Reviews The Notch ligand Delta-like 4 (DLL4) as a target in angiogenesis-based cancer therapy?

Abstract

Angiogenesis is a complex multistep process by which new capillary structures arise from pre-existing vessels in response to angiogenic stimuli. This process plays a key role during tumorigenesis because the vascular network within the tumor enables malignant cells to establish distant metastases. Thus, it is not surprising that targeting tumors with angiogenesis-based therapy remains a significant area of preclinical and clinical studies. One of the most prominent factors considered as a promising target in such therapy is the Notch ligand Delta-like 4 (DLL4). Emerging evidence suggests that blockade of DLL4 in tumors results in excessive but non-productive angiogenesis which affects tumor growth, even in tumors which are insensitive to anti-VEGF therapy. Nevertheless, the careful evaluation of adverse effects on normal organs’ physiology in relation to therapeutic doses of DLL4 inhibitors will be critical for advancement of DLL4 blocking agents in clinical practice.

miRNA‐30e regulates abnormal differentiation of small intestinal epithelial cells in diabetic mice by downregulating Dll4 expression

“…This point requires further study. Dll4 plays a key role in development of some cancers, and in cardiovascular and metabolic diseases, by altering Notch activity (34,(36)(37)(38). As previous reports have indicated that miRNA can regulate the Notch signalling pathway (39), we assessed miRNA expression profiles to find miRNAs that were differentially expressed in small intestinal epithelium in DM mice; we identified 107 miRNAs that were significantly altered in them (Fig.…”

PlGF-induced VEGFR1-dependent vascular remodeling determines opposing antitumor effects and drug resistance to Dll4-Notch inhibitors

“…Targeting the Dll4-Notch signaling pathway provides an attractive approach in antiangiogenic cancer therapy ( 21 ). Unlike other antiangiogenic drugs, Dll4-Notch inhibitors increase, rather than decrease, the tumor microvessel density.…”

Role of delta-like ligand-4 in chemoresistance against docetaxel in MCF-7 cells

“…An increase of vascular leakiness connected with impaired vascular integrity may explain a rapid decrease in tumour perfusion. 21,22 These findings clearly provide a rationale for DLL4 targeting for improved treatment of cancer patients.…”