Tumor microvasculature with endothelial fenestrations in VHL null clear cell renal cell carcinomas as a potent target of anti‐angiogenic therapy

摘要

Vascular endothelial growth factor (VEGF)‐targeted therapies show significant antitumor effects for advanced clear cell renal cell carcinomas (CC‐RCCs). Previous studies using VEGF inhibitors in mice models revealed that VEGF‐dependent capillaries were characterized by the existence of endothelial fenestrations (EFs). In this study, we revealed that capillaries with abundant EFs did exist, particularly in CC‐RCCs harboring VHL mutation. This finding was recapitulated in mice xenograft models, in which tumors from VHL null cells showed more abundant EFs compared to those from VHL wild‐type cells. Importantly, treatment with bevacizumab resulted in a significant decrease of tumor size established from VHL null cells. Additionally, a significant reduction of EFs and microvessel density was observed in VHL null tumors. Indeed, xenograft from 786‐O/mock (pRC3) cells developed four times more abundant EFs than that from 786‐O/VHL (WT8). However, introduction of the constitutively active form of hypoxia‐inducible factor (HIF)‐2α to WT8 cells failed to either augment the number of EFs or restore the sensitivity to bevacizumab in mice xenograft, irrespective of the equivalent production of VEGF to 786‐O/mock cells. These results indicated that HIF‐2α independent factors also play significant roles in the development of abundant EFs. In fact, several angiogenesis‐related genes including CCL2 were upregulated in 786‐O cells in a HIF‐2α independent manner. Treatment with CCL2 neutralizing antibody caused significant reduction of capillaries with EFs in 786‐O xenograft, indicating that they were also sensitive to CCL2 inhibition as well as VEGF. Collectively, these results strongly indicated that capillaries with distinctive phenotype developed in VHL null CC‐RCCs are potent targets for anti‐angiogenic therapy.