Eukaryotic initiation factor-4E in superficial and muscle invasive bladdercancer and its correlation with vascular endothelial growth factor expression and tumour progression

Vascular endothelial growth factor (VEGF) is an important factor mediating tumour angiogenesis. VEGF mRNA is differentially expressed in bladder cance r with high expression in superficial tumours (stage pT(a) and pT(1)) contr asting with low expression in muscle invasive tumours (stage greater than o r equal to pT(2)), To investigate mechanisms regulating VEGF expression in bladder cancer, VEGF mRNA and protein were measured in normal bladder (n = 12) and primary bladder cancers (n = 57), VEGF protein levels correlated wi th mRNA expression in normal bladder (r = 0.68, P = 0.02) and bladder cance r (r = 0.46, P = 0.0007). Whilst VEGF mRNA expression was threefold higher in superficial compared to muscle invasive bladder cancers (P = 0.0001) the re was no difference in VEGF protein (P = 0.81). Accordingly, the median pr otein,mRNA ratios increased more than 15-fold with increasing tumour stage (P < 0.0001) suggesting translational regulation. Expression of the eukaryo tic initiation factor-4E (elF-4E), a factor implicated in the translational regulation of VEGF, was greater in tumours than normal bladder (P < 0.0001 ) and correlated with VEGF protein,mRNA ratios (n = 43, r = 0.54, P = 0.000 4) pointing to its role in the regulation of VEGF. In superficial tumours ( n = 37) high expression of elF-4E was associated with a poor prognosis and reduced stage progression-free survival (P = 0.04, Cox proportional hazards model). The study demonstrates that elF-4E may be involved in translationa l regulation of VEGF in bladder cancer and might have a role as a prognosti c factor in bladder cancer. (C) 2000 Cancer Research Campaign.