Delta-like 4 Notch Ligand Regulates Tumor Angiogenesis, Improves Tumor Vascular Function, and Promotes Tumor Growth In vivo

Abstract

The vascular endothelial growth factor (VEGF) plays a key role in tumor angiogenesis. However, clinical trials targeting the VEGF pathway are often ineffective, suggesting that other factors/pathways are also important in tumor angiogenesis. We have previously shown that the Notch ligand Delta-like 4 (DLL4) is up-regulated in tumor vasculature. Here, we show that DLL4, when expressed in tumor cells, functions as a negative regulator of tumor angiogenesis by reducing the number of blood vessels in all five types of xenografts, but acts as a positive driver for tumor growth in two of them (human glioblastoma and prostate cancer). The growth of in vivo models was not related to the effects on growth in vitro. DLL4 expressed in the tumor cells activated Notch signaling in host stromal/endothelial cells, increased blood vessel size, and improved vascular function within tumors. The promotion of tumor growth was, to some extent, due to a reduction of tumor hypoxia and apoptosis. DLL4-expressing tumor cells responded to anti-VEGF therapy with bevacizumab. A soluble form of DLL4 (D4ECD-Fc) blocked tumor growth in both bevacizumab-sensitive and bevacizumab-resistant tumors by disrupting vascular function despite increased tumor vessel density. In addition, we show that DLL4 is up-regulated in tumor cells and tumor endothelial cells of human glioblastoma. Our findings provide a rational basis for the development of novel antiangiogenic strategies via blockade of DLL4/ Notch signaling and suggest that combined approaches for interrupting both DLL4 and VEGF pathways may improve antiangiogenic therapy. [Cancer Res 2007;67(23):11244-53]

Cross-talk between endothelial cells and tumor via delta-like ligand4/Notch/PTEN signaling inhibits lung cancer growth

“…The enhanced Dll4 could activate Notch in the adjacent stalk cells, which exhibit high Notch and low Dll4 (Hofmann and Luisa Iruela-Arispe, 2007;Phng and Gerhardt, 2009). Notch activation sequentially improves the function of microvessels, and lack of Dll4 in stalk cells also permits the proliferation of neighboring tumor cells (Li et al, 2007;Phng and Gerhardt, 2009). Antiangiogenic therapy for cancer emerged in early 1970s, marked with the publication of the Folkman's hypothesis (Folkman, 1971).…”

The characteristics of bone marrow-derived endothelial progenitor cells and their effect on glioma

“…It is well known that the pivotal process of tumor growth and metastasis is angiogenesis. In clinical, more and more anti-angiogenesis drugs have been developed to control this process [23,24]. Angiogenesis is a complex process and its mechanisms still remain unclear.…”

The brain tumor microenvironment

“…The notch ligand, Deltalike 4 (DLL4), is up-regulated in endothelial and glioblastoma cells. In a mouse model of glioblastomas, DLL4 expression in tumor cells was demonstrated to drive tumor angiogenesis via activation of the Notch pathway in endothelial cells (Li et al, 2007).…”