Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity.
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.
Wang
Biao
B
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
Xiao
Yang
Y
Ding
Bei Bei
BB
Zhang
Na
N
Yuan
Xiao bin
Xb
Gui
Lü
L
Qian
Kai Xian
KX
Duan
Shumin
S
Chen
Zhengjun
Z
Rao
Yi
Y
Geng
Jian Guo
JG
D000818:Animals; D002455:Cell Division; D002465:Cell Movement; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000517:prevention & control*; D051379:Mice; D008833:Microcirculation; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D014407:Tumor Cells, Cultured / Q000637:transplantation; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D019869:Phosphatidylinositol 3-Kinases; D011971:Receptors, Immunologic; D011993:Recombinant Fusion Proteins; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein