Skip to main content

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 515))

Abstract

Neuropilins (NRPs) are receptors for class 3 Semaphorins and function as co-receptors for Vascular endothelial growth factor isoforms, VEGF165 and VEGF145 and related molecules. NRPs are expressed in a variety of neural and non-neural tissues and are required for normal development. Interestingly, class 3 Semaphorins and VEGF compete for common NRP binding. As a consequence, Semaphorins and VEGF appear to be mutually antagonistic. In the lung, NRP levels increase during development and NRPs and Semaphorins are involved in lung branching, probably by altering cell morphology or by regulating cell motility and migration. During lung tumorigenesis, both NRP and VEGF expression increase on dysplastic lung epithelial cells; SEMA3F expression is reduced and SEMA3F protein is delocalized from the membrane to the cytoplasm. In lung cancers, SEMA3F staining correlates inversely with tumor stage with high SEMA3F associated with less aggressive tumors. Conversely, more aggressive tumors are associated with increased VEGF staining and a corresponding loss in membranous SEMA3F.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Fujisawa H, Kitsukawa T. Receptors for collapsin/Semaphorins. Curr. Opin. Neurobiol. 1998; 8:587–592

    Article  PubMed  CAS  Google Scholar 

  2. He Z, Tessier-Lavigne M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell 1997; 90:739–751

    Article  PubMed  CAS  Google Scholar 

  3. Kolodkin A, Levengood D, Rowe E et al. Neuropilin is a Semaphorin III receptor. Cell 1997; 90:753–762

    Article  PubMed  CAS  Google Scholar 

  4. Soker S, Takashima S, Miao H et al. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 1998; 92:735–745

    Article  PubMed  CAS  Google Scholar 

  5. Unified nomenclature for the Semaphorins/collapsins. Semaphorin Nomenclature Committee. Cell 1999; 97:551–2

    Article  Google Scholar 

  6. Raper J. Semaphorins and their receptors in vertebrates and invertebrates. Current Opinion in Neurobiology 2000; 10:88–94.

    Article  PubMed  CAS  Google Scholar 

  7. Chen H, Chedotal A, He Z et al. 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 1997; 19:547–559.

    CAS  Google Scholar 

  8. Kitsukawa T, Shimizu M, Sanbo M et al. Neuropilin-Semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron 1997; 19:995–1005.

    Article  PubMed  CAS  Google Scholar 

  9. Chedotal A, Del Rio JA, Ruiz M et al. Semaphorins III and IV repel hippocampal axons via two distinct receptors. Development 1998; 125:4313–4323.

    CAS  Google Scholar 

  10. Chen H, He Z, Tessier-Lavigne M. Axon guidance mechanisms: Semaphorins as simultaneous repellents and anti-repellents. Nat. Neurosci. 1998; 1:436–439.

    CAS  Google Scholar 

  11. Giger RJ, Urquhart ER, Gillespie SK et al. Neuropilin-2 is a receptor for Semaphorin IV: insight into the structural basis of receptor function and specificity. Neuron 1998; 21:1079–1092.

    Article  PubMed  CAS  Google Scholar 

  12. Takahashi T, Nakamura F, Jin Z et al. Semaphorins A and E act as antagonists of Neuropilin1 and agonists of Neuropilin-2 receptors. Nat. Neurosci. 1998; 1:487–493.

    CAS  Google Scholar 

  13. Tamagnone L, Artigiani S, Chen H et al. Plexins are a large family of receptors for trans-membrane, secreted, and GPI-anchored Semaphorins in vertebrates. Cell 1999; 99:71–80.

    Article  PubMed  CAS  Google Scholar 

  14. Goshima Y, Nakamura F, Strittmatter P et al. Collapsin-induced growth cone collapse mediated by an intracellular protein related to UNC-33. Nature 1995; 376:509–514.

    Article  PubMed  CAS  Google Scholar 

  15. Deckers MM, Karperien M, van der Bent C et al. Expression of vascular endothelial growth factors and their receptors during osteoblast differentiation. Endocrinology 2000; 141:1667–74.

    Article  PubMed  CAS  Google Scholar 

  16. Midy V, Plouet J. Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem Biophys Res Commun 1994; 199:380–6.

    Article  PubMed  CAS  Google Scholar 

  17. Sondell M, Lundborg G, Kanje M. Vascular endothelial growth factor stimulates Schwann cell invasion and neovascularization of acellular nerve grafts. Brain Res 1999; 846:219–28.

    Article  PubMed  CAS  Google Scholar 

  18. Byzova TV, Goldman CK, Pampori N et al. A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol Cell 2000; 6:851–60.

    PubMed  CAS  Google Scholar 

  19. Gluzman-Poltorak Z, Cohen T, Herzog Y et al. Neuropilin-2 and Neuropilin-I are receptors for VEGF165 and PLGF- 2, but only Neuropilin-2 functions as a receptor for VEGFI45. J Biol Chem 2000; 275:18040–18045.

    CAS  Google Scholar 

  20. Kitsukawa T, Shimono A, Kawakami A et al. Overexpression of a membrane protein, Neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development 1995; 121:4309–18.

    CAS  Google Scholar 

  21. Behar 0, Golden JA, Mashimo H et al. Semaphorin III is needed for normal patterning and growth of nerves, bones and heart. Nature 1996; 383:525–528.

    CAS  Google Scholar 

  22. Miao HQ, Soker S, Feiner L 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 1999; 146:233–42.

    PubMed  CAS  Google Scholar 

  23. Bagnard D, Vaillant C, Khuth ST et al. Semaphorin 3A-vascular endothelial growth factor165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor. J Neurosci 2001; 21:3332–41.

    PubMed  CAS  Google Scholar 

  24. Hogan BL, Yingling JM. Epithelial/mesenchymal interactions and branching morphogenesis of the lung. Curr Opin Genet Dev 1998; 8:481–6.

    Article  PubMed  CAS  Google Scholar 

  25. Metzger RJ, Krasnow MA. Genetic control of branching morphogenesis. Science 1999; 284:1635–9.

    Article  PubMed  CAS  Google Scholar 

  26. Cardoso WV. Lung morphogenesis revisited: old facts, current ideas. Dev Dyn 2000; 219:121–30.

    Article  PubMed  CAS  Google Scholar 

  27. Warburton D, Schwarz M, Tefft D et al. The molecular basis of lung morphogenesis. Mech Dev 2000; 92:55–81.

    Article  PubMed  CAS  Google Scholar 

  28. Bellusci S, de Maximy A, Thiery JP. Controle moleculaire de la morphogenese pulmonaire chez la souris. Medecine Sciences 1999; 15:815–822.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  30. Takahashi T, Nakamura F, Stittmatter S. Neuronal and non-neuronal collapsin-1 binding sites in developing chick are distinct from other Semaphorin binding sites. The Journal of Neuroscience 1997; 17:9183–9193.

    PubMed  CAS  Google Scholar 

  31. Wang L, Strittmatter S. A family of rat CRMP genes is differentially expressed in the nervous system. J Neurosci 1996; 16:6197–6207.

    PubMed  CAS  Google Scholar 

  32. Shih JY, Yang SC, Hong TM et al. Collapsin response mediator protein-1 and the invasion and metastasis of cancer cells. J Nat Cancer Inst 2001, 93, 1392–1400.

    Article  PubMed  CAS  Google Scholar 

  33. Ito T, Kagoshima M, Sasaki Y et al. Repulsive axon guidance molecule Sema3A inhibits branching morphogenesis of fetal mouse lung. Mech Dev 2000; 97:35–45.

    Article  PubMed  CAS  Google Scholar 

  34. Giger RJ, Cloutier JF, Sahay A et al. Neuropilin-2 is required in vivo for selective axon guidance responses to secreted Semaphorins. Neuron 2000; 25:29–41.

    Article  PubMed  CAS  Google Scholar 

  35. Chen H, Bagri A, Zupicich JA et al. Neuropilin-2 regulates the development of selective cranial and sensory nerves and hippocampal mossy fiber projections. Neuron 2000; 25:43–56

    Article  PubMed  Google Scholar 

  36. Taniguchi M, Yuasa S, Fujisawa H et al. Disruption of Semaphorin III/D gene causes severe abnormality in peripheral nerve projection. Neuron 1997; 19:519–530.

    Article  PubMed  CAS  Google Scholar 

  37. White FA, Behar O. The development and subsequent elimination of aberrant peripheral axon projections in Semaphorin3A null mutant mice. Dev Biol 2000; 225:79–86.

    Article  PubMed  CAS  Google Scholar 

  38. Kagoshima M, Ito T. Diverse gene expression and function of Semaphorins in developing lung: positive and negative regulatory roles of Semaphorins in lung branching morphogenesis. Genes Cells 2001; 6:559–71.

    Article  PubMed  CAS  Google Scholar 

  39. Goshima Y, Hori H, Sasaki Y et al. Growth cone Neuropilin-1 mediates collapsin-1/Sema III facilitation of antero-and retrograde axoplasmic transport. J Neurobiol 1999; 39:579–89

    Article  PubMed  CAS  Google Scholar 

  40. Bagnard D, Lohrum M, Uziel D et al. Semaphorins act as attractive and repulsive guidance signals during the development of cortical projections. Development 1998; 125:5043–5053

    PubMed  CAS  Google Scholar 

  41. Song H, Ming G, He Z et al. Conversion of neuronal growth cone responses from repulsion to attraction by cyclic nucleotides. Science 1998; 281:1515–1518.

    Article  PubMed  CAS  Google Scholar 

  42. Takahashi T, Fournier A, Nakamura F et al. Plexin-Neuropilin-1 complexes form functional Semaphorin-3A receptors. Cell 1999; 99:59–69.

    Article  PubMed  CAS  Google Scholar 

  43. Eickholt B, Mackenzie S, Graham A et al. Evidence for collapsin-1 functioning in the control of neural crest migration in both trunk and hindbrain regions. Development 1999; 126:2181–2189.

    PubMed  CAS  Google Scholar 

  44. Roy PJ, Zheng H, Warren CE et al. mab-20 encodes Semaphorin-2a and is required to prevent ectopic cell contacts during epidermal morphogenesis in Caenorhabditis elegans. Development 2000; 127:755–767.

    PubMed  CAS  Google Scholar 

  45. Brambilla E, Constantin B, Drabkin H et al. Semaphorin SEMA3F localization in malignant human lung and cell lines: A suggested role in cell adhesion and cell migration. Am J Pathol 2000; 156:939–950.

    Article  PubMed  CAS  Google Scholar 

  46. Roche J, Boldog F, Robinson M et al. Distinct 3p21.3 deletions in lung cancer, analysis of deleted genes and identification of a new human Semaphorin. Oncogene 1996; 12:1289–1297.

    PubMed  CAS  Google Scholar 

  47. Xiang R, Hensel C, Garcia D et al. Isolation of the human Semaphorin III/F gene (SEMA3F) at chromosome 3p21, a region deleted in lung cancer. Genomics 1996; 32:39–48.

    Article  PubMed  CAS  Google Scholar 

  48. Sekido Y, Bader S, Latif F et al. 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 1996; 93:4120–4125.

    Article  CAS  Google Scholar 

  49. Kok K, Naylor S, Buys C. Deletions of the short arm of chromosome 3 in solid tumors and the search for suppressor genes. Adv Cancer Res 1997; 71:27–92.

    Article  PubMed  CAS  Google Scholar 

  50. Lerman MI, Minna JD. The 630-kb lung cancer homozygous deletion region on human chromosome 3p21.3: identification and evaluation of the resident candidate tumor suppressor genes. The International Lung Cancer Chromosome 3p21.3 Tumor Suppressor Gene Consortium. Cancer Res 2000; 60:6116–33.

    PubMed  CAS  Google Scholar 

  51. Todd M, Xiang R, Garcia D et al. An 80 Kb P1 clone from chromosome 3p21.3 suppresses tumor growth in vivo. Oncogene 1996; 13:2387–2396.

    PubMed  CAS  Google Scholar 

  52. Xiang R, Xhou X, Tse C et al. Expression of human Semaphorin 3F in a human ovarian cancer cell line (Hey) suppresses tumor formation in nude mice and blocks program cell death caused by adriamycin or taxol. 915tProceedings of the American Association for Cancer Research, Abstract 5216, San Francisco 2000.

    Google Scholar 

  53. Sundaresan V, Roberts I, Bateman A et al. The DUTTI Gene, a Novel NCAM Family Member Is Expressed in Developing Murine Neural Tissues and Has an Unusually Broad Pattern of Expression. Mol Cell Neurosci 1998; 11:29–35.

    Article  PubMed  CAS  Google Scholar 

  54. Kidd T, Brose K, Mitchell KJ et al. Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 1998; 92:205–15.

    Article  PubMed  CAS  Google Scholar 

  55. Yamada T, Endo R, Gotoh M et al. Identification of Semaphorin E as non-MDR drug resistance gene of human cancers. Proc. Natl. Acad. Sci., USA 1997; 94:14713–14718.

    CAS  Google Scholar 

  56. Martin-Satue M, Blanco J. Identification of Semaphorin E gene expression in metastatic human lung adenocarcinoma cells by mRNA differential display. J Surg Oncol 1999; 72:18–23

    CAS  Google Scholar 

  57. Christensen CR, Klingelhofer J, Tarabykina S et al. Transcription of a novel mouse Semaphorin gene, M-semaH, correlates with the metastatic ability of mouse tumor cell lines. Cancer Res 1998; 58:1238–1244.

    PubMed  CAS  Google Scholar 

  58. Dorfman D, Shahsafaei A, Nadler L et al. The leukocyte Semaphorin CD100 is expressed in most T-cell, but few B-cell, non-Hodgkin’s lymphomas. Am. J. Pathol. 1998; 153:255–262

    Article  PubMed  CAS  Google Scholar 

  59. Hirsch E, Hu L-J, Prigent A et al. Distribution of Semaphorin IV in adult human brain. Brain Res. 1999; 823:67–79.

    Article  PubMed  CAS  Google Scholar 

  60. Miao HQ, Lee P, Lin H et al. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. Faseb J 2000; 14:2532–9.

    Article  PubMed  CAS  Google Scholar 

  61. Bachelder RE, Crago A, Chung J et al. Vascular endothelial growth factor is an autocrine survival factor for Neuropilin-expressing breast carcinoma cells. Cancer Res 2001; 61:5736–40.

    PubMed  CAS  Google Scholar 

  62. Latil A, Bieche I, Pesche S et al. VEGF overexpression in clinically localized prostate tumors and Neuropilin-1 overexpression in metastatic forms. Int J Cancer 2000; 89:167–71

    Article  PubMed  CAS  Google Scholar 

  63. Ding H, Wu X, Roncari L et al. Expression and regulation of Neuropilin-1 in human astrocytomas. Int J Cancer 2000; 88:584–92.

    Article  PubMed  CAS  Google Scholar 

  64. Banerjee SK, Zoubine MN, Tran TM et al. Overexpression of vascular endothelial growth factor164 and its co-receptor Neuropilin-1 in estrogen-induced rat pituitary tumors and GH3 rat pituitary tumor cells. Int J Oncol 2000; 16:253–60.

    PubMed  CAS  Google Scholar 

  65. Gagnon ML, Bielenberg DR, Gechtman Z et al. Identification of a natural soluble Neuropilin1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity. Proc Natl Acad Sci USA 2000; 97:2573–8.

    Article  PubMed  CAS  Google Scholar 

  66. Brabletz T, Jung A, Hermann K et al. Nuclear overexpression of the oncoprotein beta-catenin in colorectal cancer is localized predominantly at the invasion front. Pathol Res Pract 1998; 194:701–4.

    Article  PubMed  CAS  Google Scholar 

  67. Graff JR, Gabrielson E, Fujii H et al. Methylation patterns of the E-cadherin 5’ CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J Biol Chem 2000; 275:2727–32.

    Article  PubMed  CAS  Google Scholar 

  68. Tomizawa Y, Sekido Y, Kondo M. et al. Inhibition of lung cancer cell growth and induction of apoptosis following re-expression of 3p21.3 tumor suppressor gene candidate SEMA3B. Proc Natl Acad of Sci USA 2001; 98:13954–13959.

    Article  CAS  Google Scholar 

  69. Gagliardini V, Fankhauser C. Semaphorin III Can Induce Death in Sensory Neurons. Mol Cell Neurosci 1999; 14:301–316.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2002 Springer Science+Business Media New York

About this chapter

Cite this chapter

Roche, J., Drabkin, H., Brambilla, E. (2002). Neuropilin and Its Ligands in Normal Lung and Cancer. In: Bagnard, D. (eds) Neuropilin: From Nervous System to Vascular and Tumor Biology. Advances in Experimental Medicine and Biology, vol 515. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0119-0_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-4615-0119-0_9

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-4932-7

  • Online ISBN: 978-1-4615-0119-0

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics