Expression of the endothelin axis and microvessel density in bladder cancer

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4583 Background: Endothelin-1 (ET-1) and its receptors ETAR and ETBR, referred to as the Endothelin (ET)-axis play an emerging role in cancer. The ET-axis has been shown to be involved in proliferation, angiogenesis and metastasis. We investigated the effect of the ET-axis on microvessel density (MVD) and on the clinical prognosis in patients with invasive carcinoma of the bladder. Methods: Archival tumor tissue of 157 consecutive patients was reviewed and representing tumor blocks were selected. Paraffin sections were assessed immunhistochemically using mono- and polyclonal antibodies for ET-1, ETAR,ETBR and CD34 (MVD). Staining intensities were analyzed semiquantitatively and the MVD was calculated as vessels per field. The results were correlated with various pathological and clinical factors, as well as with disease-free and overall survival. Results: Overexpression of ET-1, ETAR and ETBR was identified in 26.8%, 58.8% and 76.9% of cases, respectively. Normal urothelium was constantly negative. No association with TNM staging and histologic grading was found. However, patients with ETBR expression tended to have organ-confined tumors (P = 0.16) and no vascular invasion (P = 0.09), the latter being statistically significant in the subgroup of G3 tumors (P = 0.02). T1 and T2 (MVD = 32,2) tumors had greater MVD compared to T3 and T4 tumors (MVD = 21,2) (P = 0.02), showing an association of MVD and overexpression of ET-1 (P = 0.027). ETBR-positive tumors were associated with favorable disease-free survival (P = 0.04). In urothelial carcinomas the MVD was 23,7, whereas squamous cell carcinomas had a MVD of 17,8 (P = 0.04). Conclusion: The ET-axis is overexpressed in invasive bladder cancer. Urothelial carcinomas are significantly greater vascularized compared to squamous cell carcinomas. Organ-confined tumors showed more MVD than T3 and T4 tumors, which is related to ET-1 expression in this subgroup. ETBR appears to predominate in bladder cancer and is associated with a more favorable prognosis. No significant financial relationships to disclose.