Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells.
Neuropilin-1 (NP1), in conjunction with plexins, promotes axon repulsion by binding to semaphorin 3A (SEMA3A). Although NP1 is expressed in carcinoma cells, its functions have remained elusive, and neither SEMA3A nor plexin expression has been explored in cancer. Here we provide evidence that breast carcinoma cells support an autocrine pathway involving SEMA3A, plexin-A1, and NP1 that impedes their ability to chemotax. Reducing SEMA3A or NP1 expression by RNA interference or inhibiting plexin-A1 signaling enhanced migration. Conversely, expression of constitutively active plexin-A1 impaired chemotaxis. The paradox of how breast carcinoma cells expressing these endogenous chemotaxis inhibitors are able to migrate is explained by their expression of vascular endothelial growth factor (VEGF), a NP1 ligand that competes with SEMA3A for receptor binding. Finally, we establish that the ratio of endogenous VEGF and SEMA3A concentrations in carcinoma cells determines their chemotactic rate. Our findings lead to the surprising conclusion that opposing autocrine loops involving NP1 regulate the chemotaxis of breast carcinoma cells. Moreover, our data indicate a novel autocrine function for VEGF in chemotaxis.
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002633:Chemotaxis / Q000502:physiology*; D016228:Endothelial Growth Factors / Q000502:physiology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D008024:Ligands; D008222:Lymphokines / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D039942:Neuropilin-1 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D034622:RNA Interference; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D040121:Semaphorin-3A / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D008222:Lymphokines; D009419:Nerve Tissue Proteins; C492116:PLXNA1 protein, human; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D040121:Semaphorin-3A; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D039942:Neuropilin-1