Magic roundabout, a tumor endothelial marker: expression and signaling.
Molecular signals that guide blood vessels to specific paths are not fully deciphered, but are thought to be similar to signals that mediate neuronal guidance. These cues are not only critical for normal blood vessel development, but may also play a major role in tumor angiogenesis. In this study, we have demonstrated the tumor endothelial specific expression of a Robo family member, magic roundabout (MRB), functionally characterized its role in endothelial cell migration and defined a signaling pathway that might mediate this function. We show that MRB is differentially over-expressed in tumor endothelial cells versus normal adult endothelial cells in numerous solid tumors. Moreover, over-expression of MRB in endothelial cells activates MRB in a ligand-independent fashion, and activation of MRB via Slit2, a putative ligand, results in inhibition of VEGF and FGF induced migration. We also demonstrate that MRB induced inhibition of endothelial migration is partially mediated by the Ras-Raf-Mek-Erk signaling pathway. We therefore hypothesize that expression of MRB is involved in regulating the migration of endothelial cells during tumor angiogenesis.
Seth
Pankaj
P
Renal Division and Center for Study of the Tumor Microenvironment, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Lin
Yanfeng
Y
Hanai
Jun-ichi
J
Shivalingappa
Venkatesha
V
Duyao
Mabel P
MP
Sukhatme
Vikas P
VP
D014408:Biomarkers, Tumor / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D009369:Neoplasms / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000098552:Slit Homolog 2 Protein; D000097905:Roundabout Proteins
D014408:Biomarkers, Tumor; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011956:Receptors, Cell Surface; D000098552:Slit Homolog 2 Protein; C462951:ROBO4 protein, human; D000097905:Roundabout Proteins