Different angiogenic potential in low and high grade sporadic clear cell renal cell carcinoma is not related to alterations in the von Hippel-Lindau gene
Baldewijns, Marcella M × van Vlodrop, Iris J H Smits, Kim M Vermeulen, Peter B Van den Eynden, Gert G Schot, Fiona Roskams, Tania Van Poppel, Hendrik van Engeland, Manon de Bruïne, Adriaan P #
Cellular Oncology vol:31 issue:5 pages:371-382
BACKGROUND: von Hippel-Lindau (VHL) inactivation is common in sporadic clear cell renal cell carcinomas (ccRCC). pVHL is part of the ubiquitin ligase complex that targets the alpha subunits of hypoxia-inducible transcription factor (HIF) for degradation under well-oxygenated conditions. In the absence of wild-type pVHL, as observed in VHL patients and most sporadic ccRCCs, constitutive upregulation of HIF results in transcriptional activation of angiogenesis-related genes, such as VEGF. Differences in angiogenic activity within the group of ccRCCs were reported and strong genotype-phenotype correlations were found in patients with VHL disease, raising a question about the importance of VHL inactivation status in angiogenic behaviour and tumour progression.
METHODS: To address this question, we investigated the influence of VHL mutation (direct sequencing)/hypermethylation (methylation-specific PCR) on angiogenesis/tumour parameters (immunohistochemistry) in 150 patients with sporadic ccRCC.
RESULTS: We found no significant association between VHL mutation or methylation and angiogenesis/tumour parameters. CONCLUSION: These data indicate that tumour progression and angiogenesis are not directly influenced by VHL alterations and that additional genetic/epigenetic events should be considered to explain the diverse angiogenic and proliferative behaviour during tumour progression.