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Clinical Cancer Research Vol. 7, 1263-1272, May 2001
© 2001 American Association for Cancer Research

Molecular Oncology

Relation of Vascular Endothelial Growth Factor Production to Expression and Regulation of Hypoxia-inducible Factor-1{alpha} and Hypoxia-inducible Factor-2{alpha} in Human Bladder Tumors and Cell Lines1

Adam Jones2, Chisato Fujiyama2, Christine Blanche, John W. Moore, Sue Fuggle, David Cranston, Roy Bicknell and Adrian. L. Harris3

Molecular Oncology Unit, Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS [A.J., C.F., J.W.M., R.B., A.L.H., C.B.]; Department of Urology, Churchill Hospital, Oxford, OX3 7LJ [A.J., D.C.], and Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DU [A.J., C.F., S.F.], United Kingdom

Hypoxia is an important regulator of vascular endothelial growth factor (VEGF) expression, and VEGF is associated with poor prognosis in bladder cancer. To investigate further the mechanisms of VEGF regulation, we examined VEGF expression by mRNA and protein analysis in four human bladder cancer cell lines, showing a progression from well to poorly differentiated phenotypes under varying conditions of confluence and hypoxia (0.1% O2) and with chemical mimics of hypoxia. Hypoxia significantly increased VEGF protein expression in all cell lines, although this effect was dependent on the degree of confluence. The superficial bladder cancer cell line RT4 lost hypoxia inducibility at confluence, whereas inducibility was maintained in the invasive cell lines 253J and EJ28. This pattern of VEGF expression in the invasive cell lines correlated with the expression of the transcription factor hypoxia inducible factor-1{alpha} (HIF-1{alpha}) and with hypoxia-inducible factor-2{alpha} (HIF-2{alpha}) and in RT4 correlated with a marked reduction in HIF-1{alpha} inducibility at confluence. Using the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitor LY 294002, we show that this VEGF hypoxia-inducible pathway regulated by HIF-1{alpha} is distinct from a PI 3-kinase-dependent pathway, which regulates basal amounts of VEGF, but does not affect inducibility. Both HIF-1{alpha} and HIF-2{alpha} protein and mRNA were up-regulated in primary human bladder tumors (n = 12) compared with normal bladder specimens (n = 4), with significant intertumor variation. These results suggest that components of the hypoxia response pathway, including HIF-1{alpha} and HIF-2{alpha}, are important cofactors in the regulation of VEGF in bladder cancer and are therapeutic targets in this disease.




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Copyright © 2001 by the American Association for Cancer Research.