Up-regulation of endothelial delta-like 4 expression correlates with vessel maturation in bladder cancer.
OBJECTIVE
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.


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


CONCLUSIONS
DLL4 expression is associated with vascular differentiation in bladder cancer; thus, targeting DLL4 may be a novel antiangiogenic therapy.
Patel
Nilay S
NS
Growth Factor Group, Cancer Research UK, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom.
Dobbie
Michael S
MS
Rochester
Mark
M
Steers
Graham
G
Poulsom
Richard
R
Le Monnier
Karena
K
Cranston
David W
DW
Li
Ji-Liang
JL
Harris
Adrian L
AL
D000199:Actins / Q000096:biosynthesis / Q000235:genetics; D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000096:biosynthesis / Q000235:genetics; D002135:Calcium-Binding Proteins; D002295:Carcinoma, Transitional Cell / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011379:Prognosis; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; D018952:Antigens, CD34; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D042461:Vascular Endothelial Growth Factor A