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      Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis.

      Nature

      Adenoviridae, genetics, Animals, Cell Hypoxia, Cell Line, Tumor, Gene Expression Regulation, Genes, Reporter, Humans, Intracellular Signaling Peptides and Proteins, Membrane Proteins, antagonists & inhibitors, biosynthesis, metabolism, Mice, Neoplasms, blood supply, drug therapy, pathology, Neovascularization, Pathologic, Rats, Receptors, Notch, Signal Transduction, Vascular Endothelial Growth Factor A

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          Abstract

          Tumour growth requires accompanying expansion of the host vasculature, with tumour progression often correlated with vascular density. Vascular endothelial growth factor (VEGF) is the best-characterized inducer of tumour angiogenesis. We report that VEGF dynamically regulates tumour endothelial expression of Delta-like ligand 4 (Dll4), which was previously shown to be absolutely required for normal embryonic vascular development. To define Dll4 function in tumour angiogenesis, we manipulated this pathway in murine tumour models using several approaches. Here we show that blockade resulted in markedly increased tumour vascularity, associated with enhanced angiogenic sprouting and branching. Paradoxically, this increased vascularity was non-productive-as shown by poor perfusion and increased hypoxia, and most importantly, by decreased tumour growth-even for tumours resistant to anti-VEGF therapy. Thus, VEGF-induced Dll4 acts as a negative regulator of tumour angiogenesis; its blockade results in a striking uncoupling of tumour growth from vessel density, presenting a novel therapeutic approach even for tumours resistant to anti-VEGF therapies.

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          Most cited references 19

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          Angiogenesis in life, disease and medicine.

          The growth of blood vessels (a process known as angiogenesis) is essential for organ growth and repair. An imbalance in this process contributes to numerous malignant, inflammatory, ischaemic, infectious and immune disorders. Recently, the first anti-angiogenic agents have been approved for the treatment of cancer and blindness. Angiogenesis research will probably change the face of medicine in the next decades, with more than 500 million people worldwide predicted to benefit from pro- or anti-angiogenesis treatments.
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            Vascular-specific growth factors and blood vessel formation.

            A recent explosion in newly discovered vascular growth factors has coincided with exploitation of powerful new genetic approaches for studying vascular development. An emerging rule is that all of these factors must be used in perfect harmony to form functional vessels. These new findings also demand re-evaluation of therapeutic efforts aimed at regulating blood vessel growth in ischaemia, cancer and other pathological settings.
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              Notch Signaling: Cell Fate Control and Signal Integration in Development

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                Author and article information

                Journal
                17183313
                10.1038/nature05355

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