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

• Published in: Clinical cancer research Vol. 12; no. 16; pp. 4836 - 4844
• Main Authors: PATEL, Nilay S, DOBBIE, Michael S, ROCHESTER, Mark, STEERS, Graham, POULSOM, Richard, LE MONNIER, Karena, CRANSTON, David W, LI, Ji-Liang, HARRIS, Adrian L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 15.08.2006
• Subjects: Actins - biosynthesis; Actins - genetics; Adult; Aged; Aged, 80 and over; angiogenesis; Antigens, CD34 - biosynthesis; Antigens, CD34 - genetics; Antineoplastic agents; Biological and medical sciences; bladder cancer; Carcinoma, Transitional Cell - blood supply; Carcinoma, Transitional Cell - genetics; Carcinoma, Transitional Cell - metabolism; Cohort Studies; Female; Humans; Immunohistochemistry; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - genetics; Male; Medical sciences; Middle Aged; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Nephrology. Urinary tract diseases; Notch; Pharmacology. Drug treatments; Polymerase Chain Reaction; Prognosis; Tumors of the urinary system; Up-Regulation; Urinary Bladder Neoplasms - blood supply; Urinary Bladder Neoplasms - genetics; Urinary Bladder Neoplasms - metabolism; Urinary system involvement in other diseases. Miscellaneous; Urinary tract. Prostate gland; Vascular Endothelial Growth Factor A - biosynthesis; Vascular Endothelial Growth Factor A - genetics; Endothelial cell; Urinary system disease; Blood vessel; Bladder disease; Circulatory system; Malignant tumor; Urinary tract disease; Gene expression; Bladder cancer; Endothelium
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0285

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 α-smooth muscle actin (α-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 α-SMA, 98.7% of DLL4-positive tumor vessels coexpressed α-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.