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Regulation of Angiogenesis and Tumor Progression by Semaphorins

  • Chapter
Semaphorins

Abstract

The semaphorins constitute a large family of secreted and membrane-bound proteins that were initially characterized as axon-guidance factors. In addition, several semaphorins, such as sema3B, sema3E, sema3F, sema4D, and a few additional less studied, were found to function as suppressors or inducers of tumor progression. These semaphorins were found to modulate tumor progression by a variety of mechanisms that include direct effects on tumor cells expressing semaphorin receptors, promotion or inhibition of tumor angiogenesis or tumor lymphangiogenesis, and recruitment or inhibition of the recruitment of various nonmalignant cell types such as bone marrow-derived cells capable of modulating tumor progression into the tumor microenvironment. In this review, we focus on the mechanisms by which semaphorins modulate tumor progression, excluding the effects of the semaphorins on the immune system, which obviously also contributes to the regulation of tumor progression.

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References

  • Acevedo LM, Barillas S, Weis SM, Gothert JR, Cheresh DA (2008) Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood 111:2674–2680

    PubMed Central  CAS  PubMed  Google Scholar 

  • Alon T, Hemo I, Itin A, Peer J, Stone J, Keshet E (1995) Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity. Nat Med 1:1024–1028

    CAS  PubMed  Google Scholar 

  • Antipenko A, Himanen JP, van Leyen K, Nardi-Dei V, Lesniak J, Barton WA, Rajashankar KR, Lu M, Hoemme C, Puschel AW, Nikolov DB (2003) Structure of the semaphorin-3A receptor binding module. Neuron 39:589–598

    CAS  PubMed  Google Scholar 

  • Appleton BA, Wu P, Maloney J, Yin J, Liang WC, Stawicki S, Mortara K, Bowman KK, Elliott J, Desmarais W, Bazan JF, Bagri A, Tessier-Lavigne M, Koch AW, Wu Y, Watts RJ, Wiesmann C (2007) Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding. EMBO J 26:4902–4912

    PubMed Central  CAS  PubMed  Google Scholar 

  • Arribas J, Esselens C (2009) ADAM17 as a therapeutic target in multiple diseases. Curr Pharm Des 15:2319–2335

    CAS  PubMed  Google Scholar 

  • Artigiani S, Conrotto P, Fazzari P, Gilestro GF, Barberis D, Giordano S, Comoglio PM, Tamagnone L (2004) Plexin-B3 is a functional receptor for semaphorin 5A. EMBO Rep 5:710–714

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bachelder RE, Lipscomb EA, Lin X, Wendt MA, Chadborn NH, Eickholt BJ, Mercurio AM (2003) Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Res 63:5230–5233

    CAS  PubMed  Google Scholar 

  • Bagci T, Wu JK, Pfannl R, Ilag LL, Jay DG (2009) Autocrine semaphorin 3A signaling promotes glioblastoma dispersal. Oncogene 28:3537–3550

    CAS  PubMed  Google Scholar 

  • Banu N, Teichman J, Dunlap-Brown M, Villegas G, Tufro A (2006) Semaphorin 3C regulates endothelial cell function by increasing integrin activity. FASEB J 20:2150–2152

    CAS  PubMed  Google Scholar 

  • Barresi V, Tuccari G (2010) Increased ratio of vascular endothelial growth factor to semaphorin3A is a negative prognostic factor in human meningiomas. Neuropathology 30:537–546

    Google Scholar 

  • Basile JR, Barac A, Zhu T, Guan KL, Gutkind JS (2004) Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res 64:5212–5224

    CAS  PubMed  Google Scholar 

  • Basile JR, Afkhami T, Gutkind JS (2005) Semaphorin 4D/plexin-B1 induces endothelial cell migration through the activation of PYK2, Src, and the phosphatidylinositol 3-kinase-Akt pathway. Mol Cell Biol 25:6889–6898

    PubMed Central  CAS  PubMed  Google Scholar 

  • Basile JR, Castilho RM, Williams VP, Gutkind JS (2006) Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci U S A 103:9017–9022

    PubMed Central  CAS  PubMed  Google Scholar 

  • Basile JR, Gavard J, Gutkind JS (2007a) Plexin-B1 utilizes RhoA and Rho kinase to promote the integrin-dependent activation of Akt and ERK and endothelial cell motility. J Biol Chem 282:34888–34895

    CAS  PubMed  Google Scholar 

  • Basile JR, Holmbeck K, Bugge TH, Gutkind JS (2007b) MT1-MMP controls tumor-induced angiogenesis through the release of semaphorin 4D. J Biol Chem 282:6899–6905

    CAS  PubMed  Google Scholar 

  • Bassi DE, Fu J, de Lopez CR, Klein-Szanto AJ (2005) Proprotein convertases: “master switches” in the regulation of tumor growth and progression. Mol Carcinog 44:151–161

    CAS  PubMed  Google Scholar 

  • Bates D, Taylor GI, Minichiello J, Farlie P, Cichowitz A, Watson N, Klagsbrun M, Mamluk R, Newgreen DF (2003) Neurovascular congruence results from a shared patterning mechanism that utilizes semaphorin3A and neuropilin-1. Dev Biol 255:77–98

    CAS  PubMed  Google Scholar 

  • Ben-Zvi A, Ben-Gigi L, Klein H, Behar O (2007) Modulation of semaphorin3A activity by p75 neurotrophin receptor influences peripheral axon patterning. J Neurosci 27:13000–13011

    CAS  PubMed  Google Scholar 

  • Beuten J, Garcia D, Brand TC, He X, Balic I, Canby-Hagino E, Troyer DA, Baillargeon J, Hernandez J, Thompson IM, Leach RJ, Naylor SL (2009) Semaphorin 3B and 3F single nucleotide polymorphisms are associated with prostate cancer risk and poor prognosis. J Urol 182:1614–1620

    CAS  PubMed  Google Scholar 

  • Bielenberg DR, Hida Y, Shimizu A, Kaipainen A, Kreuter M, Kim CC, Klagsbrun M (2004) Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest 114:1260–1271

    PubMed Central  CAS  PubMed  Google Scholar 

  • Binmadi NO, Proia P, Zhou H, Yang YH, Basile JR (2011) Rho-mediated activation of PI(4)P5K and lipid second messengers is necessary for promotion of angiogenesis by Semaphorin 4D. Angiogenesis 14:309–319

    CAS  PubMed  Google Scholar 

  • Binmadi NO, Yang YH, Zhou H, Proia P, Lin YL, Batista De Paula AM, Sena Guimaraes AL, Poswar FO, Sundararajan D, Basile JR (2012) Plexin-B1 and semaphorin 4D cooperate to promote perineural invasion in a RhoA/ROK-dependent manner. Am J Pathol 180:1232–1242

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bouvree K, Brunet I, Del TR, Gordon E, Prahst C, Cristofaro B, Mathivet T, Xu Y, Soueid J, Fortuna V, Miura N, Aigrot MS, Maden CH, Ruhrberg C, Thomas JL, Eichmann A (2012) Semaphorin3A, neuropilin-1, and plexinA1 are required for lymphatic valve formation. Circ Res 111:437–445

    CAS  PubMed  Google Scholar 

  • Buehler A, Sitaras N, Favret S, Bucher F, Berger S, Pielen A, Joyal JS, Juan AM, Martin G, Schlunck G, Agostini HT, Klagsbrun M, Smith LE, Sapieha P, Stahl A (2013) Semaphorin 3F forms an anti-angiogenic barrier in outer retina. FEBS Lett 587:1650–1655

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bussolino F, Di Renzo MF, Ziche M, Bocchietto E, Olivero M, Naldini L, Gaudino G, Tamagnone L, Coffer A, Comoglio PM (1992) Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119:629–641

    CAS  PubMed  Google Scholar 

  • Cai HB, Reed RR (1999) Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1. J Neurosci 19:6519–6527

    CAS  PubMed  Google Scholar 

  • Campioni M, Ambrogi V, Pompeo E, Citro G, Castelli M, Spugnini EP, Gatti A, Cardelli P, Lorenzon L, Baldi A, Mineo TC (2008) Identification of genes down-regulated during lung cancer progression: a cDNA array study. J Exp Clin Cancer Res 27:38

    PubMed Central  PubMed  Google Scholar 

  • Campos M, DE Campos SG, Ribeiro GG, Eguchi FC, Silva SR, De Oliveira CZ, Da Costa AM, Curcelli EC, Nunes MC, Penna V, Longatto-Filho A (2013) Ki-67 and CD100 immunohistochemical expression is associated with local recurrence and poor prognosis in soft tissue sarcomas, respectively. Oncol Lett 5:1527–1535

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cao S, Yaqoob U, Das A, Shergill U, Jagavelu K, Huebert RC, Routray C, Abdelmoneim S, Vasdev M, Leof E, Charlton M, Watts RJ, Mukhopadhyay D, Shah VH (2010) Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-beta signaling in hepatic stellate cells. J Clin Invest 120:2379–2394

    PubMed Central  CAS  PubMed  Google Scholar 

  • Carrer A, Moimas S, Zacchigna S, Pattarini L, Zentilin L, Ruozi G, Mano M, Sinigaglia M, Maione F, Serini G, Giraudo E, Bussolino F, Giacca M (2012) Neuropilin-1 identifies a subset of bone marrow Gr1-monocytes that can induce tumor vessel normalization and inhibit tumor growth. Cancer Res 15:6371–6381

    Google Scholar 

  • Casazza A, Finisguerra V, Capparuccia L, Camperi A, Swiercz JM, Rizzolio S, Rolny C, Christensen C, Bertotti A, Sarotto I, Risio M, Trusolino L, Weitz J, Schneider M, Mazzone M, Comoglio PM, Tamagnone L (2010) Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J Clin Invest 120:2684–2698

    PubMed Central  CAS  PubMed  Google Scholar 

  • Casazza A, Fu X, Johansson I, Capparuccia L, Andersson F, Giustacchini A, Squadrito ML, Venneri MA, Mazzone M, Larsson E, Carmeliet P, De PM, Naldini L, Tamagnone L, Rolny C (2011) Systemic and targeted delivery of semaphorin 3A inhibits tumor angiogenesis and progression in mouse tumor models. Arterioscler Thromb Vasc Biol 31:741–749

    CAS  PubMed  Google Scholar 

  • Casazza A, Kigel B, Maione F, Capparuccia L, Kessler O, Giraudo E, Mazzone M, Neufeld G, Tamagnone L (2012) Tumour growth inhibition and anti-metastatic activity of a mutated furin-resistant Semaphorin 3E isoform. EMBO Mol Med 4:234–250

    PubMed Central  CAS  PubMed  Google Scholar 

  • Castellani V, De Angelis E, Kenwrick S, Rougon G (2002) Cis and trans interactions of L1 with neuropilin-1 control axonal responses to semaphorin 3A. EMBO J 21:6348–6357

    PubMed Central  CAS  PubMed  Google Scholar 

  • Castro-Rivera E, Ran S, Thorpe P, Minna JD (2004) Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect. Proc Natl Acad Sci U S A 101:11432–11437

    PubMed Central  CAS  PubMed  Google Scholar 

  • Castro-Rivera E, Ran S, Brekken RA, Minna JD (2008) Semaphorin 3B inhibits the phosphatidylinositol 3-kinase/Akt pathway through neuropilin-1 in lung and breast cancer cells. Cancer Res 68:8295–8303

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chakraborty G, Kumar S, Mishra R, Patil TV, Kundu GC (2012) Semaphorin 3A suppresses tumor growth and metastasis in mice melanoma model. PLoS One 7:e33633

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chauvet S, Cohen S, Yoshida Y, Fekrane L, Livet J, Gayet O, Segu L, Buhot MC, Jessell TM, Henderson CE, Mann F (2007) Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development. Neuron 56:807–822

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen H, Chedotal A, He Z, Goodman CS, Tessier-Lavigne M (1997) Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins sema E and sema IV but not sema III. Neuron 19:547–559

    CAS  PubMed  Google Scholar 

  • Christensen CR, Klingelhofer J, Tarabykina S, Hulgaard EF, Kramerov D, Lukanidin E (1998) Transcription of a novel mouse semaphorin gene, M-semaH, correlates with the metastatic ability of mouse tumor cell lines. Cancer Res 58:1238–1244

    CAS  PubMed  Google Scholar 

  • Christensen C, Ambartsumian N, Gilestro G, Thomsen B, Comoglio P, Tamagnone L, Guldberg P, Lukanidin E (2005) Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res 65:6167–6177

    CAS  PubMed  Google Scholar 

  • Clarhaut J, Gemmill RM, Potiron VA, Ait-Si-Ali S, Imbert J, Drabkin HA, Roche J (2009) ZEB-1, a repressor of the semaphorin 3F tumor suppressor gene in lung cancer cells. Neoplasia 11:157–166

    PubMed Central  CAS  PubMed  Google Scholar 

  • Coma S, Amin DN, Shimizu A, Lasorella A, Iavarone A, Klagsbrun M (2010) Id2 promotes tumor cell migration and invasion through transcriptional repression of semaphorin 3F. Cancer Res 70:3823–3832

    PubMed Central  CAS  PubMed  Google Scholar 

  • Conrotto P, Corso S, Gamberini S, Comoglio PM, Giordano S (2004) Interplay between scatter factor receptors and B plexins controls invasive growth. Oncogene 23:5131–5137

    CAS  PubMed  Google Scholar 

  • Conrotto P, Valdembri D, Corso S, Serini G, Tamagnone L, Comoglio PM, Bussolino F, Giordano S (2005) Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood 105:4321–4329

    CAS  PubMed  Google Scholar 

  • Damola A, Legendre A, Ball S, Masters JR, Williamson M (2013) Function of mutant and wild-type plexinb1 in prostate cancer cells. Prostate 73:1326–1335

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dhanabal M, Wu F, Alvarez E, McQueeney KD, Jeffers M, Macdougall J, Boldog FL, Hackett C, Shenoy S, Khramtsov N, Weiner J, Lichenstein HS, LaRochelle WJ (2005) Recombinant semaphorin 6A-1 ectodomain inhibits in vivo growth factor and tumor cell line-induced angiogenesis. Cancer Biol Ther 4:659–668

    CAS  PubMed  Google Scholar 

  • Ding S, Luo JH, Yuan XB (2007) Semaphorin-3F attracts the growth cone of cerebellar granule cells through cGMP signaling pathway. Biochem Biophys Res Commun 356:857–863

    CAS  PubMed  Google Scholar 

  • Drenberg CD, Livingston S, Chen R, Kruk PA, Nicosia SV (2009) Expression of semaphorin 3F and its receptors in epithelial ovarian cancer, fallopian tubes, and secondary Mullerian tissues. Obstet Gynecol Int 2009:730739

    PubMed Central  PubMed  Google Scholar 

  • Eilken HM, Adams RH (2010) Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol 22:617–625

    CAS  PubMed  Google Scholar 

  • Falk J, Bechara A, Fiore R, Nawabi H, Zhou H, Hoyo-Becerra C, Bozon M, Rougon G, Grumet M, Puschel AW, Sanes JR, Castellani V (2005) Dual functional activity of semaphorin 3B is required for positioning the anterior commissure. Neuron 48:63–75

    PubMed  Google Scholar 

  • Fantin A, Schwarz Q, Davidson K, Normando EM, Denti L, Ruhrberg C (2011) The cytoplasmic domain of neuropilin 1 is dispensable for angiogenesis, but promotes the spatial separation of retinal arteries and veins. Development (Camb) 138:4185–4191

    CAS  Google Scholar 

  • Feiner L, Koppel AM, Kobayashi H, Raper JA (1997) Secreted chick semaphorins bind recombinant neuropilin with similar affinities but bind different subsets of neurons in situ. Neuron 19:539–545

    CAS  PubMed  Google Scholar 

  • Feiner L, Webber AL, Brown CB, Lu MM, Jia L, Feinstein P, Mombaerts P, Epstein JA, Raper JA (2001) Targeted disruption of semaphorin 3C leads to persistent truncus arteriosus and aortic arch interruption. Development (Camb) 128:3061–3070

    CAS  Google Scholar 

  • Folkman J (1990) What is the evidence that tumors are angiogenesis dependent. J Natl Cancer Inst 82:4–7

    CAS  PubMed  Google Scholar 

  • Franco M, Tamagnone L (2008) Tyrosine phosphorylation in semaphorin signalling: shifting into overdrive. EMBO Rep 9:865–871

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fukushima Y, Okada M, Kataoka H, Hirashima M, Yoshida Y, Mann F, Gomi F, Nishida K, Nishikawa SI, Uemura A (2011) Sema3E-PlexinD1 signaling selectively suppresses disoriented angiogenesis in ischemic retinopathy in mice. J Clin Invest 121:1974–1985

    PubMed Central  CAS  PubMed  Google Scholar 

  • Futamura M, Kamino H, Miyamoto Y, Kitamura N, Nakamura Y, Ohnishi S, Masuda Y, Arakawa H (2007) Possible role of semaphorin 3F, a candidate tumor suppressor gene at 3p21.3, in p53-regulated tumor angiogenesis suppression. Cancer Res 67:1451–1460

    CAS  PubMed  Google Scholar 

  • Ghanem RC, Han KY, Rojas J, Ozturk O, Kim DJ, Jain S, Chang JH, Azar DT (2011) Semaphorin 7A promotes angiogenesis in an experimental corneal neovascularization model. Curr Eye Res 36:989–996

    PubMed Central  CAS  PubMed  Google Scholar 

  • Giacobini P, Messina A, Morello F, Ferraris N, Corso S, Penachioni J, Giordano S, Tamagnone L, Fasolo A (2008) Semaphorin 4D regulates gonadotropin hormone-releasing hormone-1 neuronal migration through PlexinB1-Met complex. J Cell Biol 183:555–566

    PubMed Central  CAS  PubMed  Google Scholar 

  • Giger RJ, Urquhart ER, Gillespie SK, Levengood DV, Ginty DD, Kolodkin AL (1998) Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity. Neuron 21:1079–1092

    CAS  PubMed  Google Scholar 

  • Giordano S, Corso S, Conrotto P, Artigiani S, Gilestro G, Barberis D, Tamagnone L, Comoglio PM (2002) The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol 4:720–724

    CAS  PubMed  Google Scholar 

  • Gitay-Goren H, Cohen T, Tessler S, Soker S, Gengrinovitch S, Rockwell P, Klagsbrun M, Levi B-Z, Neufeld G (1996) Selective binding of VEGF121 to one of the three VEGF receptors of vascular endothelial cells. J Biol Chem 271:5519–5523

    CAS  PubMed  Google Scholar 

  • Gitler AD, Lu MM, Epstein JA (2004) PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development. Dev Cell 7:107–116

    CAS  PubMed  Google Scholar 

  • Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G (2000) Neuropilin-2 and neuropilin-1 are receptors for 165-amino acid long form of vascular endothelial growth factor (VEGF) and of placenta growth factor-2, but only neuropilin-2 functions as a receptor for the 145 amino acid form of VEGF. J Biol Chem 275:18040–18045

    CAS  PubMed  Google Scholar 

  • Gluzman-Poltorak Z, Cohen T, Shibuya M, Neufeld G (2001) Vascular endothelial growth factor receptor-1 and neuropilin-2 form complexes. J Biol Chem 276:18688–18694

    CAS  PubMed  Google Scholar 

  • Goodman CS, Kolodkin AL, Luo Y, Pueschel AW, Raper JA (1999) Unified nomenclature for the semaphorins collapsins. Cell 97:551–552

    Google Scholar 

  • Gospodarowicz D, Abraham JA, Schilling J (1989) Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci U S A 86:7311–7315

    PubMed Central  CAS  PubMed  Google Scholar 

  • Grundmann S, Lindmayer C, Hans FP, Hoefer I, Helbing T, Pasterkamp G, Bode C, De Kleijn D, Moser M (2013) FoxP1 stimulates angiogenesis by repressing the inhibitory guidance protein semaphorin 5B in endothelial cells. PLoS One 8:e70873

    PubMed Central  CAS  PubMed  Google Scholar 

  • Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Yung S, Chimenti S, Landsman L, Abramovitch R, Keshet E (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124:175–189

    CAS  PubMed  Google Scholar 

  • Gu C, Rodriguez ER, Reimert DV, Shu T, Fritzsch B, Richards LJ, Kolodkin AL, Ginty DD (2003) Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev Cell 5:45–57

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J, Henderson CE, Jessell TM, Kolodkin AL, Ginty DD (2005) Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307:265–268

    CAS  PubMed  Google Scholar 

  • Guo HF, Li X, Parker MW, Waltenberger J, Becker PM, Vander Kooi CW (2013) Mechanistic basis for the potent anti-angiogenic activity of semaphorin 3F. Biochemistry 52:7551–7558

    CAS  PubMed  Google Scholar 

  • Gutmann-Raviv N, Kessler O, Shraga-Heled N, Lange T, Herzog Y, Neufeld G (2006) The neuropilins and their roll in tumorigenesis and tumor progression. Cancer Lett 231:1–11

    Google Scholar 

  • Guttmann-Raviv N, Shraga-Heled N, Varshavsky A, Guimaraes-Sternberg C, Kessler O, Neufeld G (2007) Semaphorin-3A and semaphorin-3F work together to repel endothelial cells and to inhibit their survival by induction of apoptosis. J Biol Chem 282:26294–26305

    CAS  PubMed  Google Scholar 

  • Hanahan D, Folkman J (1996) Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86:353–364

    CAS  PubMed  Google Scholar 

  • He Z, Tessier-Lavigne M (1997) Neuropilin is a receptor for the axonal chemorepellent semaphorin III. Cell 90:739–751

    CAS  PubMed  Google Scholar 

  • He H, Yang T, Terman JR, Zhang X (2009) Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration. Proc Natl Acad Sci U S A 106:15610–15615

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature (London) 445:776–780

    Google Scholar 

  • Herman JG, Meadows GG (2007) Increased class 3 semaphorin expression modulates the invasive and adhesive properties of prostate cancer cells. Int J Oncol 30:1231–1238

    CAS  PubMed  Google Scholar 

  • Hinck L (2004) The versatile roles of “axon guidance” cues in tissue morphogenesis. Dev Cell 7:783–793

    CAS  PubMed  Google Scholar 

  • Hota PK, Buck M (2012) Plexin structures are coming: opportunities for multilevel investigations of semaphorin guidance receptors, their cell signaling mechanisms, and functions. Cell Mol Life Sci 69:3765–3805

    CAS  PubMed  Google Scholar 

  • Huang S, Mills L, Mian B, Tellez C, Mccarty M, Yang XD, Gudas JM, Bar-Eli M (2002) Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 161:125–134

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hung RJ, Yazdani U, Yoon J, Wu H, Yang T, Gupta N, Huang Z, van Berkel WJ, Terman JR (2010) Mical links semaphorins to F-actin disassembly. Nature (London) 463:823–827

    CAS  Google Scholar 

  • Hung RJ, Pak CW, Terman JR (2011) Direct redox regulation of F-actin assembly and disassembly by mical. Science 334:1710–1713

    PubMed Central  CAS  PubMed  Google Scholar 

  • Janssen BJ, Robinson RA, Perez-Branguli F, Bell CH, Mitchell KJ, Siebold C, Jones EY (2010) Structural basis of semaphorin-plexin signalling. Nature (London) 467:1118–1122

    CAS  Google Scholar 

  • Janssen BJ, Malinauskas T, Weir GA, Cader MZ, Siebold C, Jones EY (2012) Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex. Nat Struct Mol Biol 19:1293–1299

    PubMed Central  CAS  PubMed  Google Scholar 

  • Joseph D, Ho SM, Syed V (2010) Hormonal regulation and distinct functions of semaphorin-3B and semaphorin-3F in ovarian cancer. Mol Cancer Ther 9:499–509

    PubMed Central  CAS  PubMed  Google Scholar 

  • Joyal JS, Sitaras N, Binet F, Rivera JC, Stahl A, Zaniolo K, Shao Z, Polosa A, Zhu T, Hamel D, Djavari M, Kunik D, Honore JC, Picard E, Zabeida A, Varma DR, Hickson G, Mancini J, Klagsbrun M, Costantino S, Beausejour C, Lachapelle P, Smith LE, Chemtob S, Sapieha P (2011) Ischemic neurons prevent vascular regeneration of neural tissue by secreting semaphorin 3A. Blood 117:6024–6035

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kantor DB, Chivatakarn O, Peer KL, Oster SF, Inatani M, Hansen MJ, Flanagan JG, Yamaguchi Y, Sretavan DW, Giger RJ, Kolodkin AL (2004) Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 44:961–975

    CAS  PubMed  Google Scholar 

  • Kato S, Kubota K, Shimamura T, Shinohara Y, Kobayashi N, Watanabe S, Yoneda M, Inamori M, Nakamura F, Ishiguro H, Nakaigawa N, Nagashima Y, Taguri M, Kubota Y, Goshima Y, Morita S, Endo I, Maeda S, Nakajima A, Nakagama H (2011) Semaphorin 4D, a lymphocyte semaphorin, enhances tumor cell motility through binding its receptor, plexinB1, in pancreatic cancer. Cancer Sci 102:2029–2037

    CAS  PubMed  Google Scholar 

  • Kawasaki T, Kitsukawa T, Bekku Y, Matsuda Y, Sanbo M, Yagi T, Fujisawa H (1999) A requirement for neuropilin-1 in embryonic vessel formation. Development (Camb) 126:4895–4902

    CAS  Google Scholar 

  • Keck PJ, Hauser SD, Krivi G, Sanzo K, Warren T, Feder J, Connolly DT (1989) Vascular permeability factor, an endothelial cell mitogen related to PDGF. Science 246:1309–1312

    CAS  PubMed  Google Scholar 

  • Kessler O, Shraga-Heled N, Lange T, Gutmann-Raviv N, Sabo E, Baruch L, Machluf M, Neufeld G (2004) Semaphorin-3F is an inhibitor of tumor angiogenesis. Cancer Res 64:1008–1015

    CAS  PubMed  Google Scholar 

  • Kigel B, Varshavsky A, Kessler O, Neufeld G (2008) Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells. PLoS One 3:e3287

    PubMed Central  PubMed  Google Scholar 

  • Kigel B, Rabinowicz N, Varshavsky A, Kessler O, Neufeld G (2011) Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling. Blood 118:4285–4296

    CAS  PubMed  Google Scholar 

  • Kim J, Oh WJ, Gaiano N, Yoshida Y, Gu (2011) Semaphorin 3E–Plexin-D1 signaling regulates VEGF function in developmental angiogenesis via a feedback mechanism. Genes Dev 25:1399–1411

    PubMed Central  CAS  PubMed  Google Scholar 

  • Klostermann A, Lohrum M, Adams RH, Puschel AW (1998) The chemorepulsive activity of the axonal guidance signal semaphorin D requires dimerization. J Biol Chem 273:7326–7331

    CAS  PubMed  Google Scholar 

  • Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD (1997) Neuropilin is a semaphorin III receptor. Cell 90:753–762

    CAS  PubMed  Google Scholar 

  • Kumanogoh A, Watanabe C, Lee I, Wang X, Shi W, Araki H, Hirata H, Iwahori K, Uchida J, Yasui T, Matsumoto M, Yoshida K, Yakura H, Pan C, Parnes JR, Kikutani H (2000) Identification of CD72 as a lymphocyte receptor for the class IV semaphorin CD100: a novel mechanism for regulating B cell signaling. Immunity 13:621–631

    CAS  PubMed  Google Scholar 

  • Kumanogoh A, Marukawa S, Suzuki K, Takegahara N, Watanabe C, Ch’ng E, Ishida I, Fujimura H, Sakoda S, Yoshida K, Kikutani H (2002) Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature (London) 419:629–633

    CAS  Google Scholar 

  • Kuroki T, Trapasso F, Yendamuri S, Matsuyama A, Alder H, Williams NN, Kaiser LR, Croce CM (2003) Allelic loss on chromosome 3p21.3 and promoter hypermethylation of semaphorin 3B in non-small cell lung cancer. Cancer Res 63:3352–3355

    CAS  PubMed  Google Scholar 

  • Kusy S, Nasarre P, Chan D, Potiron V, Meyronet D, Gemmill RM, Constantin B, Drabkin HA, Roche J (2005) Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells. Neoplasia 7:457–465

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lanahan A, Zhang X, Fantin A, Zhuang Z, Rivera-Molina F, Speichinger K, Prahst C, Zhang J, Wang Y, Davis G, Toomre D, Ruhrberg C, Simons M (2013) The neuropilin 1 cytoplasmic domain is required for VEGF-a-dependent arteriogenesis. Dev Cell 25:156–168

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lepore JJ, Mericko PA, Cheng L, Lu MM, Morrisey EE, Parmacek MS (2006) GATA-6 regulates semaphorin 3C and is required in cardiac neural crest for cardiovascular morphogenesis. J Clin Invest 116:929–939

    PubMed Central  CAS  PubMed  Google Scholar 

  • Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N (1989) Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246:1306–1309

    CAS  PubMed  Google Scholar 

  • Li X, Lee AY (2010) Semaphorin 5A and plexin-B3 inhibit human glioma cell motility through RhoGDI{alpha}-mediated inactivation of Rac1 GTPase. J Biol Chem 285:32436–32445

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liu H, Juo ZS, Shim AH, Focia PJ, Chen X, Garcia KC, He X (2010) Structural basis of semaphorin-plexin recognition and viral mimicry from Sema7A and A39R complexes with plexinC1. Cell 142:749–761

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ (2007) Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci U S A 104:3219–3224

    PubMed Central  CAS  PubMed  Google Scholar 

  • Love CA, Harlos K, Mavaddat N, Davis SJ, Stuart DI, Jones EY, Esnouf RM (2003) The ligand-binding face of the semaphorins revealed by the high-resolution crystal structure of SEMA4D. Nat Struct Biol 10:843–848

    CAS  PubMed  Google Scholar 

  • Luchino J, Hocine M, Amoureux MC, Gibert B, Bernet A, Royet A, Treilleux I, Lecine P, Borg JP, Mehlen P, Chauvet S, Mann F (2013) Semaphorin 3E suppresses tumor cell death triggered by the plexin D1 dependence receptor in metastatic breast cancers. Cancer Cell 24:673–685

    CAS  PubMed  Google Scholar 

  • Luo Y, Raible D, Raper JA (1993) Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75:217–227

    CAS  PubMed  Google Scholar 

  • Maione F, Molla F, Meda C, Latini R, Zentilin L, Giacca M, Seano G, Serini G, Bussolino F, Giraudo E (2009) Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J Clin Invest 119:3356–3372

    PubMed Central  CAS  PubMed  Google Scholar 

  • Maione F, Capano S, Regano D, Zentilin L, Giacca M, Casanovas O, Bussolino F, Serini G, Giraudo E (2012) Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J Clin Invest 122:1832–1848

    PubMed Central  CAS  PubMed  Google Scholar 

  • Marsit CJ, Wiencke JK, Liu M, Kelsey KT (2005) The race associated allele of semaphorin 3B (SEMA3B) T415I and its role in lung cancer in African-Americans and Latino-Americans. Carcinogenesis (Oxf) 26:1446–1449

    CAS  Google Scholar 

  • Matsuoka RL, Chivatakarn O, Badea TC, Samuels IS, Cahill H, Katayama K, Kumar SR, Suto F, Chedotal A, Peachey NS, Nathans J, Yoshida Y, Giger RJ, Kolodkin AL (2011) Class 5 transmembrane semaphorins control selective Mammalian retinal lamination and function. Neuron 71:460–473

    PubMed Central  CAS  PubMed  Google Scholar 

  • McClelland L, Chen Y, Soong J, Kuo I, Scott G (2011) Plexin B1 inhibits integrin-dependent pp125(FAK) and Rho activity in melanoma. Pigment Cell Melanoma Res 24:165–174

    Google Scholar 

  • Meadows SM, Fletcher PJ, Moran C, Xu K, Neufeld G, Chauvet S, Mann F, Krieg PA, Cleaver O (2012) Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels. Circ Res 110:34–46

    PubMed Central  CAS  PubMed  Google Scholar 

  • Meda C, Molla F, De Pizzol M, Regano D, Maione F, Capano S, Locati M, Mantovani A, Latini R, Bussolino F, Giraudo E (2012) Semaphorin 4A exerts a proangiogenic effect by enhancing vascular endothelial growth factor-a expression in macrophages. J Immunol 188:4081–4092

    CAS  PubMed  Google Scholar 

  • Mey L, Hormann M, Schleicher N, Reuter P, Donges S, Kinscherf R, Gassmann M, Gerriets T, Al-Fakhri N (2013) Neuropilin-1 modulates vascular endothelial growth factor-induced poly(ADP-ribose)-polymerase leading to reduced cerebrovascular apoptosis. Neurobiol Dis 59:111–125

    CAS  PubMed  Google Scholar 

  • Miao HQ, Soker S, Feiner L, Alonso JL, Raper JA, Klagsbrun M (1999) Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility. Functional competition of collapsin-1 and vascular endothelial growth factor-165. J Cell Biol 146:233–242

    PubMed Central  CAS  PubMed  Google Scholar 

  • Miyato H, Tsuno NH, Kitayama J (2012) Semaphorin 3C is involved in the progression of gastric cancer. Cancer Sci 103:1961–1966

    CAS  PubMed  Google Scholar 

  • Moretti S, Procopio A, Lazzarini R, Rippo MR, Testa R, Marra M, Tamagnone L, Catalano A (2007) Semaphorin3A signaling controls Fas (CD95)-mediated apoptosis by promoting Fas translocation into lipid rafts. Blood 111:2290–2299

    PubMed  Google Scholar 

  • Muller MW, Giese NA, Swiercz JM, Ceyhan GO, Esposito I, Hinz U, Buchler P, Giese T, Buchler MW, Offermanns S, Friess H (2007) Association of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer. Int J Cancer 121:2421–2433

    PubMed  Google Scholar 

  • Nair PN, McArdle L, Cornell J, Cohn SL, Stallings RL (2007) High-resolution analysis of 3p deletion in neuroblastoma and differential methylation of the SEMA3B tumor suppressor gene. Cancer Genet Cytogenet 174:100–110

    CAS  PubMed  Google Scholar 

  • Nasarre P, Constantin B, Rouhaud L, Harnois T, Raymond G, Drabkin HA, Bourmeyster N, Roche J (2003) Semaphorin SEMA3F and VEGF have opposing effects on cell attachment and spreading. Neoplasia 5:83–92

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nasarre P, Kusy S, Constantin B, Castellani V, Drabkin HA, Bagnard D, Roche J (2005) Semaphorin SEMA3F has a repulsing activity on breast cancer cells and inhibits E-cadherin-mediated cell adhesion. Neoplasia 7:180–189

    PubMed Central  CAS  PubMed  Google Scholar 

  • Negishi M, Oinuma I, Katoh H (2005a) Plexins: axon guidance and signal transduction. Cell Mol Life Sci 62(12):1363–1371

    CAS  PubMed  Google Scholar 

  • Negishi M, Oinuma I, Katoh H (2005b) R-ras as a key player for signaling pathway of plexins. Mol Neurobiol 32:217–222

    CAS  PubMed  Google Scholar 

  • Neufeld G, Kessler O (2008) The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer 8:632–645

    CAS  PubMed  Google Scholar 

  • Nguyen H, Ivanova VS, Kavandi L, Rodriguez GC, Maxwell G, Syed V (2011) Progesterone and 1,25-dihydroxyvitamin D3 inhibit endometrial cancer cell growth by upregulating semaphorin 3B and semaphorin 3F. Mol Cancer Res 9:1479–1492

    CAS  PubMed  Google Scholar 

  • Nkyimbeng-Takwi E, Chapoval SP (2011) Biology and function of neuroimmune semaphorins 4A and 4D. Immunol Res 50:10–21

    PubMed Central  CAS  PubMed  Google Scholar 

  • Nogi T, Yasui N, Mihara E, Matsunaga Y, Noda M, Yamashita N, Toyofuku T, Uchiyama S, Goshima Y, Kumanogoh A, Takagi J (2010) Structural basis for semaphorin signalling through the plexin receptor. Nature (London) 467:1123–1127

    CAS  Google Scholar 

  • Oinuma I, Ishikawa Y, Katoh H, Negishi M (2004) The semaphorin 4D receptor plexin-B1 is a GTPase activating protein for R-Ras. Science 305:862–865

    CAS  PubMed  Google Scholar 

  • Pan G, Zhang X, Ren J, Lu J, Li W, Fu H, Zhang S, Li J (2012) Semaphorin 5A, an axon guidance molecule, enhances the invasion and metastasis of human gastric cancer through activation of MMP9. Pathol Oncol Res 19:11–18

    PubMed  Google Scholar 

  • Parker MW, Hellman LM, Xu P, Fried MG, Vander Kooi CW (2010) Furin processing of semaphorin 3F determines its anti-angiogenic activity by regulating direct binding and competition for neuropilin. Biochemistry 18:4068–4075

    Google Scholar 

  • Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben Neriah Y (2004) NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature (London) 431:461–466

    CAS  Google Scholar 

  • Potiron VA, Sharma G, Nasarre P, Clarhaut JA, Augustin HG, Gemmill RM, Roche J, Drabkin HA (2007) Semaphorin SEMA3F affects multiple signaling pathways in lung cancer cells. Cancer Res 67:8708–8715

    CAS  PubMed  Google Scholar 

  • Puschel AW (2007) GTPases in semaphorin signaling. Adv Exp Med Biol 600:12–23

    PubMed  Google Scholar 

  • Rizzolio S, Rabinoviz N, Rainero E, Lanzetti L, Serini G, Norman JC, Neufeld G, Tamagnone L (2012) Neuropilin-1 dependent regulation of EGF-receptor signaling. Cancer Res 72:5801–5811

    CAS  PubMed  Google Scholar 

  • Roche J, Boldog F, Robinson M, Robinson L, Varella-Garcia M, Swanton M, Waggoner B, Fishel R, Franklin W, Gemmill R, Drabkin H (1996) Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin. Oncogene 12:1289–1297

    CAS  PubMed  Google Scholar 

  • Rolny C, Capparuccia L, Casazza A, Mazzone M, Vallario A, Cignetti A, Medico E, Carmeliet P, Comoglio PM, Tamagnone L (2008) The tumor suppressor semaphorin 3B triggers a prometastatic program mediated by interleukin 8 and the tumor microenvironment. J Exp Med 205:1155–1171

    PubMed Central  CAS  PubMed  Google Scholar 

  • Roodink I, Kats G, van Kempen L, Grunberg M, Maass C, Verrijp K, Raats J, Leenders W (2008) Semaphorin 3E expression correlates inversely with plexin D1 during tumor progression. Am J Pathol 173:1873–1881

    PubMed Central  PubMed  Google Scholar 

  • Ruhrberg C, Bautch VL (2013) Neurovascular development and links to disease. Cell Mol Life Sci 70:1675–1684

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sabag AD, Bode J, Fink D, Kigel B, Kugler W, Neufeld G (2012) Semaphorin-3D and semaphorin-3E inhibit the development of tumors from glioblastoma cells implanted in the cortex of the brain. PLoS One 7:e42912

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sadanandam A, Varney ML, Singh S, Ashour AE, Moniaux N, Deb S, Lele SM, Batra SK, Singh RK (2010) High gene expression of semaphorin 5A in pancreatic cancer is associated with tumor growth, invasion and metastasis. Int J Cancer 127:1373–1383

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sadanandam A, Sidhu SS, Wullschleger S, Singh S, Varney ML, Yang CS, Ashour AE, Batra SK, Singh RK (2012) Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation. Br J Cancer 107:501–507

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sakurai A, Gavard J, Annas-Linhares Y, Basile JR, Amornphimoltham P, Palmby TR, Yagi H, Zhang F, Randazzo PA, Li X, Weigert R, Gutkind JS (2010) Semaphorin 3E initiates anti-angiogenic signaling through Plexin-D1 by regulating Arf6 and R-Ras. Mol Cell Biol 30:3086–3098

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sakurai A, Jian X, Lee CJ, Manavski Y, Chavakis E, Donaldson J, Randazzo PA, Gutkind JS (2011) Phosphatidylinositol-4-phosphate 5-kinase and GEP100/Brag2 protein mediate antiangiogenic signaling by semaphorin 3E-plexin-D1 through Arf6 protein. J Biol Chem 286:34335–34345

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schmidt AM, Moore KJ (2013) The semaphorin 3E/PlexinD1 axis regulates macrophage inflammation in obesity. Cell Metab 18:461–462

    CAS  PubMed  Google Scholar 

  • Schwarz Q, Waimey KE, Golding M, Takamatsu H, Kumanogoh A, Fujisawa H, Cheng HJ, Ruhrberg C (2008) Plexin A3 and plexin A4 convey semaphorin signals during facial nerve development. Dev Biol 324:1–9

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schwarz Q, Maden CH, Davidson K, Ruhrberg C (2009) Neuropilin-mediated neural crest cell guidance is essential to organise sensory neurons into segmented dorsal root ganglia. Development (Camb) 136:1785–1789

    CAS  Google Scholar 

  • Segarra M, Ohnuki H, Maric D, Salvucci O, Hou X, Kumar A, Li X, Tosato G (2012) Semaphorin 6A regulates angiogenesis by modulating VEGF signaling. Blood 120:4104–4115

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sekido Y, Bader S, Latif F, Chen JY, Duh FM, Wei MH, Albanesi JP, Lee CC, Lerman MI, Minna JD (1996) Human semaphorins A(V) and IV reside in the 3p21.3 small cell lung cancer deletion region and demonstrate distinct expression patterns. Proc Natl Acad Sci U S A 93:4120–4125

    PubMed Central  CAS  PubMed  Google Scholar 

  • Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F, Zammataro L, Primo L, Tamagnone L, Logan M, Tessier-Lavigne M, Taniguchi M, Puschel AW, Bussolino F (2003) Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature (London) 424:391–397

    CAS  Google Scholar 

  • Shi W, Kumanogoh A, Watanabe C, Uchida J, Wang X, Yasui T, Yukawa K, Ikawa M, Okabe M, Parnes JR, Yoshida K, Kikutani H (2000) The class IV semaphorin CD100 plays nonredundant roles in the immune system: defective B and T cell activation in CD100-deficient mice. Immunity 13:633–642

    CAS  PubMed  Google Scholar 

  • Shimizu I, Yoshida Y, Moriya J, Nojima A, Uemura A, Kobayashi Y, Minamino T (2013) Semaphorin3E-induced inflammation contributes to insulin resistance in dietary obesity. Cell Metab 18:491–504

    CAS  PubMed  Google Scholar 

  • Shraga-Heled N, Kessler O, Prahst C, Kroll J, Augustin HG, Neufeld G (2007) Neuropilin-1 and neuropilin-2 enhance VEGF121 stimulated signal transduction by the VEGFR-2 receptor. FASEB J 21:915–926

    CAS  PubMed  Google Scholar 

  • Siekmann AF, Covassin L, Lawson ND (2008) Modulation of VEGF signalling output by the Notch pathway. Bioessays 30:303–313

    CAS  PubMed  Google Scholar 

  • Sierra JR, Corso S, Caione L, Cepero V, Conrotto P, Cignetti A, Piacibello W, Kumanogoh A, Kikutani H, Comoglio PM, Tamagnone L, Giordano S (2008) Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med 205:1673–1685

    PubMed Central  CAS  PubMed  Google Scholar 

  • Soker S, Fidder H, Neufeld G, Klagsbrun M (1996) Characterization of novel VEGF binding proteins associated with tumor cells that bind VEGF165 but not VEGF121. J Biol Chem 271:5761–5767

    CAS  PubMed  Google Scholar 

  • Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform specific receptor for vascular endothelial growth factor. Cell 92:735–745

    CAS  PubMed  Google Scholar 

  • Song X, Zhang W, Zhang Y, Zhang H, Fu Z, Ye J, Liu L, Song X, Wu Y (2012) Expression of semaphorin 3A and neuropilin 1 with clinicopathological features and survival in human tongue cancer. Med Oral Patol Oral Cir Bucal 17:e962–e968

    PubMed Central  PubMed  Google Scholar 

  • Soong J, Scott G (2012) Plexin B1 inhibits MET through direct association and regulates Shp2 expression in melanocytes. J Cell Sci 126:688–695

    PubMed  Google Scholar 

  • Soong J, Chen Y, Shustef EM, Scott GA (2012) Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth. J Invest Dermatol 132:1230–1238

    PubMed Central  CAS  PubMed  Google Scholar 

  • Staton CA, Shaw LA, Valluru M, Hoh L, Koay I, Cross SS, Reed MW, Brown NJ (2011) Expression of class 3 semaphorins and their receptors in human breast neoplasia. Histopathology 59:274–282

    PubMed  Google Scholar 

  • Stone J, Itin A, Alon T, Peer J, Gnessin H, Chanling T, Keshet E (1995) Development of retinal vasculature is mediated by hypoxia- induced vascular endothelial growth factor (VEGF) expression by neuroglia. J Neurosci 15:4738–4747

    CAS  PubMed  Google Scholar 

  • Strieter RM, Kunkel SL, Elner VM, Martonyi CL, Koch AE, Polverini PJ, Elner SG (1992) Interleukin-8: a corneal factor that induces neovascularization. Am J Pathol 141:1279–1284

    PubMed Central  CAS  PubMed  Google Scholar 

  • Strongin AY (2010) Proteolytic and non-proteolytic roles of membrane type-1 matrix metalloproteinase in malignancy. Biochim Biophys Acta 1803:133–141

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sulpice E, Plouet J, Berge M, Allanic D, Tobelem G, Merkulova-Rainon T (2007) Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity. Blood 111:2036–2045

    PubMed  Google Scholar 

  • Sun T, Krishnan R, Swiercz JM (2012) Grb2 mediates semaphorin-4D-dependent RhoA inactivation. J Cell Sci 125:3557–3567

    CAS  PubMed  Google Scholar 

  • Suto F, Ito K, Uemura M, Shimizu M, Shinkawa Y, Sanbo M, Shinoda T, Tsuboi M, Takashima S, Yagi T, Fujisawa H (2005) Plexin-a4 mediates axon-repulsive activities of both secreted and transmembrane semaphorins and plays roles in nerve fiber guidance. J Neurosci 25:3628–3637

    CAS  PubMed  Google Scholar 

  • Suto F, Tsuboi M, Kamiya H, Mizuno H, Kiyama Y, Komai S, Shimizu M, Sanbo M, Yagi T, Hiromi Y, Chedotal A, Mitchell KJ, Manabe T, Fujisawa H (2007) Interactions between plexin-A2, plexin-A4, and semaphorin 6A control lamina-restricted projection of hippocampal mossy fibers. Neuron 53:535–547

    CAS  PubMed  Google Scholar 

  • Swiercz JM, Kuner R, Offermanns S (2004) Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol 165:869–880

    PubMed Central  CAS  PubMed  Google Scholar 

  • Swiercz JM, Worzfeld T, Offermanns S (2008) ERBB-2 and met reciprocally regulate cellular signaling via plexin-B1. J Biol Chem 283:1893–1901

    CAS  PubMed  Google Scholar 

  • Takahashi T, Strittmatter SM (2001) PlexinA1 autoinhibition by the plexin sema domain. Neuron 29:429–439

    CAS  PubMed  Google Scholar 

  • Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RG, Fujisawa H, Strittmatter SM (1999) Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 99:59–69

    CAS  PubMed  Google Scholar 

  • Takamatsu H, Kumanogoh A (2012) Diverse roles for semaphorin-plexin signaling in the immune system. Trends Immunol 33:127–135

    CAS  PubMed  Google Scholar 

  • Takashima S, Kitakaze M, Asakura M, Asanuma H, Sanada S, Tashiro F, Niwa H, Miyazaki JJ, Hirota S, Kitamura Y, Kitsukawa T, Fujisawa H, Klagsbrun M, Hori M (2002) Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci U S A 99:3657–3662

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tamagnone L, Artigiani S, Chen H, He Z, Ming GI, Song H, Chedotal A, Winberg ML, Goodman CS, Poo M, Tessier-Lavigne M, Comoglio PM (1999) Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99:71–80

    CAS  PubMed  Google Scholar 

  • Terman JR, Mao T, Pasterkamp RJ, Yu HH, Kolodkin AL (2002) MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion. Cell 109:887–900

    CAS  PubMed  Google Scholar 

  • Tischoff I, Markwarth A, Witzigmann H, Uhlmann D, Hauss J, Mirmohammadsadegh A, Wittekind C, Hengge UR, Tannapfel A (2005) Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors. Int J Cancer 115:684–689

    CAS  PubMed  Google Scholar 

  • Tomizawa Y, Sekido Y, Kondo M, Gao B, Yokota J, Roche J, Drabkin H, Lerman MI, Gazdar AF, Minna JD (2001) Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B. Proc Natl Acad Sci U S A 98:13954–13959

    PubMed Central  CAS  PubMed  Google Scholar 

  • Toyofuku T, Zhang H, Kumanogoh A, Takegahara N, Suto F, Kamei J, Aoki K, Yabuki M, Hori M, Fujisawa H, Kikutani H (2004) Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, plexin-A1, with off-track and vascular endothelial growth factor receptor type 2. Genes Dev 18:435–447

    PubMed Central  CAS  PubMed  Google Scholar 

  • Toyofuku T, Yoshida J, Sugimoto T, Zhang H, Kumanogoh A, Hori M, Kikutani H (2005) FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nat Neurosci 8:1712–1719

    CAS  PubMed  Google Scholar 

  • Toyofuku T, Yabuki M, Kamei J, Kamei M, Makino N, Kumanogoh A, Hori M (2007) Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1. EMBO J 26:1373–1384

    PubMed Central  CAS  PubMed  Google Scholar 

  • Toyofuku T, Yoshida J, Sugimoto T, Yamamoto M, Makino N, Takamatsu H, Takegahara N, Suto F, Hori M, Fujisawa H, Kumanogoh A, Kikutani H (2008) Repulsive and attractive semaphorins cooperate to direct the navigation of cardiac neural crest cells. Dev Biol 321:251–262

    CAS  PubMed  Google Scholar 

  • Toyofuku T, Nojima S, Ishikawa T, Takamatsu H, Tsujimura T, Uemura A, Matsuda J, Seki T, Kumanogoh A (2012) Endosomal sorting by Semaphorin 4A in retinal pigment epithelium supports photoreceptor survival. Genes Dev 26:816–829

    PubMed Central  CAS  PubMed  Google Scholar 

  • Trusolino L, Bertotti A, Comoglio PM (2010) MET signalling: principles and functions in development, organ regeneration and cancer. Nat Rev Mol Cell Biol 11:834–848

    CAS  PubMed  Google Scholar 

  • Tse C, Xiang RH, Bracht T, Naylor SL (2002) Human semaphorin 3B (SEMA3B) located at chromosome 3p21.3 suppresses tumor formation in an adenocarcinoma cell line. Cancer Res 62:542–546

    CAS  PubMed  Google Scholar 

  • Urbich C, Kaluza D, Fromel T, Knau A, Bennewitz K, Boon RA, Bonauer A, Doebele C, Boeckel JN, Hergenreider E, Zeiher AM, Kroll J, Fleming I, Dimmeler S (2012) MicroRNA-27a/b controls endothelial cell repulsion and angiogenesis by targeting semaphorin 6A. Blood 119:1607–1618

    CAS  PubMed  Google Scholar 

  • Vacca A, Scavelli C, Serini G, Di Pietro G, Cirulli T, Merchionne F, Ribatti D, Bussolino F, Guidolin D, Piaggio G, Bacigalupo A, Dammacco F (2006) Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma. Blood 108:1661–1667

    CAS  PubMed  Google Scholar 

  • Valente G, Nicotra G, Arrondini M, Castino R, Capparuccia L, Prat M, Kerim S, Tamagnone L, Isidoro C (2009) Co-expression of plexin-B1 and Met in human breast and ovary tumours enhances the risk of progression. Cell Oncol 31:423–436

    CAS  PubMed  Google Scholar 

  • Varshavsky A, Kessler O, Abramovitch S, Kigel B, Zaffryar S, Akiri G, Neufeld G (2008) Semaphorin-3B is an angiogenesis inhibitor that is inactivated by furin-like pro-protein convertases. Cancer Res 68:6922–6931

    CAS  PubMed  Google Scholar 

  • Wen H, Lei Y, Eun S-Y, Ting JP (2010) Plexin-A4 semaphorin 3A signaling is required for Toll-like receptor- and sepsis-induced cytokine storm. J Exp Med 207:2943–2957

    PubMed Central  CAS  PubMed  Google Scholar 

  • West DC, Chris RG, Duchesne L, Patey SJ, Terry CJ, Turnbull JE, Delehedde M, Heegaard CW, Allain F, Vanpouille C, Ron D, Fernig DG (2005) Interactions of multiple heparin-binding growth factors with neuropilin-1 and potentiation of the activity of fibroblast growth factor-2. J Biol Chem 280:13457–13464

    CAS  PubMed  Google Scholar 

  • Wolman MA, Liu Y, Tawarayama H, Shoji W, Halloran MC (2004) Repulsion and attraction of axons by Semaphorin3D are mediated by different neuropilins in vivo. J Neurosci 24:8428–8435

    CAS  PubMed  Google Scholar 

  • Wong HK, Shimizu A, Kirkpatrick ND, Garkavtsev I, Chan AW, di Tomaso E, Klagsbrun M, Jain RK (2012) Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism. Neoplasia 14:84–94

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wu F, Zhou Q, Yang J, Duan G, Ou J, Zhang R, Pan F, Peng Q, Tan H, Ping YF, Cui Y, Qian C, Yan XC, Bian XW (2011) Axon guiding chemorepulsant semaphorin-3F inhibits tumor growth and metastasis of colorectal carcinoma. Clin Cancer Res 17:2702–2711

    CAS  PubMed  Google Scholar 

  • Xiang RH, Hensel CH, Garcia DK, Carlson HC, Kok K, Daly MC, Kerbacher K, van den Berg A, Veldhuis P, Buys CH, Naylor SL (1996) Isolation of the human semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer. Genomics 32:39–48

    CAS  PubMed  Google Scholar 

  • Xiang R, Davalos AR, Hensel CH, Zhou XJ, Tse C, Naylor SL (2002) Semaphorin 3F gene from human 3p21.3 suppresses tumor formation in nude mice. Cancer Res 62:2637–2643

    CAS  PubMed  Google Scholar 

  • Xiong G, Wang C, Evers BM, Zhou BP, Xu R (2012) RORalpha suppresses breast tumor invasion by inducing SEMA3F expression. Cancer Res 72:1728–1739

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yang YH, Zhou H, Binmadi NO, Proia P, Basile JR (2011) Plexin-B1 activates NF-kappaB and IL-8 to promote a pro-angiogenic response in endothelial cells. PLoS One 6:e25826

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yao HP, Zhou YQ, Zhang R, Wang MH (2013) MSP-RON signalling in cancer: pathogenesis and therapeutic potential. Nat Rev Cancer 13:466–481

    CAS  PubMed  Google Scholar 

  • Yaqoob U, Cao S, Shergill U, Jagavelu K, Geng Z, Yin M, de Assuncao TM, Cao Y, Szabolcs A, Thorgeirsson S, Schwartz M, Yang JD, Ehman R, Roberts L, Mukhopadhyay D, Shah VH (2012) Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment. Cancer Res 72:4047–4059

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zacchigna S, Pattarini L, Zentilin L, Moimas S, Carrer A, Sinigaglia M, Arsic N, Tafuro S, Sinagra G, Giacca M (2008) Bone marrow cells recruited through the neuropilin-1 receptor promote arterial formation at the sites of adult neoangiogenesis in mice. J Clin Invest 118:2062–2075

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhou H, Binmadi NO, Yang YH, Proia P, Basile JR (2012) Semaphorin 4D cooperates with VEGF to promote angiogenesis and tumor progression. Angiogenesis 15:391–407

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhu L, Bergmeier W, Wu J, Jiang H, Stalker TJ, Cieslak M, Fan R, Boumsell L, Kumanogoh A, Kikutani H, Tamagnone L, Wagner DD, Milla ME, Brass LF (2007) Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc Natl Acad Sci U S A 104:1621–1626

    PubMed Central  PubMed  Google Scholar 

  • Zygmunt T, Gay CM, Blondelle J, Singh MK, Flaherty KM, Means PC, Herwig L, Krudewig A, Belting HG, Affolter M, Epstein JA, Torres-Vazquez J (2011) Semaphorin-PlexinD1 signaling limits angiogenic potential via the VEGF decoy receptor sFlt1. Dev Cell 21:301–314

    PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was supported by grants from the Israel Academy of Sciences (ISF) and the Rappaport Family Institute for Research in the Medical Sciences of Technion (to G.N.).

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Authors and Affiliations

  1. The Cancer and Vascular Biology Research Center, Rappaport Research Institute in the Medical Sciences, The Bruce Rappaport Faculty of Medicine, Technion – Israel Institute of Technology, 1 Efron St., 9679, Haifa, 31096, Israel

    Gera Neufeld, Adi D. Sabag, Yelena Mumblat, Tatyana Smolkin & Ofra Kessler

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  1. Gera Neufeld
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  2. Adi D. Sabag
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  3. Yelena Mumblat
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  4. Tatyana Smolkin
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  5. Ofra Kessler
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Correspondence to Gera Neufeld .

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Editors and Affiliations

  1. Department of Respiratory Medicine Allergy and Rheumatic Diseases, Graduate School of Medicine Osaka University, Suita, Osaka, Japan

    Atsushi Kumanogoh

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Neufeld, G., Sabag, A.D., Mumblat, Y., Smolkin, T., Kessler, O. (2015). Regulation of Angiogenesis and Tumor Progression by Semaphorins. In: Kumanogoh, A. (eds) Semaphorins. Springer, Tokyo. https://doi.org/10.1007/978-4-431-54385-5_6

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