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Delta-like Ligand 4/Notch Pathway in Tumor Angiogenesis

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Book cover Angiogenesis

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

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Authors and Affiliations

  1. Regeneron Pharmaceuticals, 10591, Tarrytown, NY, USA

    Gavin Thurston, Irene Noguera-Troise, Ivan B. Lobov, Christopher Daly, John S. Rudge, Nicholas W. Gale, Stanley J. Wiegand & George D. Yancopoulos

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  1. Gavin Thurston
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  2. Irene Noguera-Troise
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  3. Ivan B. Lobov
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  1. Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA

    William D. Figg

  2. Department of Surgery Harvard Medical School and Vascular Biology Program, Children's Hospital Boston, Boston, MA, USA

    Judah Folkman

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Thurston, G. et al. (2008). Delta-like Ligand 4/Notch Pathway in Tumor Angiogenesis. In: Figg, W.D., Folkman, J. (eds) Angiogenesis. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-71518-6_19

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