Abstract
Slit is a secreted protein known to function through the Roundabout (Robo) receptor as a chemorepellent in axon guidance and neuronal migration, and as an inhibitor in leukocyte chemotaxis. Here we show Slit2 expression in a large number of solid tumors and Robo1 expression in vascular endothelial cells. Recombinant Slit2 protein attracted endothelial cells and promoted tube formation in a Robo1- and phosphatidylinositol kinase-dependent manner. Neutralization of Robo1 reduced the microvessel density and the tumor mass of human malignant melanoma A375 cells in vivo. These findings demonstrate the angiogenic function of Slit-Robo signaling, reveal a mechanism in mediating the crosstalk between cancer cells and endothelial cells, and indicate the effectiveness of blocking this signaling pathway in treating cancers.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Division
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Cell Movement
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Endothelium, Vascular / metabolism
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Endothelium, Vascular / pathology
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Gene Expression Regulation
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Humans
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Intercellular Signaling Peptides and Proteins
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Melanoma, Experimental / blood supply*
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Melanoma, Experimental / prevention & control*
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Mice
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Microcirculation
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Neovascularization, Pathologic / metabolism*
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Nerve Tissue Proteins / antagonists & inhibitors
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / immunology
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Nerve Tissue Proteins / metabolism
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Nerve Tissue Proteins / physiology*
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Phosphatidylinositol 3-Kinases / metabolism
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Rabbits
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Rats
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Receptors, Immunologic / antagonists & inhibitors
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Receptors, Immunologic / physiology*
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Recombinant Fusion Proteins
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Roundabout Proteins
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Signal Transduction
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Tumor Cells, Cultured / transplantation
Substances
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Intercellular Signaling Peptides and Proteins
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Nerve Tissue Proteins
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Receptors, Immunologic
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Recombinant Fusion Proteins
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Phosphatidylinositol 3-Kinases
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Slit homolog 2 protein