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Ref Type Journal Article
PMID (22931246)
Authors Yamasaki T, Kamba T, Kanno T, Inoue T, Shibasaki N, Arakaki R, Yamada T, Kondo K, Kamoto T, Nishiyama H, Ogawa O, Nakamura E
Title Tumor microvasculature with endothelial fenestrations in VHL null clear cell renal cell carcinomas as a potent target of anti-angiogenic therapy.
Journal Cancer science
Vol 103
Issue 11
Date 2012 Nov
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
VHL L184P VEGFR Inhibitor (Pan)
VHL Q96* VEGFR Inhibitor (Pan)
VHL D126N VEGFR Inhibitor (Pan)
VHL G114R VEGFR Inhibitor (Pan)
VHL S111N VEGFR Inhibitor (Pan)
VHL L158P VEGFR Inhibitor (Pan)
VHL S111R VEGFR Inhibitor (Pan)
VHL inact mut VEGFR Inhibitor (Pan)
VHL R82P VEGFR Inhibitor (Pan)
VHL V62fs VEGFR Inhibitor (Pan)
VHL H115Q VEGFR Inhibitor (Pan)
VHL S65L VEGFR Inhibitor (Pan)
VHL P86H VEGFR Inhibitor (Pan)
VHL R167Q VEGFR Inhibitor (Pan)
VHL Y112H VEGFR Inhibitor (Pan)
VHL N90I VEGFR Inhibitor (Pan)
VHL S65W VEGFR Inhibitor (Pan)
VHL S80I VEGFR Inhibitor (Pan)
VHL L163P VEGFR Inhibitor (Pan)
VHL N78S VEGFR Inhibitor (Pan)
VHL L116fs VEGFR Inhibitor (Pan)
VHL C77* VEGFR Inhibitor (Pan)
VHL R79P VEGFR Inhibitor (Pan)
VHL S68* VEGFR Inhibitor (Pan)
VHL P154L VEGFR Inhibitor (Pan)
VHL V155fs VEGFR Inhibitor (Pan)
VHL Y98N VEGFR Inhibitor (Pan)
VHL R161P VEGFR Inhibitor (Pan)
VHL V74G VEGFR Inhibitor (Pan)
VHL N131fs VEGFR Inhibitor (Pan)
VHL Y98H VEGFR Inhibitor (Pan)
VHL R167W VEGFR Inhibitor (Pan)
VHL C162F VEGFR Inhibitor (Pan)
VHL L158fs VEGFR Inhibitor (Pan)
VHL F148fs VEGFR Inhibitor (Pan)
VHL H110Q VEGFR Inhibitor (Pan)
VHL W88* VEGFR Inhibitor (Pan)
VHL S80R VEGFR Inhibitor (Pan)
VHL W117C VEGFR Inhibitor (Pan)
VHL S183L VEGFR Inhibitor (Pan)
VHL C162W VEGFR Inhibitor (Pan)
VHL V130F VEGFR Inhibitor (Pan)
VHL S68fs VEGFR Inhibitor (Pan)
VHL H115R VEGFR Inhibitor (Pan)
VHL Q132fs VEGFR Inhibitor (Pan)
VHL P81S VEGFR Inhibitor (Pan)
VHL loss VEGFR Inhibitor (Pan)
VHL R161G VEGFR Inhibitor (Pan)
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
VHL loss renal cell carcinoma sensitive Bevacizumab Preclinical Actionable In a preclinical study, clear cell renal cell carcinoma xenograft models with VHL loss demonstrated sensitivity to Avastin (bevacizumab) (PMID: 22931246). 22931246