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Blood, 1 September 2008, Vol. 112, No. 5, pp. 1904-1911. Prepublished online as a Blood First Edition Paper on June 24, 2008; DOI 10.1182/blood-2007-11-126045. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2007-11-126045v1 112/5/1904    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Segarra, M. Articles by Tosato, G. Search for Related Content PubMed PubMed Citation Articles by Segarra, M. Articles by Tosato, G. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted November 27, 2007 Accepted June 4, 2008 Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth Marta Segarra*, Cassin Kimmel Williams, Maria de la Luz Sierra, Marcelino Bernardo, Peter J McCormick, Dragan Maric, Celeste Regino, Peter Choyke, and Giovanna Tosato Laboratory of Cellular Oncology, Center for Cancer Reserach, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States Laboratory Animal Science Program, SAIC-Frederick, National Cancer Institute, Frederick, MD, United States Flow Cytometry Core Facility, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States Molecular Imaging Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States * Corresponding author; email: segarram{at}mail.nih.gov. Gene targeting experiments have shown that Delta-like 4 (Dll4) is a vascular-specific Notch ligand critical to normal vascular development. Recent studies have demonstrated that inhibition of Dll4/Notch signaling in tumor bearing mice resulted in excessive, yet non-productive tumor neovascularization and unexpectedly reduced tumor growth. Since non-functional blood vessels have the potential to normalize, we explored the alternative approach of stimulating Notch signaling in the tumor vasculature to inhibit tumor growth. Here we show that retrovirus-induced over-expression of Dll4 in tumor cells activates Notch signaling in co-cultured endothelial cells and limits vascular endothelial growth factor (VEGF)-induced endothelial cell growth. Tumors produced in mice by injection of human and murine tumor cells transduced with Dll4 were significantly smaller, less vascularized and more hypoxic than controls, and displayed evidence of Notch activation. Also, tumor blood perfusion was reduced as documented by vascular imaging. These results demonstrate that Notch activation in the tumor microenvironment reduces tumor neovascularization and blood perfusion, and suggest that Dll4-induced Notch activation may represent an effective therapeutic approach for the treatment of solid tumors. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: O. Salvucci, D. Maric, M. Economopoulou, S. Sakakibara, S. Merlin, A. Follenzi, and G. Tosato EphrinB reverse signaling contributes to endothelial and mural cell assembly into vascular structures Blood, August 20, 2009; 114(8): 1707 - 1716. [Abstract] [Full Text] [PDF] F. De Smet, I. Segura, K. De Bock, P. J. Hohensinner, and P. Carmeliet Mechanisms of Vessel Branching: Filopodia on Endothelial Tip Cells Lead the Way Arterioscler Thromb Vasc Biol, May 1, 2009; 29(5): 639 - 649. [Abstract] [Full Text] [PDF]

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