Renal cell carcinoma (RCC) is the commonest adult renal neoplasm, and often proves resistant to treatment once metastasis has occurred. A number of therapies that are potentially useful for the treatment of secondary RCC are currently under close investigation. To understand the formation and development of this cancer, vascular endothelial growth factor-A (VEGF-A), a cytokine known for its role in angiogenesis, tumour formation and metastasis in several human tumours has been investigated in renal cell cancer by employing in vivo and in vitro studies.
Northern and Western blot hybridisation demonstrated upregulation of VEGF-A expression in human renal tumour samples compared to adjacent normal renal parenchymal tissue.
Immunohistological analysis showed cytoplasmic staining for VEGF-A in renal cancer cells, and membrane staining of intra-tumoural vascular
These results suggest a role for VEGF-A in RCC angiogenesis, possibly via a paracrine mechanism on vascular endothelial cells. Hypoxia, one of the known key factors that regulates VEGF-A expression, was investigated by subjecting SN12K-1, a human RCC cell line, to in vitro and in vivo hypoxia using cobalt chloride, and kidney ligation in a mouse xenograft model of RCC, respectively. In vitro analysis demonstrated up-regulation of VEGF-A mRNA expression whereas the in vivo study did not. In addition, analysis of the effect of hypoxia on VEGF-B showed no apparent up-regulation in its mRNA expression, thus suggesting a different regulatory mechanism from VEGF-A.
von Hippel-Lindau (VHL) mutation has been implicated in the up-regulation of VEGF-A expression. In a VHL-associated RCC family studied, the tumours analysed in all affected family members were of non-VHL,
non-papillary clear cell type. VEGF-A protein was not elevated in these tumour samples compared to the paired normal renal tissues. The linkage analyses excluded this family from having VHL and c-MET gene mutations, genes that are associated with sporadic clear cell and papillary RCC, respectively.
To study and characterise the functional role of VEGF-A, an animal model was developed by xenografting SN12K-1 cells into the severe combined immunodeficient (SCIO) mouse. This model has enabled the subsequent study of an anti-renin-angiotensin system (RAS) drug, captopril, which was shown to significantly inhibit primary tumour growth and secondary metastasis. In vitro experiments did not show any apparent difference in VEGF-A mRNA expression upon exposure to captopril. However, down-regulation of MMP-9 activity in endothelial cells using SOS gelatin zymographic assay suggests a possible direct inhibition by captopril of MMP-9 activity in these