Serum Levels of Angiogenic Factors and their Prognostic Relevance in Bladder Cancer
Angiogenesis plays a critical role in tumor growth. VEGF, angiopoietins (Ang-1, Ang-2) and their tyrosine kinase receptor Tie2 are major regulators of angiogenesis. The aim of this study was to evaluate the prognostic value of the serum levels of these factors in bladder cancer. We analyzed the serum samples of 117 bladder cancer patients and 64 healthy volunteers by enzyme linked immunosorbent assay (ELISA) for Ang-1, Ang-2, VEGF and the extracellular domain of Tie2. The statistical evaluation of the obtained data was performed via Kaplan–Meier log-rank test, univariate Cox analyses as well as Cox proportional hazards regression model. Serum Ang-1 levels of bladder cancer patients were significantly higher (p < 0.001), while soluble Ang-2 and Tie2 levels were significantly lower (p = 0.016 and p = 0.001 respectively) in patients than those in controls. Cox univariate analysis revealed high sTie2 serum level as a risk factor for metastasis and as a borderline significant risk factor for disease related death (p = 0.022 and p = 0.081 respectively). These correlations were independent from tumor stage and grade in a Cox multivariate model (p = 0.016 and p = 0.069). These data indicate that the serum levels of analyzed angiogenic factors do change characteristically in bladder cancer. The soluble extracellular serum level of Tie2 may provide a stage and grade independent diagnostic tool to select a high risk group of bladder cancer patients.
KeywordsBladder cancer Serum Angiopoietin Tie2 VEGF Prognosis
transitional cell carcinoma
We thank Jacqueline Wittschier for excellent technical assistance. Grant support from the German National Federal Ministry of Education and Research (0313659B) is also acknowledged.
- 4.Maisonpierre PC, Suri C, Jones PF, Bartunkova S, Wiegand SJ, Radziejewski C, Compton D, McClain J, Aldrich TH, Papadopoulos N, Daly TJ, Davis S, Sato TN, Yancopoulos GD (1997) Angiopoietin-2, a natural antagonist for Tie2 that disrupts in vivo angiogenesis. Science 277:55–60CrossRefPubMedGoogle Scholar
- 21.Eble JN, Epstein JI, Sesterhenn I, World Health Organization classification of tumors (2004) Pathology and genetics of tumors of the urinary system and male genital organs. IARCC, Lyon, pp 89–158Google Scholar
- 24.Crew JP, Fuggle S, Bicknell R, Cranston DW, de Benedetti A, Harris AL (2000) Eukaryotic initiation factor-4E in superficial and muscle invasive bladder cancer and its correlation with vascular endothelial growth factor expression and tumour progression. Br J Cancer 82:161–166CrossRefPubMedGoogle Scholar
- 26.Quentin T, Schlott T, Korabiowska M, Kathei N, Zoller G, Glaser F, Kunze E (2004) Alteration of the vascular endothelial growth factor and angiopoietins-1 and -2 pathways in transitional cell carcinomas of the urinary bladder associated with tumor progression. Anticancer Res 24:2745–2756PubMedGoogle Scholar
- 27.Oliveira-Ferrer L, Tilki D, Ziegeler G, Hauschild J, Loges S, Irmak S, Kilic E, Huland H, Friedrich M, Ergün S (2004) Dual role of carcinoembryonic antigen-related cell adhesion molecule 1 in angiogenesis and invasion of human urinary bladder cancer. Cancer Res 64:8932–8938CrossRefPubMedGoogle Scholar