Slit-Robo signaling mediates lymphangiogenesis and promotes tumor lymphatic metastasis.
The Slit family of guidance cues binds to Roundabout (Robo) receptors to modulate neuronal, leukocytic, and endothelial migration. Slit-Robo signaling had been reported to function as chemoattractive signal for vascular endothelial cells during angiogenesis. In this study, we found that Robo1 was expressed in lymphatic endothelial cells to mediate the migration and tube formation of these cells upon Slit2 stimulation, which were specifically inhibited by the function-blocking antibody R5 to Slit2/Robo1 interaction. To further explore the lymphangiogenic effect and significance mediated by Slit-Robo signaling, we intercrossed Slit2 transgenic mice with a non-metastatic RIP1-Tag2 mouse tumor model, and found that transgenic overexpression of Slit2 significantly enhanced tumor lymphangiogenesis and subsequently promoted mesenteric lymph node metastasis of pancreatic islet tumors. Taken together, our findings reveal that through interacting with Robo1, Slit2 is a novel and potent lymphangiogenic factor and contributes to tumor lymphatic metastasis.
Yang
Xiao-Mei
XM
Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, The Graduate School of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
Han
Hai-Xiong
HX
Sui
Fei
F
Dai
Yu-Min
YM
Chen
Ming
M
Geng
Jian-Guo
JG
D000818:Animals; D002277:Carcinoma / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D042783:Endothelial Cells / Q000378:metabolism; D006801:Humans; D007340:Insulinoma / Q000378:metabolism / Q000473:pathology; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D042583:Lymphangiogenesis / Q000235:genetics*; D008207:Lymphatic Metastasis / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein
D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011971:Receptors, Immunologic; D000097905:Roundabout Proteins; D000098552:Slit Homolog 2 Protein