Delta-like Ligand 4/Notch Pathway in Tumor Angiogenesis

摘要: The process of angiogenesis, be it physiological or pathological, requires the coordinated interplay a variety vascular growth factor systems. Many preclinical models, and more recently several clinical trials, have shown that endothelial (VEGF) is an essential mediator developmental pathological angiogenesis. Recent evidence suggests another pathway—the Delta/ Notch pathway, Delta-like ligand 4 (Dll4) in particular—also plays specific critical role acting part to restrain VEGF-mediated Perturbation this Dll4-mediated restraint can result excessive non-productive vessel growth. For example, during embryogenesis, genetic deletion even one allele Dll4 mice results profound defects significant embryonic lethality at approx E10.5. include abnormal remodeling yolk sac reduced invasion placental labyrinth, poor formation major arteries embryo, sprouting/branching certain beds. In backgrounds permit survival heterozygous mice, other are found, including maturation bed developing post natal retina. also fundamental as blockers / pathway decreased tumor growth, for tumors resistant anti-VEGF therapies. This associated with markedly increased vascularity, enhanced angiogenic sprouting, branching. However, vascularity disorg anized non-productive, evidenced by perfusion hypoxia. current model VEGF induces negative feedback regulator thus helping coordinate VEGF-induced sprouting promoting functional specialization cells (ECs) network. Although clearly induced helps regulate appears functions independent VEGF, blockade both show potent anti-tumor effects than either alone. Thus, presents novel therapeutic approach,