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Up-Regulation of Endothelial Delta-like 4 Expression Correlates with Vessel Maturation in Bladder Cancer

Authors' Affiliations: ¹ Growth Factor Group, Cancer Research UK, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital; ² Department of Urology, Churchill Hospital, University of Oxford, Oxford, United Kingdom; and ³ In-situ Hybridization Service, Cancer Research UK London Research Institute, London, United Kingdom

Requests for reprints: Adrian L. Harris, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford OX3 9DJ, United Kingdom. Phone: 44-1865-222457; Fax: 44-1865-222431; E-mail: aharris.lab{at}cancer.org.uk.

Purpose: Angiogenesis and vascular endothelial growth factor (VEGF) expression are associated with a poor outcome in bladder cancer. To understand more about the mechanisms, we studied the role of delta-like 4 (DLL4), an endothelial-specific ligand of the Notch signaling pathway, in bladder cancer angiogenesis.

Experimental Design: The expression of DLL4, CD34, and VEGF were studied in a cohort of 60 bladder tumors and 10 normal samples using quantitative PCR. In situ hybridization was used to study the pattern of DLL4 expression in 22 tumor and 9 normal samples. Serial sections were also stained for CD34 and -smooth muscle actin (-SMA) using conventional immunohistochemistry.

Results: The expression of DLL4 was significantly up-regulated in superficial (P < 0.01) and invasive (P < 0.05) bladder cancers. DLL4 expression significantly correlated with CD34 (P < 0.001) and VEGF (P < 0.001) expression. The in situ hybridization studies showed that DLL4 was highly expressed within bladder tumor vasculature. Additionally, DLL4 expression significantly correlated with vessel maturation as judged by periendothelial cell expression of -SMA, 98.7% of DLL4-positive tumor vessels coexpressed -SMA, compared with 64.5% of DLL4-negative tumor vessels (P < 0.001). High DLL4 expression may have prognostic value in superficial and invasive bladder.

Conclusion: DLL4 expression is associated with vascular differentiation in bladder cancer; thus, targeting DLL4 may be a novel antiangiogenic therapy.

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