Missing content? – Request curation!
Request curation for specific Genes, Variants, or PubMed publications.
Have questions, comments, or suggestions? - Let us know!
Email us at : ckbsupport@genomenon.com
| 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. | ||||||||||||
|
|||||||||||||
| 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. | ||||||||||||
| 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 |