Up-regulation of endothelial delta-like 4 expression correlates with vessel maturation in bladder cancer
Up-regulation of endothelial delta-like 4 expression correlates with vessel maturation in bladder cancer
复制标题
DOI：
10.1158/1078-0432.ccr-06-0285
复制
发表时间：
2006-08-15
影响因子：
11.5
通讯作者：
Harris, Adrian L.
中科院分区：
文献类型：
--
作者：
Patel, Nilay S.;Dobbie, Michael S.;Harris, Adrian L.
目的：血管生成和血管内皮生长因子(VEGF)表达与膀胱癌预后不良有关。为了更深入地了解这一机制，我们研究了Notch信号通路的内皮特异性配体--类增量4(DLL4)在膀胱癌血管生成中的作用。实验设计：采用定量PCR方法研究DLL4、CD34和血管内皮生长因子在60例膀胱肿瘤和10例正常膀胱组织中的表达。应用原位杂交法研究DLL4在22例肿瘤和9例正常组织中的表达模式。结果：DLL4在浅表性(P<；0.01)和浸润性(P<；0.05)膀胱癌中的表达显著上调。DLL4的表达与CD34(P<；0.001)和血管内皮生长因子(P<；0.001)的表达显著相关。原位杂交研究表明，DLL4在膀胱肿瘤血管中高表达。此外，DLL4的表达与血管成熟度显著相关，在DLL4阳性的肿瘤血管中，98.7%的肿瘤血管同时表达α-SMA，而在DLL4阴性的肿瘤血管中，这一比例为64.5%(P<；0.001)。结论：DLL4表达与膀胱癌的血管分化有关，靶向DLL4可能是一种新的抗血管生成治疗方法。
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 a-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 a-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.Conclusion: DLL4 expression is associated with vascular differentiation in bladder cancer; thus, targeting DLL4 may be a novel antiangiogenic therapy.