贝伐单抗治疗导致pRC 3的平均肿瘤大小显著减小，但后两种细胞没有。在贝伐单抗敏感的PRC 3异种移植物，内皮开窗和微血管密度的数量显着减少后观察treatment.ConclusionsOur结果表明，散发性RCC与VHL突变窝藏VEGF依赖的肿瘤血管和毛细血管是抗VEGF治疗的可能目标。因此，内皮开窗可能是一个有用的替代指标，预测RCC的易感性的治疗。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于随后的VEGF过量产生和随后的HIF 2 α积聚引起的。

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.