Dufraine J, Funahashi Y, Kitajewski J
Department of Pathology, Columbia University Medical Center, New York, NY 10032, USA.
Oncogene. 2008 Sep 1;27(38):5132-7. doi: 10.1038/onc.2008.227.
The Notch signaling pathway is fundamental to proper cardiovascular development and is now recognized as an important player in tumor angiogenesis. Two key Notch ligands have been implicated in tumor angiogenesis, Delta-like 4 and Jagged1. We introduce the proteins and how they work in normal developing vasculature and then discuss differing models describing the action of these Notch ligands in tumor angiogenesis. Endothelial Dll4 expression activates Notch resulting in restriction of new sprout development; for instance, in growing retinal vessels. In agreement with this activity, inhibition of Dll4-mediated Notch signaling in tumors results in hypersprouting of nonfunctional vasculature. This Dll4 inhibition may paradoxically lead to increased angiogenesis but poor tumor growth because the newly growing vessels are not functional. In contrast, Jagged1 has been described as a Notch ligand expressed in tumor cells that can have a positive influence on tumor angiogenesis, possibly by activating Notch on tumor endothelium. A novel Notch inhibitor, the Notch1 decoy, which blocks both Dll4 and Jagged1 has been recently shown to restrict tumor vessel growth. We discuss these models and speculate on therapeutic approaches.
Notch信号通路对正常心血管发育至关重要，目前被认为是肿瘤血管生成中的重要参与者。两种关键的Notch配体与肿瘤血管生成有关，即Delta样4（Dll4）和Jagged1。我们介绍这些蛋白质及其在正常血管发育中的作用方式，然后讨论描述这些Notch配体在肿瘤血管生成中作用的不同模型。内皮细胞Dll4表达激活Notch，导致新生血管芽发育受限；例如，在生长中的视网膜血管中。与此活性一致，在肿瘤中抑制Dll4介导的Notch信号会导致无功能血管的过度出芽。这种对Dll4的抑制可能反常地导致血管生成增加，但肿瘤生长不佳，因为新生长的血管没有功能。相比之下，Jagged1被描述为在肿瘤细胞中表达的一种Notch配体，可能通过激活肿瘤内皮细胞上的Notch对肿瘤血管生成产生积极影响。一种新型的Notch抑制剂，即Notch1诱饵，可同时阻断Dll4和Jagged1，最近已被证明能限制肿瘤血管生长。我们讨论这些模型并推测治疗方法。
