Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

The semaphorins: versatile regulators of tumour progression and tumour angiogenesis

Nature Reviews Cancer volume 8, pages 632–645 (2008)Cite this article

Key Points

  • Semaphorins are members of a large gene family of secreted and membrane-anchored proteins containing more than 20 vertebrate genes. They were initially characterized as axon guidance factors and are divided into eight subfamilies. The nine receptors belonging to the plexin family function as semaphorin receptors.

  • The secreted semaphorins belonging to the class 3 semaphorin subfamily are unique as they do not bind to plexins but instead bind to the neuropilin 1 or neuropilin 2 receptors. The neuropilins form complexes with members of the plexin family and function as the semaphorin binding elements and the plexins function as the signal transducing elements. The neuropilins also function as receptors for several pro-angiogenic factors, including several heparin-binding forms of vascular endothelial growth factor and hepatocyte growth factor.

  • Because of their role as transducers of pro-angiogenic signals, the neuropilins are viewed as targets for the development of anti-angiogenic drugs that function by inhibiting the binding of vascular endothelial growth factor to neuropilins.

  • The activation of plexins by semaphorins modulates cell adhesion and induces changes in the organization of the cytoskeleton of target cells. Prolonged exposure inhibits cell proliferation and induces apoptosis.

  • Several class 3 semaphorins such as semaphorin 3B and semaphorin 3F have been characterized as tumour suppressors.

  • The presence of neuropilins and plexins on endothelial cells also resulted in the realization that semaphorins such as semaphorin 3F and semaphorin 3A can function as anti-angiogenic factors and semaphorin 3F can inhibit the development of tumours by inhibition of tumour angiogenesis.

  • By contrast, semaphorins such as semaphorin 4D have been found to function as pro-angiogenic factors and to promote tumour progression.

  • Many types of tumour cells express semaphorin receptors. Several types of semaphorins have been found to induce pro-tumorigenic or anti-tumorigenic effects as a result of their interaction with semaphorin receptors expressed by tumour cells.

Abstract

The semaphorins and their receptors, the neuropilins and the plexins, were originally characterized as constituents of the complex regulatory system responsible for the guidance of axons during the development of the central nervous system. However, a growing body of evidence indicates that various semaphorins can either promote or inhibit tumour progression through the promotion or inhibition of processes such as tumour angiogenesis, tumour metastasis and tumour cell survival. This Review focuses on the emerging role of the semaphorins in cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The structure of the semaphorins and their receptors.
Figure 2: The interaction of semaphorins with various types of semaphorin receptors.
Figure 3: Interactions of neuropilins and plexins with other cell surface receptors.
Figure 4: The molecular mechanism by which semaphorin 3A (SEMA3A) inhibits cell adhesion to the extracellular matrix.
Figure 5: Molecular mechanisms by which semaphorin 3A (SEMA3A) and SEMA4D affect the cytoskeleton and cell survival.

Similar content being viewed by others

References

  1. Luo, Y., Raible, D. & Raper, J. A. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell 75, 217–227 (1993). This is the first description of a semaphorin.

    CAS  PubMed  Google Scholar 

  2. Goodman, C. S., Kolodkin, A. L., Luo, Y., Pueschel, A. W. & Raper, J. A. Unified nomenclature for the semaphorins collapsins. Cell 97, 551–552 (1999).

    Google Scholar 

  3. Gherardi, E., Love, C. A., Esnouf, R. M. & Jones, E. Y. The sema domain. Curr. Opin. Struct. Biol. 14, 669–678 (2004).

    CAS  PubMed  Google Scholar 

  4. Koppel, A. M., Feiner, L., Kobayashi, H. & Raper, J. A. A 70 amino acid region within the semaphorin domain activates specific cellular response of semaphorin family members. Neuron 19, 531–537 (1997).

    CAS  PubMed  Google Scholar 

  5. Bork, P., Doerks, T., Springer, T. A. & Snel, B. Domains in plexins: links to integrins and transcription factors. Trends Biochem. Sci. 24, 261–263 (1999).

    CAS  PubMed  Google Scholar 

  6. Comoglio, P. M., Boccaccio, C. & Trusolino, L. Interactions between growth factor receptors and adhesion molecules: breaking the rules. Curr. Opin. Cell Biol. 15, 565–571 (2003).

    CAS  PubMed  Google Scholar 

  7. Koppel, A. M. & Raper, J. A. Collapsin-1 covalently dimerizes, and dimerization is necessary for collapsing activity. J. Biol. Chem. 273, 15708–15713 (1998).

    CAS  PubMed  Google Scholar 

  8. Klostermann, A., Lohrum, M., Adams, R. H. & Puschel, A. W. The chemorepulsive activity of the axonal guidance signal semaphorin D requires dimerization. J. Biol. Chem. 273, 7326–7331 (1998).

    CAS  PubMed  Google Scholar 

  9. Basile, J. R., Holmbeck, K., Bugge, T. H. & Gutkind, J. S. MT1-MMP controls tumor-induced angiogenesis through the release of semaphorin 4D. J. Biol. Chem. 282, 6899–6905 (2007).

    CAS  PubMed  Google Scholar 

  10. Oinuma, I., Ishikawa, Y., Katoh, H. & Negishi, M. The Semaphorin 4D receptor Plexin-B1 is a GTPase activating protein for R-Ras. Science 305, 862–865 (2004). The first paper in which it was found that plexins have a functional GAP domain that controls integrin function.

    CAS  PubMed  Google Scholar 

  11. Tong, Y. et al. Binding of Rac1, Rnd1 and RhoD to a novel Rho GTPase interaction motif destabilizes dimerization of the plexin-B1 effector domain. J. Biol. Chem. 282, 37215–37224 (2007).

    CAS  PubMed  Google Scholar 

  12. Driessens, M. H. et al. Plexin-B semaphorin receptors interact directly with active Rac and regulate the actin cytoskeleton by activating Rho. Curr. Biol. 11, 339–344 (2001).

    CAS  PubMed  Google Scholar 

  13. Rohm, B., Rahim, B., Kleiber, B., Hovatta, I. & Puschel, A. W. The semaphorin 3A receptor may directly regulate the activity of small GTPases. FEBS Lett. 486, 68–72 (2000).

    CAS  PubMed  Google Scholar 

  14. Vikis, H. G., Li, W. & Guan, K. L. The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding. Genes Dev. 16, 836–845 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Aurandt, J., Vikis, H. G., Gutkind, J. S., Ahn, N. & Guan, K. L. The semaphorin receptor plexin-B1 signals through a direct interaction with the Rho-specific nucleotide exchange factor, LARG. Proc. Natl Acad. Sci. USA 99, 12085–12090 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Perrot, V., Vazquez-Prado, J. & Gutkind, J. S. Plexin B regulates Rho through the guanine nucleotide exchange factors Leukemia-associated RhoGEF (LARG) and PDZ-RhoGEF. J. Biol. Chem. 278, 26111–26119 (2002).

    Google Scholar 

  17. Swiercz, J. M., Kuner, R., Behrens, J. & Offermanns, S. Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology. Neuron 35, 51–63 (2002).

    CAS  PubMed  Google Scholar 

  18. Artigiani, S. et al. Functional regulation of semaphorin receptors by proprotein convertases. J. Biol. Chem. 278, 10094–10101 (2003).

    CAS  PubMed  Google Scholar 

  19. Takahashi, T. et al. Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 99, 59–69 (1999). The first description of the role of plexins in neuropilin-mediated signal transduction.

    CAS  PubMed  Google Scholar 

  20. Tamagnone, L. et al. Plexins are a large family of receptors for transmembrane, secreted, and GPI-anchored semaphorins in vertebrates. Cell 99, 71–80 (1999). The first description of the role of plexins in neuropilin-mediated signal transduction.

    CAS  PubMed  Google Scholar 

  21. Takagi, S. et al. The A5 antigen, a candidate for the neuronal recognition molecule, has homologies to complement components and coagulation factors. Neuron 7, 295–307 (1991).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. Kolodkin, A. L. et al. Neuropilin is a semaphorin III receptor. Cell 90, 753–762 (1997). References 22 and 23 are the first descriptions of neuropilin 1 as a SEMA3A receptor.

    CAS  PubMed  Google Scholar 

  24. Giger, R. J. et al. Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity. Neuron 21, 1079–1092 (1998).

    CAS  PubMed  Google Scholar 

  25. Chen, H., Chedotal, A., He, Z., Goodman, C. S. & Tessier-Lavigne, M. 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 (1997).

    CAS  PubMed  Google Scholar 

  26. Tomizawa, Y. et al. Inhibition of lung cancer cell growth and induction of apoptosis after reexpression of 3p21.3 candidate tumor suppressor gene SEMA3B. Proc. Natl Acad. Sci. USA 98, 13954–13959 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Julien, F. et al. Dual functional activity of semaphorin 3B is required for positioning the anterior commissure. Neuron 48, 63–75 (2005).

    CAS  PubMed  Google Scholar 

  28. Roth, L. et al. Transmembrane domain interactions control biological functions neuropilin-1. Mol. Biol. Cell 19 646–654 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Gu, C. et al. Characterization of neuropilin-1 structural features that confer binding to semaphorin 3A and vascular endothelial growth factor 165. J. Biol. Chem. 277, 18069–18076 (2002).

    CAS  PubMed  Google Scholar 

  30. Vander Kooi, C. W. et al. Structural basis for ligand and heparin binding to neuropilin B domains. Proc. Natl Acad. Sci. USA 104, 6157–6152 (2007).

    Google Scholar 

  31. Cai, H. B. & Reed, R. R. 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 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Gao, Y., Li, M., Chen, W. & Simons, M. Synectin, syndecan-4 cytoplasmic domain binding PDZ protein, inhibits cell migration. J. Cell Physiol. 184, 373–379 (2000).

    CAS  PubMed  Google Scholar 

  33. Shintani, Y. et al. Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling. EMBO J. 25, 3045–3055 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Gitay-Goren, H. et al. Selective binding of VEGF121 to one of the three VEGF receptors of vascular endothelial cells. J. Biol. Chem. 271, 5519–5523 (1996).

    CAS  PubMed  Google Scholar 

  35. Soker, S., Takashima, S., Miao, H. Q., Neufeld, G. & Klagsbrun, M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform specific receptor for vascular endothelial growth factor. Cell 92, 735–745 (1998). The first description of neuropilin 1 as a functional VEGF receptor.

    CAS  PubMed  Google Scholar 

  36. Gluzman-Poltorak, Z., Cohen, T., Herzog, Y. & Neufeld, G. 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 (2000).

    CAS  PubMed  Google Scholar 

  37. Miao, H. Q. et al. 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 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  39. Soker, S., Miao, H. Q., Nomi, M., Takashima, S. & Klagsbrun, M. VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. J. Cell. Biochem. 85, 357–368 (2002).

    CAS  PubMed  Google Scholar 

  40. Shraga-Heled, N. et al. Neuropilin-1 and neuropilin-2 enhance VEGF121 stimulated signal transduction by the VEGFR-2 receptor. FASEB J. 21, 915–926 (2007).

    CAS  PubMed  Google Scholar 

  41. Favier, B. et al. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood 108, 1243–1250 (2006).

    CAS  PubMed  Google Scholar 

  42. Pan, Q. et al. Neuropilin-1 binds to VEGF121 and regulates endothelial cell migration and sprouting. J. Biol. Chem. 282, 24049–24056 (2007).

    CAS  PubMed  Google Scholar 

  43. Wang, L. et al. Neuropilin-1 modulates p53/caspases axis to promote endothelial cell survival. PLoS ONE 2, e1161 (2007).

    PubMed  PubMed Central  Google Scholar 

  44. Sulpice, E. et al. Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity. Blood 111, 2036–2045 (2007). Characterization of neuropilins as receptors for HGF.

    PubMed  Google Scholar 

  45. Herzog, Y., Kalcheim, C., Kahane, N., Reshef, R. & Neufeld, G. Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins. Mech. Dev. 109, 115–119 (2001).

    CAS  PubMed  Google Scholar 

  46. Yuan, L. et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129, 4797–4806 (2002).

    CAS  PubMed  Google Scholar 

  47. Moyon, D., Pardanaud, L., Yuan, L., Breant, C. & Eichmann, A. Plasticity of endothelial cells during arterial-venous differentiation in the avian embryo. Development 128, 3359–3370 (2001).

    CAS  PubMed  Google Scholar 

  48. Shalaby, F. et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376, 62–66 (1995).

    CAS  PubMed  Google Scholar 

  49. Takashima, S. et al. Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc. Natl Acad. Sci. USA 99, 3657–3662 (2002). A paper showing that neuropilins are essential for vasculogenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Makinen, T. et al. Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1. J. Biol. Chem. 274, 21217–21222 (1999).

    CAS  PubMed  Google Scholar 

  51. Migdal, M. et al. Neuropilin-1 is a placenta growth factor-2 receptor. J. Biol. Chem. 273, 22272–22278 (1998).

    CAS  PubMed  Google Scholar 

  52. Karkkainen, M. J. et al. A model for gene therapy of human hereditary lymphedema. Proc. Natl Acad. Sci. USA 98, 12677–12682 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Karpanen, T. et al. Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J. 20, 1462–1472 (2006).

    CAS  PubMed  Google Scholar 

  54. Banerjee, S. et al. 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 (2006).

    CAS  PubMed  Google Scholar 

  55. Armulik, A., Abramsson, A. & Betsholtz, C. Endothelial/pericyte interactions. Circ. Res. 97, 512–523 (2005).

    CAS  PubMed  Google Scholar 

  56. West, D. C. et al. 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 (2005).

    CAS  PubMed  Google Scholar 

  57. Hsieh, S. H. et al. Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene 28 Jan 2008 (doi: 10.1038/sj.onc.1211029).

    CAS  PubMed  Google Scholar 

  58. Castellani, V., Chedotal, A., Schachner, M., Faivre-Sarrailh, C. & Rougon, G. Analysis of the L1-deficient mouse phenotype reveals cross-talk between Sema3A and L1 signaling pathways in axonal guidance. Neuron 27, 237–249 (2000). A paper showing that SEMA3A is turned from a repulsive agent into an attractive agent in the presence of the extracellular domain of L1CAM.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Wright, A. G. et al. Close homolog of L1 and neuropilin 1 mediate guidance of thalamocortical axons at the ventral telencephalon. J. Neurosci. 27, 13667–13679 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Schlatter, M. C., Buhusi, M., Wright, A. G. & Maness, P. F. CHL1 promotes Sema3A-induced growth cone collapse and neurite elaboration through a motif required for recruitment of ERM proteins to the plasma membrane. J. Neurochem. 104, 731–744 (2008).

    CAS  PubMed  Google Scholar 

  62. Fukasawa, M., Matsushita, A. & Korc, M. Neuropilin-1 interacts with integrin β1 and modulates pancreatic cancer cell growth, survival and invasion. Cancer Biol. Ther. 6, (2007).

  63. Ellis, L. M. The role of neuropilins in cancer. Mol. Cancer Ther. 5, 1099–1107 (2006).

    CAS  PubMed  Google Scholar 

  64. Miao, H. Q., Lee, P., Lin, H., Soker, S. & Klagsbrun, M. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J. 14, 2532–2539 (2000).

    CAS  PubMed  Google Scholar 

  65. Parikh, A. A. et al. Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis. Am. J. Pathol. 164, 2139–2151 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Gray, M. J. et al. Neuropilin-1 suppresses tumorigenic properties in a human pancreatic adenocarcinoma cell line lacking neuropilin-1 coreceptors. Cancer Res. 65, 3664–3670 (2005).

    CAS  PubMed  Google Scholar 

  67. Kamiya, T. et al. The preserved expression of neuropilin (NRP) 1 contributes to a better prognosis in colon cancer. Oncol. Rep. 15, 369–373 (2006).

    CAS  PubMed  Google Scholar 

  68. Gray, M. J. et al. Therapeutic targeting of neuropilin-2 on colorectal carcinoma cells implanted in the murine liver. J. Natl Cancer Inst. 100, 109–120 (2008).

    CAS  PubMed  Google Scholar 

  69. Roodink, I. et al. Plexin d1 expression is induced on tumor vasculature and tumor cells: a novel target for diagnosis and therapy? Cancer Res. 65, 8317–8323 (2005).

    CAS  PubMed  Google Scholar 

  70. Bachelder, R. E. et al. Competing autocrine pathways involving alternative neuropilin-1 ligands regulate chemotaxis of carcinoma cells. Cancer Res. 63, 5230–5233 (2003).

    CAS  PubMed  Google Scholar 

  71. Rieger, J., Wick, W. & Weller, M. Human malignant glioma cells express semaphorins and their receptors, neuropilins and plexins. Glia 42, 379–389 (2003).

    PubMed  Google Scholar 

  72. Syed, V. et al. Profiling estrogen-regulated gene expression changes in normal and malignant human ovarian surface epithelial cells. Oncogene 24, 8128–8143 (2005).

    CAS  PubMed  Google Scholar 

  73. Nguyen, Q. D. et al. Inhibition of vascular endothelial growth factor (VEGF)-165 and semaphorin 3A-mediated cellular invasion and tumor growth by the VEGF signaling inhibitor ZD4190 in human colon cancer cells and xenografts. Mol. Cancer Ther. 5, 2070–2077 (2006).

    CAS  PubMed  Google Scholar 

  74. Wong, O. G. et al. Plexin-B1 mutations in prostate cancer. Proc. Natl Acad. Sci. USA 48, 19040–19045 (2007).

    Google Scholar 

  75. Rody, A. et al. Poor outcome in estrogen receptor-positive breast cancers predicted by loss of plexin b1. Clin. Cancer Res. 13, 1115–1122 (2007).

    CAS  PubMed  Google Scholar 

  76. Kuroki, T. et al. Allelic loss on chromosome 3p21.3 and promoter hypermethylation of semaphorin 3b in non-small cell lung cancer. Cancer Res. 63, 3352–3355 (2003).

    CAS  PubMed  Google Scholar 

  77. Tischoff, I. et al. Allele loss and epigenetic inactivation of 3p21.3 in malignant liver tumors. Int. J. Cancer 115, 684–689 (2005).

    CAS  PubMed  Google Scholar 

  78. Nair, P. N., McArdle, L., Cornell, J., Cohn, S. L. & Stallings, R. L. High-resolution analysis of 3p deletion in neuroblastoma and differential methylation of the SEMA3B tumor suppressor gene. Cancer Genet. Cytogenet. 174, 100–110 (2007).

    CAS  PubMed  Google Scholar 

  79. Marsit, C. J., Wiencke, J. K., Liu, M. & Kelsey, K. T. The race associated allele of semaphorin 3B (SEMA3B) T415I and its role in lung cancer in African-Americans and Latino-Americans. Carcinogenesis 26, 1446–1449 (2005).

    CAS  PubMed  Google Scholar 

  80. van der Weyden, L. et al. Null and conditional semaphorin 3B alleles using a flexible puroΔtk loxP/FRT vector. Genesis 41, 171–178 (2005).

    CAS  PubMed  Google Scholar 

  81. Castro-Rivera, E., Ran, S., Thorpe, P. & Minna, J. D. Semaphorin 3B (SEMA3B) induces apoptosis in lung and breast cancer, whereas VEGF165 antagonizes this effect. Proc. Natl Acad. Sci. USA 101, 11432–11437 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Xiang, R. H. et al. Isolation of the human semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer. Genomics 32, 39–48 (1996).

    CAS  PubMed  Google Scholar 

  83. Roche, J. et al. Distinct 3p21.3 deletions in lung cancer and identification of a new human semaphorin. Oncogene 12, 1289–1297 (1996).

    CAS  PubMed  Google Scholar 

  84. Xiang, R. et al. Semaphorin 3F gene from human 3p21.3 suppresses tumor formation in nude mice. Cancer Res. 62, 2637–2643 (2002).

    CAS  PubMed  Google Scholar 

  85. Nasarre, P. et al. Semaphorin SEMA3F and VEGF have opposing effects on cell attachment and spreading. Neoplasia 5, 83–92 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Nasarre, P. et al. Semaphorin SEMA3F has a repulsing activity on breast cancer cells and inhibits E-cadherin-mediated cell adhesion. Neoplasia 7, 180–189 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Bielenberg, D. R. et al. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J. Clin. Invest. 114, 1260–1271 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Potiron, V. A. et al. Semaphorin SEMA3F affects multiple signaling pathways in lung cancer cells. Cancer Res. 67, 8708–8715 (2007).

    CAS  PubMed  Google Scholar 

  89. Kusy, S. et al. Selective suppression of in vivo tumorigenicity by semaphorin SEMA3F in lung cancer cells. Neoplasia 7, 457–465 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Osada, R. et al. Expression of semaphorins, vascular endothelial growth factor, and their common receptor neuropilins and alleic loss of semaphorin locus in epithelial ovarian neoplasms: increased ratio of vascular endothelial growth factor to semaphorin is a poor prognostic factor in ovarian carcinomas. Hum. Pathol. 37, 1414–1425 (2006).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  92. Muller, M. W. et al. Association of axon guidance factor semaphorin 3A with poor outcome in pancreatic cancer. Int. J. Cancer 121, 2421–2433 (2007).

    PubMed  Google Scholar 

  93. Catalano, A. et al. Cross-talk between vascular endothelial growth factor and semaphorin-3A pathway in the regulation of normal and malignant mesothelial cell proliferation. FASEB J. 18, 358–360 (2004).

    CAS  PubMed  Google Scholar 

  94. Acevedo, L. M., Barillas, S., Weis, S. M., Gothert, J. R. & Cheresh, D. A. Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood 111, 2674–2680 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Martin-Satue, M. & Blanco, J. Identification of semaphorin E gene expression in metastatic human lung adenocarcinoma cells by mRNA differential display. J. Surg. Oncol. 72, 18–23 (1999).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  97. Giordano, S. et al. The Semaphorin 4D receptor controls invasive growth by coupling with Met. Nature Cell Biol. 4, 720–724 (2002). The first description of plexin-mediated activation of a tyrosine kinase receptor by a semaphorin.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  99. Hu, B. et al. Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway. Oncogene 26, 5577–5586 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Citri, A. & Yarden, Y. EGF–ERBB signalling: towards the systems level. Nature Rev. Mol. Cell Biol. 7, 505–516 (2006).

    CAS  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  103. Artigiani, S. et al. Plexin-B3 is a functional receptor for semaphorin 5A. EMBO Rep. 5, 710–714 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Hirota, E. et al. Genome-wide gene expression profiles of clear cell renal cell carcinoma: Identification of molecular targets for treatment of renal cell carcinoma. Int. J. Oncol. 29, 799–827 (2006).

    CAS  PubMed  Google Scholar 

  105. Nagai, H. et al. CLCP1 interacts with semaphorin 4B and regulates motility of lung cancer cells. Oncogene 26, 4025–4031 (2007).

    CAS  PubMed  Google Scholar 

  106. Serini, G. et al. Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424, 391–397 (2003). First description of semaphorins as modulators of integrin function.

    CAS  PubMed  Google Scholar 

  107. Guttmann-Raviv, N. et al. 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 (2007).

    CAS  PubMed  Google Scholar 

  108. Vieira, J. M., Schwarz, Q. & Ruhrberg, C. Selective requirements for NRP1 ligands during neurovascular patterning. Development 134, 1833–1843 (2007).

    CAS  PubMed  Google Scholar 

  109. Gu, C. et al. Neuropilin-1 conveys semaphorin and VEGF signaling during neural and cardiovascular development. Dev. Cell 5, 45–57 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Kessler, O. et al. Semaphorin-3F is an inhibitor of tumor angiogenesis. Cancer Res. 64, 1008–1015 (2004). The first description of a semaphorin as an inhibitor of tumour angiogenesis.

    CAS  PubMed  Google Scholar 

  111. Futamura, M. et al. Possible role of semaphorin 3F, a candidate tumor suppressor gene at 3p21.3, in p53-regulated tumor angiogenesis suppression. Cancer Res. 67, 1451–1460 (2007).

    CAS  PubMed  Google Scholar 

  112. Gu, C. et al. Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307, 265–268 (2005). This paper changes a dogma by showing that the class 3 semaphorin SEMA3E signals directly through plexin D1 and repels blood vessels during embryonic development.

    CAS  PubMed  Google Scholar 

  113. Gitler, A. D., Lu, M. M. & Epstein, J. A. PlexinD1 and semaphorin signaling are required in endothelial cells for cardiovascular development. Dev. Cell 7, 107–116 (2004).

    CAS  PubMed  Google Scholar 

  114. Chauvet, S. et al. Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development. Neuron 56, 807–822 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Toyofuku, T. et al. Semaphorin-4A, an activator for T-cell-mediated immunity, suppresses angiogenesis via plexin-D1. EMBO J. 26, 1373–1384 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Dhanabal, M. et al. Recombinant semaphorin 6A-1 ectodomain inhibits in vivo growth factor and tumor cell line-induced angiogenesis. Cancer Biol. Ther. 4, 659–668 (2005).

    CAS  PubMed  Google Scholar 

  117. Caunt, M. et al. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13, 331–342 (2008). This manuscript demonstrates that antibodies to neuropilin 2 can inhibit tumour metastasis through inhibition of lymphangiogenesis.

    CAS  PubMed  Google Scholar 

  118. Zhu, L. et al. Regulated surface expression and shedding support a dual role for semaphorin 4D in platelet responses to vascular injury. Proc. Natl Acad. Sci. USA 104, 1621–1626 (2007).

    PubMed  PubMed Central  Google Scholar 

  119. Basile, J. R., Barac, A., Zhu, T., Guan, K. L. & Gutkind, J. S. Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res. 64, 5212–5224 (2004).

    CAS  PubMed  Google Scholar 

  120. Basile, J. R., Castilho, R. M., Williams, V. P. & Gutkind, J. S. Semaphorin 4D provides a link between axon guidance processes and tumor-induced angiogenesis. Proc. Natl Acad. Sci. USA 103, 9017–9022 (2006). The first demonstration that a semaphorin can promote tumour progression through induction of angiogenesis.

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Conrotto, P. et al. Sema4D induces angiogenesis through Met recruitment by Plexin B1. Blood 105, 4321–4329 (2005).

    CAS  PubMed  Google Scholar 

  122. Fazzari, P. et al. PlexinB1 plays a redundant role during mouse development and in tumour angiogenesis. BMC Dev. Biol. 7, 55 (2007).

    PubMed  PubMed Central  Google Scholar 

  123. Toyofuku, T. et al. 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 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  124. Pan, Q. et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11, 53–67 (2007). This paper shows that antibodies directed against neuropilins have a potential use as supressors of tumour development.

    CAS  PubMed  Google Scholar 

  125. Matsushita, A., Gotze, T. & Korc, M. Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res. 67, 10309–10316 (2007).

    CAS  PubMed  Google Scholar 

  126. Deaglio, S. et al. CD38 and CD100 lead a network of surface receptors relaying positive signals for B-CLL growth and survival. Blood 105, 3042–3050 (2005).

    CAS  PubMed  Google Scholar 

  127. Granziero, L. et al. CD100/Plexin-B1 interactions sustain proliferation and survival of normal and leukemic CD5+ B lymphocytes. Blood 101, 1962–1969 (2003).

    CAS  PubMed  Google Scholar 

  128. Bassi, D. E., Fu, J., Lopez de, C. R. & Klein-Szanto, A. J. Proprotein convertases: “master switches” in the regulation of tumor growth and progression. Mol. Carcinog. 44, 151–161 (2005).

    CAS  PubMed  Google Scholar 

  129. Adams, R. H., Lohrum, M., Klostermann, A., Betz, H. & Puschel, A. W. The chemorepulsive activity of secreted semaphorins is regulated by furin-dependent proteolytic processing. EMBO J. 16, 6077–6086 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Christensen, C. et al. Proteolytic processing converts the repelling signal sema3e into an inducer of invasive growth and lung metastasis. Cancer Res. 65, 6167–6177 (2005).

    CAS  PubMed  Google Scholar 

  131. Chen, G. et al. Semaphorin-3A guides radial migration of cortical neurons during development. Nature Neurosci. 11, 36–44 (2008).

    PubMed  Google Scholar 

  132. Yaron, A., Huang, P. H., Cheng, H. J. & Tessier-Lavigne, M. Differential requirement for plexin-A3 and -A4 in mediating responses of sensory and sympathetic neurons to distinct class 3 semaphorins. Neuron 45, 513–523 (2005).

    CAS  PubMed  Google Scholar 

  133. Takahashi, T. & Strittmatter, S. M. PlexinA1 autoinhibition by the plexin sema domain. Neuron 29, 429–439 (2001). This manuscript demonstrates a role for the sema domain of plexin in the inhibition of plexin activity in the absence of semaphorins.

    CAS  PubMed  Google Scholar 

  134. Toyofuku, T. et al. FARP2 triggers signals for Sema3A-mediated axonal repulsion. Nature Neurosci. 8, 1712–1719 (2005). Description of the role of FARP2 in SEMA3A-induced activation of the PLEXA1 GAP activity.

    CAS  PubMed  Google Scholar 

  135. Komatsu, M. & Ruoslahti, E. R-Ras is a global regulator of vascular regeneration that suppresses intimal hyperplasia and tumor angiogenesis. Nature Med. 11, 1346–1350 (2005).

    CAS  PubMed  Google Scholar 

  136. Zanata, S. M., Hovatta, I., Rohm, B. & Puschel, A. W. Antagonistic effects of Rnd1 and RhoD GTPases regulate receptor activity in Semaphorin 3A-induced cytoskeletal collapse. J. Neurosci. 22, 471–477 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Tadokoro, S. et al. Talin binding to integrin beta tails: a final common step in integrin activation. Science 302, 103–106 (2003).

    CAS  PubMed  Google Scholar 

  138. Aizawa, H. et al. Phosphorylation of cofilin by LIM-kinase is necessary for semaphorin 3A- induced growth cone collapse. Nature Neurosci. 4, 367–373 (2001).

    CAS  PubMed  Google Scholar 

  139. Bernard, O. Lim kinases, regulators of actin dynamics. Int. J. Biochem. Cell Biol. 39, 1071–1076 (2007).

    CAS  PubMed  Google Scholar 

  140. Mitsui, N. et al. Involvement of Fes/Fps tyrosine kinase in semaphorin3A signaling. EMBO J. 21, 3274–3285 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Shapovalova, Z., Tabunshchyk, K. & Greer, P. A. The Fer tyrosine kinase regulates an axon retraction response to Semaphorin 3A in dorsal root ganglion neurons. BMC Dev. Biol. 7, 133 (2007).

    PubMed  PubMed Central  Google Scholar 

  142. Sasaki, Y. et al. Fyn and Cdk5 mediate semaphorin-3A signaling, which is involved in regulation of dendrite orientation in cerebral cortex. Neuron 35, 907–920 (2002).

    CAS  PubMed  Google Scholar 

  143. Uchida, Y. et al. Semaphorin3A signalling is mediated via sequential Cdk5 and GSK3β phosphorylation of CRMP2: implication of common phosphorylating mechanism underlying axon guidance and Alzheimer's disease. Genes Cells 10, 165–179 (2005).

    CAS  PubMed  Google Scholar 

  144. Arimura, N. et al. Phosphorylation by Rho kinase regulates CRMP-2 activity in growth cones. Mol. Cell Biol. 25, 9973–9984 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  145. Hall, C. et al. Collapsin response mediator protein switches RhoA and Rac1 morphology in N1E-115 neuroblastoma cells and is regulated by Rho kinase. J. Biol. Chem. 276, 43482–43486 (2001).

    CAS  PubMed  Google Scholar 

  146. Terman, J. R., Mao, T., Pasterkamp, R. J., Yu, H. H. & Kolodkin, A. L. MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion. Cell 109, 887–900 (2002).

    CAS  PubMed  Google Scholar 

  147. Pasterkamp, R. J. et al. MICAL flavoprotein monooxygenases: Expression during neural development and following spinal cord injuries in the rat. Mol. Cell Neurosci. 31, 52–69 (2006).

    CAS  PubMed  Google Scholar 

  148. Schmidt, E. F., Shim, S. O. & Strittmatter, S. M. Release of MICAL autoinhibition by semaphorin–plexin signaling promotes interaction with collapsin response mediator protein. J. Neurosci. 28, 2287–2297 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Togashi, H., Schmidt, E. F. & Strittmatter, S. M. RanBPM contributes to Semaphorin3A signaling through plexin-A receptors. J. Neurosci. 26, 4961–4969 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  150. Fan, J., Mansfield, S. G., Redmond, T., Gordon-Weeks, P. R. & Raper, J. A. The organization of F-actin and microtubules in growth cones exposed to a brain-derived collapsing factor. J. Cell Biol. 121, 867–878 (1993).

    CAS  PubMed  Google Scholar 

  151. Shirvan, A. et al. Semaphorins as mediators of neuronal apoptosis. J. Neurochem. 73, 961–971 (1999). The first description of a semaphorin as an inducer of apoptosis.

    CAS  PubMed  Google Scholar 

  152. Bagnard, D. et al. Semaphorin 3A-vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor. J. Neurosci. 21, 3332–3341 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Basile, J. R., Gavard, J. & Gutkind, J. S. 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 (2007).

    CAS  PubMed  Google Scholar 

  154. Barberis, D. et al. p190 Rho-GTPase activating protein associates with plexins and it is required for semaphorin signalling. J Cell Sci. 118, 4689–4700 (2005).

    CAS  PubMed  Google Scholar 

  155. Ito, Y., Oinuma, I., Katoh, H., Kaibuchi, K. & Negishi, M. Sema4D/plexin-B1 activates GSK-3β through R-Ras GAP activity, inducing growth cone collapse. EMBO Rep. 7, 704–709 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Fukata, Y. et al. CRMP-2 binds to tubulin heterodimers to promote microtubule assembly. Nature Cell Biol. 4, 583–591 (2002).

    CAS  PubMed  Google Scholar 

  157. Potiron, V., Nasarre, P., Roche, J., Healy, C. & Boumsell, L. Semaphorin signaling in the immune system. Adv. Exp. Med. Biol. 600, 132–144 (2007).

    PubMed  Google Scholar 

  158. Kikutani, H., Suzuki, K. & Kumanogoh, A. Immune semaphorins: increasing members and their diverse roles. Adv. Immunol. 93, 121–143 (2007).

    CAS  PubMed  Google Scholar 

  159. Catalano, A. et al. Semaphorin-3A is expressed by tumor cells and alters T-cell signal transduction and function. Blood 107, 3321–3329 (2006).

    CAS  PubMed  Google Scholar 

  160. Yazdani, U. & Terman, J. R. The semaphorins. Genome Biol. 7, 211 (2006).

    PubMed  PubMed Central  Google Scholar 

  161. Kumanogoh, A. et al. Class IV semaphorin Sema4A enhances T-cell activation and interacts with Tim-2. Nature 419, 629–633 (2002).

    CAS  PubMed  Google Scholar 

  162. Kumanogoh, A. et al. 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 (2000).

    CAS  PubMed  Google Scholar 

  163. Kantor, D. B. et al. Semaphorin 5A is a bifunctional axon guidance cue regulated by heparan and chondroitin sulfate proteoglycans. Neuron 44, 961–975 (2004).

    CAS  PubMed  Google Scholar 

  164. Klagsbrun, M. & Eichmann, A. A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis. Cytokine Growth Factor Rev. 16, 535–548 (2005).

    CAS  PubMed  Google Scholar 

  165. Kuijper, S., Turner, C. J. & Adams, R. H. Regulation of angiogenesis by Eph–ephrin interactions. Trends Cardiovasc. Med. 17, 145–151 (2007).

    CAS  PubMed  Google Scholar 

  166. Wilson, N. H. & Key, B. Neogenin: one receptor, many functions. Int. J. Biochem. Cell Biol. 39, 874–878 (2007).

    CAS  PubMed  Google Scholar 

  167. Autiero, M., De Smet, F., Claes, F. & Carmeliet, P. Role of neural guidance signals in blood vessel navigation. Cardiovasc. Res. 65, 629–638 (2005).

    CAS  PubMed  Google Scholar 

  168. Mehlen, P. & Llambi, F. Role of netrin-1 and netrin-1 dependence receptors in colorectal cancers. Br. J. Cancer. 93, 1–6 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Fujiwara, M., Ghazizadeh, M. & Kawanami, O. Potential role of the Slit/Robo signal pathway in angiogenesis. Vasc. Med. 11, 115–121 (2006).

    PubMed  Google Scholar 

  170. Glinka, Y. & Prud'homme, G. J. Neuropilin-1 is a receptor for transforming growth factorβ-1, activates its latent form, and promotes regulatory T cell activity. J. Leukoc. Biol. (in the press).

Download references

Acknowledgements

This work was supported by grants from the Israel Science Foundation (ISF), by the Komen breast cancer foundation, by the International Union against Cancer (AICR), by the McDonnel foundation and by the Rappaport Family Institute for Research in the Medical Sciences of the Faculty of Medicine at the Technion, Israel Institute of Technology (to G.N.).

Author information

Authors and Affiliations

  1. Cancer Research and Vascular Biology Center, The Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, P.O. Box 9679, 1 Efron Street, Haifa, 31096, Israel

    Gera Neufeld & Ofra Kessler

Authors
  1. Gera Neufeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ofra Kessler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gera Neufeld.

Related links

Related links

DATABASES

National Cancer Institute

brain cancer

breast cancer

colon carcinoma

lung cancer

pancreatic cancer

prostate cancer

ovarian carcinoma

National Cancer Institute Drug Dictionary

bevacizumab

FURTHER INFORMATION

G. Neufeld's homepage

Glossary

Complement binding (CUB) domain

A conserved domain, spanning approximately 110 residues, originally identified in complement sub-components Cls/Clr. Complement refers to a group of about 20 interacting proteins that complement the action of antibodies.

Coagulation factor V/VIII homology domain

A domain that displays homology to the C1 and C2 domains of coagulation factors V and VIII.

VEGF165

A 165 amino acid-long splice form of VEGF. Contains exon 7 of the VEGF gene, which encodes a heparin binding domain.

VEGF121

A 121 amino acid-long splice form of VEGF that lacks exon 7.

Chick chorioallantoic membrane angiogenesis assay

The chick embryo chorioallantoic membrane is located just underneath the shell of the egg. Angiogenic substances placed on top of this membrane induce the growth of new blood vessels.

Flavoprotein monooxygenases

A family of enzymes that specifically catalyse the oxidation of a number of substrates, and in some contexts can generate reactive oxygen species.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Neufeld, G., Kessler, O. The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer 8, 632–645 (2008). https://doi.org/10.1038/nrc2404

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2404

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing