Jones, Adam; (2000) Further investigation into the roles of vascular endothelial growth factor and thymidine phosphorylase in urological malignancy. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Our group has previously demonstrated that the angiogenic factor vascular endothelial growth factor (VEGF) was elevated and prognostic in superficial bladder cancer. Another angiogenic factor, thymidine phosphorylase (TP), was particularly elevated in invasive bladder cancer. In this thesis I set out to identify potential therapeutic targets in bladder cancer by investigating the regulation of VEGF and also by determining whether TP had a functional role in bladder cancer invasion or was merely an incidental finding. VEGF expression, both messenger RNA and protein, was significantly upregulated by hypoxia in bladder cancer cell lines in vitro, although differences existed between superficial and invasive bladder cancer cell lines. Key regulators in this process were two transcription factors, hypoxia inducible factor-1α (HIF-1α) and hypoxia inducible factor-2α (HIF-2α). A second pathway regulating hypoxic expression of VEGF was also identified, independent of HIF-1α/HIF-2α. The potential clinical relevance of these findings was illustrated by demonstrating upregulation of these factors in a panel of human primary bladder cancers. Using de-epithelialised rat bladder, a novel reproducible model of bladder cancer invasion was developed that allowed for tumour cell-extracellular matrix interactions. Several agents that specifically inhibit tumour cell-extracellular matrix interactions were tested and variably inhibited invasion confirming the importance of these interactions in the model and in the mechanism of invasion. The generation of a high TP expressing transfectant was associated with invasion in this model compared with its low TP expressing parental cell line or empty vector control. This suggested functional importance of TP in bladder cancer invasion, identifying a new therapeutic target. In addition the potential to utilise high TP levels, found in human invasive bladder cancers, to activate prodrugs is illustrated with furtulon and the model resulting in abolision of invasion. Lastly the diagnostic and prognostic potential of angiogenesis is examined in prostate and testis malignancy, tumours where additional such information is needed.

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