Dll4 activation of Notch signaling reduces tumor vascularity and inhibits tumor growth.
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 nonproductive tumor neovascularization and unexpectedly reduced tumor growth. Because nonfunctional 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 cocultured 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. In addition, 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.
Segarra
Marta
M
Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA. segarram@mail.nih.gov
Williams
Cassin Kimmel
CK
Sierra
Maria de la Luz
Mde L
Bernardo
Marcelino
M
McCormick
Peter J
PJ
Maric
Dragan
D
Regino
Celeste
C
Choyke
Peter
P
Tosato
Giovanna
G
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D015870:Gene Expression; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009389:Neovascularization, Pathologic; D051880:Receptors, Notch / Q000502:physiology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014161:Transduction, Genetic
D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C424126:DLL4 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D051880:Receptors, Notch; D011994:Recombinant Proteins