Angiogenesis

, Volume 12, Issue 2, pp 187–193 | Cite as

Semaphorins and tumor angiogenesis

Original Paper

Abstract

Semaphorins belong to a large family of proteins well-conserved along evolution from viruses to mammalians. Secreted and membrane-bound semaphorins participate in a wide range of biological phenomena including development and regeneration of nervous system, cardiovascular development, and immune system activities. Different classes of semaphorins are bifunctional and often exert opposite effects (i.e., repellent or attractive) by acting through the plexin receptor family. However, some classes use other membrane receptors and the same plexin-mediated signals may be modulated by co-receptors, in particular neuropilins or some tyrosine kinase receptors. In cancer, semaphorins have both tumor-suppressor and tumor-promoting functions, by acting on both tumor and stromal components. Here, we review the role of semaphorins in tumor angiogenesis and propose that an unbalance between autocrine loops respectively involving angiogenic inducers and class 3 semaphorin is instrumental for structural and functional abnormalities observed in tumor vasculature.

Keywords

Integrin Autocrine loop Tumor growth 

Notes

Acknowledgments

This work was supported by grants from: Telethon Italy (GGP04127 to GS); Associazione Augusto per la Vita (to G.S.); Fondazione Guido Berlucchi (to GS); Associazione Italiana per la Ricerca sul Cancro (to G.S. and F.B.); Ministero della Salute—Programma Ricerca Oncologica 2006 and Ricerca Finalizzata 2006 and 2007 (to G.S. and F.B.); Regione Piemonte—Ricerca Sanitaria Finalizzata 2006 and 2008, Ricerca Scientifica Applicata 2004: grants D10 and A150, Ricerca industriale e sviluppo precompetitivo 2006: grants PRESTO, PHOENICS, and SPLASERBA (to G.S. and F.B.); Sixth Framework Programme of European Union Contract LSHM-CT-2003-503254 (to F.B.); and Fondazione Cassa di Risparmio di Torino (to F.B.)

References

  1. 1.
    Tran TS et al (2007) Semaphorin regulation of cellular morphology. Annu Rev Cell Dev Biol 23:263–292. doi:10.1146/annurev.cellbio.22.010605.093554 PubMedCrossRefGoogle Scholar
  2. 2.
    Bussolino F et al (2006) Semaphoring vascular morphogenesis. Endothelium 13:81–91. doi:10.1080/10623320600698003 PubMedCrossRefGoogle Scholar
  3. 3.
    Gitler AD et al (2004) PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development. Dev Cell 7:107–116. doi:10.1016/j.devcel.2004.06.002 PubMedCrossRefGoogle Scholar
  4. 4.
    Zhang Y et al (2009) Tie2Cre-mediated inactivation of plexinD1 results in congenital heart, vascular and skeletal defects. Dev Biol 325:82–93. doi:10.1016/j.ydbio.2008.09.031 PubMedCrossRefGoogle Scholar
  5. 5.
    Neufeld G, Kessler O (2008) The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer 8:632–645. doi:10.1038/nrc2404 PubMedCrossRefGoogle Scholar
  6. 6.
    Zhou Y et al (2008) Semaphorin signaling: progress made and promises ahead. Trends Biochem Sci 33:161–170. doi:10.1016/j.tibs.2008.01.006 PubMedCrossRefGoogle Scholar
  7. 7.
    Luo BH, Springer TA (2006) Integrin structures and conformational signaling. Curr Opin Cell Biol 18:579–586. doi:10.1016/j.ceb.2006.08.005 PubMedCrossRefGoogle Scholar
  8. 8.
    Valdembri D et al. (2009) Neuropilin-1/GIPC1 signaling regulates α5β1 integrin traffic and function in endothelial cells. PLoS Biol 7(1):e1000025. doi:10.1371/journal.pbio.1000025 CrossRefGoogle Scholar
  9. 9.
    Barberis D et al (2004) Plexin signaling hampers integrin-based adhesion, leading to Rho-kinase independent cell rounding, and inhibiting lamellipodia extension and cell motility. FASEB J 18:592–594PubMedGoogle Scholar
  10. 10.
    Butler B et al (2006) Purified integrin adhesion complexes exhibit actin-polymerization activity. Curr Biol 16:242–251. doi:10.1016/j.cub.2005.12.033 PubMedCrossRefGoogle Scholar
  11. 11.
    Takahashi T, Strittmatter SM (2001) Plexina1 autoinhibition by the plexin sema domain. Neuron 29:429–439. doi:10.1016/S0896-6273(01)00216-1 PubMedCrossRefGoogle Scholar
  12. 12.
    Oinuma I et al (2004) The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science 305:862–865. doi:10.1126/science.1097545 PubMedCrossRefGoogle Scholar
  13. 13.
    Negishi M et al (2005) R-ras as a key player for signaling pathway of plexins. Mol Neurobiol 32:217–222. doi:10.1385/MN:32:3:217 PubMedCrossRefGoogle Scholar
  14. 14.
    Oinuma I et al (2004) Molecular dissection of the semaphorin 4D receptor plexin-B1-stimulated R-Ras GTPase-activating protein activity and neurite remodeling in hippocampal neurons. J Neurosci 24:11473–11480. doi:10.1523/JNEUROSCI.3257-04.2004 PubMedCrossRefGoogle Scholar
  15. 15.
    Kinbara K et al (2003) Ras GTPases: integrins’ friends or foes? Nat Rev Mol Cell Biol 4:767–776PubMedGoogle Scholar
  16. 16.
    Toyofuku T et al (2005) FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nat Neurosci 8:1712–1719. doi:10.1038/nn1596 PubMedCrossRefGoogle Scholar
  17. 17.
    Critchley DR, Gingras AR (2008) Talin at a glance. J Cell Sci 121:1345–1347. doi:10.1242/jcs.018085 PubMedCrossRefGoogle Scholar
  18. 18.
    Conrotto P et al (2005) Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood 105:4321–4329. doi:10.1182/blood-2004-07-2885 PubMedCrossRefGoogle Scholar
  19. 19.
    Basile JR et al (2004) Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res 64:5212–5224. doi:10.1158/0008-5472.CAN-04-0126 PubMedCrossRefGoogle Scholar
  20. 20.
    Basile JR et al (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. doi:10.1128/MCB.25.16.6889-6898.2005 PubMedCrossRefGoogle Scholar
  21. 21.
    Swiercz JM et al (2004) Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J Cell Biol 165:869–880. doi:10.1083/jcb.200312094 PubMedCrossRefGoogle Scholar
  22. 22.
    Swiercz JM et al (2008) ERBB-2 and met reciprocally regulate cellular signaling via plexin-B1. J Biol Chem 283:1893–1901. doi:10.1074/jbc.M706822200 PubMedCrossRefGoogle Scholar
  23. 23.
    Toyofuku T et al (2007) Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via Plexin-D1. EMBO J 26:1373–1384. doi:10.1038/sj.emboj.7601589 PubMedCrossRefGoogle Scholar
  24. 24.
    Soker S et al (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735–745. doi:10.1016/S0092-8674(00)81402-6 PubMedCrossRefGoogle Scholar
  25. 25.
    Kawasaki T et al (1999) A requirement for neuropilin-1 in embryonic vessel formation. Development 126:4895–4902PubMedGoogle Scholar
  26. 26.
    Favier B et al (2006) Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood 108:1243–1250. doi:10.1182/blood-2005-11-4447 PubMedCrossRefGoogle Scholar
  27. 27.
    Karpanen T et al (2006) Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J 20:1462–1472. doi:10.1096/fj.05-5646com PubMedCrossRefGoogle Scholar
  28. 28.
    Matsushita A et al (2007) Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res 67:10309–10316. doi:10.1158/0008-5472.CAN-07-3256 PubMedCrossRefGoogle Scholar
  29. 29.
    Appleton BA et al (2007) Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding. EMBO J 26:4902–4912. doi:10.1038/sj.emboj.7601906 PubMedCrossRefGoogle Scholar
  30. 30.
    Miao HQ et al (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 146:233–242PubMedGoogle Scholar
  31. 31.
    West DC et al (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. doi:10.1074/jbc.M410924200 PubMedCrossRefGoogle Scholar
  32. 32.
    Migdal M et al (1998) Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem 273:22272–22278. doi:10.1074/jbc.273.35.22272 PubMedCrossRefGoogle Scholar
  33. 33.
    Glinka Y, Prud’homme GJ (2008) Neuropilin-1 is a receptor for transforming growth factor beta-1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol 84:302–310. doi:10.1189/jlb.0208090 PubMedCrossRefGoogle Scholar
  34. 34.
    Hu B et al (2007) Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway. Oncogene 26:5577–5586. doi:10.1038/sj.onc.1210348 PubMedCrossRefGoogle Scholar
  35. 35.
    Banerjee S et al (2006) Breast cancer cells secreted platelet-derived growth factor-induced motility of vascular smooth muscle cells is mediated through neuropilin-1. Mol Carcinog 45:871–880. doi:10.1002/mc.20248 PubMedCrossRefGoogle Scholar
  36. 36.
    Hsieh SH et al (2008) Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene 27:3746–3753. doi:10.1038/sj.onc.1211029 PubMedCrossRefGoogle Scholar
  37. 37.
    Herzog Y et al (2005) Segregation of arterial and venous markers in subpopulations of blood islands before vessel formation. Dev Dyn 232:1047–1055. doi:10.1002/dvdy.20257 PubMedCrossRefGoogle Scholar
  38. 38.
    Herzog Y et al (2001) Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins. Mech Dev 109:115–119. doi:10.1016/S0925-4773(01)00518-4 PubMedCrossRefGoogle Scholar
  39. 39.
    Toyofuku T et al (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. doi:10.1101/gad.1167304 PubMedCrossRefGoogle Scholar
  40. 40.
    Bussolino F et al (1992) Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth. J Cell Biol 119:629–641. doi:10.1083/jcb.119.3.629 PubMedCrossRefGoogle Scholar
  41. 41.
    Gu C et al (2005) Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307:265–268. doi:10.1126/science.1105416 PubMedCrossRefGoogle Scholar
  42. 42.
    Behar O et al (1996) Semaphorin III is needed for normal patterning and growth of nerves, bones and heart. Nature 383:525–528. doi:10.1038/383525a0 PubMedCrossRefGoogle Scholar
  43. 43.
    Kanda T et al (2007) PlexinD1 deficiency induces defects in axial skeletal morphogenesis. J Cell Biochem 101:1329–1337. doi:10.1002/jcb.21306 PubMedCrossRefGoogle Scholar
  44. 44.
    Towler DA (2007) Vascular biology and bone formation: hints from HIF. J Clin Invest 117:1477–1480. doi:10.1172/JCI32518 PubMedCrossRefGoogle Scholar
  45. 45.
    Wang Y et al (2007) The hypoxia-inducible factor alpha pathway couples angiogenesis to osteogenesis during skeletal development. J Clin Invest 117:1616–1626. doi:10.1172/JCI31581 PubMedCrossRefGoogle Scholar
  46. 46.
    Gomez C et al (2005) Expression of Semaphorin-3A and its receptors in endochondral ossification: potential role in skeletal development and innervation. Dev Dyn 234:393–403. doi:10.1002/dvdy.20512 PubMedCrossRefGoogle Scholar
  47. 47.
    Futamura M et al (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. doi:10.1158/0008-5472.CAN-06-2485 PubMedCrossRefGoogle Scholar
  48. 48.
    Sekido Y et al (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 USA 93:4120–4125. doi:10.1073/pnas.93.9.4120 PubMedCrossRefGoogle Scholar
  49. 49.
    Potiron VA et al (2009) Semaphorins and their receptors in lung cancer. Cancer Lett 273:1–14. doi:10.1016/j.canlet.2008.05.032 PubMedCrossRefGoogle Scholar
  50. 50.
    Bielenberg DR et al (2004) Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest 114:1260–1271PubMedGoogle Scholar
  51. 51.
    Kessler O et al (2004) Semaphorin-3F is an inhibitor of tumor angiogenesis. Cancer Res 64:1008–1015. doi:10.1158/0008-5472.CAN-03-3090 PubMedCrossRefGoogle Scholar
  52. 52.
    Serini G et al (2003) Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424:391–397. doi:10.1038/nature01784 PubMedCrossRefGoogle Scholar
  53. 53.
    Acevedo LM et al (2008) Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood 111:2674–2680. doi:10.1182/blood-2007-08-110205 PubMedCrossRefGoogle Scholar
  54. 54.
    Serini G et al (2008) Integrins team up with tyrosine kinase receptors and plexins to control angiogenesis. Curr Opin Hematol 15:235–242. doi:10.1097/MOH.0b013e3282fa745b PubMedCrossRefGoogle Scholar
  55. 55.
    Maione F et al. (2009) Semaphorin 3A is an endogenous angiogenic inhibitor that blocks tumor growth and normalizes the vasculature in a mouse model of multistage tumorigenesis. J Clin Invest (submitted)Google Scholar
  56. 56.
    Serini G et al (2006) Integrins and angiogenesis: a sticky business. Exp Cell Res 312:651–658. doi:10.1016/j.yexcr.2005.10.020 PubMedCrossRefGoogle Scholar
  57. 57.
    Casanovas O et al (2005) Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. Cancer Cell 8:299–309. doi:10.1016/j.ccr.2005.09.005 PubMedCrossRefGoogle Scholar
  58. 58.
    Jain RK (2008) Lessons from multidisciplinary translational trials on anti-angiogenic therapy of cancer. Nat Rev Cancer 8:309–316. doi:10.1038/nrc2346 PubMedCrossRefGoogle Scholar
  59. 59.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62. doi:10.1126/science.1104819 PubMedCrossRefGoogle Scholar
  60. 60.
    Jain RK et al (2007) Angiogenesis in brain tumours. Nat Rev Neurosci 8:610–622. doi:10.1038/nrn2175 PubMedCrossRefGoogle Scholar
  61. 61.
    Lee S et al (2007) Autocrine VEGF signaling is required for vascular homeostasis. Cell 130:691–703. doi:10.1016/j.cell.2007.06.054 PubMedCrossRefGoogle Scholar
  62. 62.
    Serini G et al (2003) Modeling the early stages of vascular network assembly. EMBO J 22:1771–1779. doi:10.1093/emboj/cdg176 PubMedCrossRefGoogle Scholar
  63. 63.
    Tang N et al (2004) Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6:485–495. doi:10.1016/j.ccr.2004.09.026 PubMedCrossRefGoogle Scholar
  64. 64.
    Damon DH (2006) Vascular endothelial-derived semaphorin 3 inhibits sympathetic axon growth. Am J Physiol Heart Circ Physiol 290:H1220–H1225. doi:10.1152/ajpheart.01232.2004 PubMedCrossRefGoogle Scholar
  65. 65.
    Ito T et al (2000) Repulsive axon guidance molecule Sema3A inhibits branching morphogenesis of fetal mouse lung. Mech Dev 97:35–45. doi:10.1016/S0925-4773(00)00401-9 PubMedCrossRefGoogle Scholar
  66. 66.
    Vacca A et al (2006) Loss of inhibitory semaphorin 3A (SEMA3A) autocrine loops in bone marrow endothelial cells of patients with multiple myeloma. Blood 108:1661–1667. doi:10.1182/blood-2006-04-014563 PubMedCrossRefGoogle Scholar
  67. 67.
    Basile JR et al (2007) 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. doi:10.1074/jbc.M705467200 PubMedCrossRefGoogle Scholar
  68. 68.
    Basile JR et al (2006) Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc Natl Acad Sci USA 103:9017–9022. doi:10.1073/pnas.0508825103 PubMedCrossRefGoogle Scholar
  69. 69.
    Sierra JR et al (2008) Tumor angiogenesis and progression are enhanced by Sema4D produced by tumor-associated macrophages. J Exp Med 205:1673–1685. doi:10.1084/jem.20072602 PubMedCrossRefGoogle Scholar
  70. 70.
    Giordano S et al (2002) The semaphorin 4D receptor controls invasive growth by coupling with Met. Nat Cell Biol 4:720–724. doi:10.1038/ncb843 PubMedCrossRefGoogle Scholar
  71. 71.
    Folkman J (2006) Angiogenesis. Annu Rev Med 57:1–8. doi:10.1146/annurev.med.57.121304.131306 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Institute for Cancer Research and TreatmentTorinoItaly
  2. 2.Department of Oncological SciencesUniversity of TorinoTorinoItaly

Personalised recommendations