Slit2 Function In Tumor Angiogenesis Research

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. Interestingly, Slit attracts vascular endothelial cells, which is opposite to its roles as repellents and inhibitors in axon guidance and neuronal and leukocyte migration. These basic findings allowed us to design a strategy of neutralizing Robo1 activity for inhibition of tumor growth. 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. Communication between tumor cells and vascular endothelial cells is along known to beimportant in tumor-induced angiogenesis. Mechanistic understanding of tumor-induced angiogenesis is crucial for designing therapeutic approaches. Our results have revealed a previously unsuspected role of Slit-Robo signaling in tumor angiogenesis and shown the importance of this pathway in tumor growth. Our results have not only uncovered a molecular mechanism for tumor-induced angiogenesis and a novel molecular target for controlling tumor growth, but also attracted other scientific researchers working in this field to pay more attention to the roles of other neuronal guidance cues in tumor angiogenesis.