title: Tumor microvasculature with endothelial fenestrations in VHL null clear cell renal cell carcinomas as a potent target of anti-angiogenic therapy.
abstract: 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.
authors.affiliation: Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Toshinari
authors.initials: T
authors.lastname: Yamasaki
authors.forename: Tomomi
authors.initials: T
authors.lastname: Kamba
authors.forename: Toru
authors.initials: T
authors.lastname: Kanno
authors.forename: Takahiro
authors.initials: T
authors.lastname: Inoue
authors.forename: Noboru
authors.initials: N
authors.lastname: Shibasaki
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Arakaki
authors.forename: Tomomi
authors.initials: T
authors.lastname: Yamada
authors.forename: Keiichi
authors.initials: K
authors.lastname: Kondo
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Kamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nishiyama
authors.forename: Osamu
authors.initials: O
authors.lastname: Ogawa
authors.forename: Eijiro
authors.initials: E
authors.lastname: Nakamura
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D000068258:Bevacizumab; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D018932:Chemokine CCL2 / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics* / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D051792:Basic Helix-Loop-Helix Proteins; D000068258:Bevacizumab; D018932:Chemokine CCL2; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C111835:CCL2 protein, human; C467484:VEGFA protein, human; C497446:VHL protein, human