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Neuropilins as Cancer Biomarkers: A Focus on Neuronal Origin and Specific Cell Functions

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Biomarkers of the Tumor Microenvironment

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Abstract

The Neuropilin (NRP) family of type I integral membrane proteins is essential for multiple steps in the metastatic cascade. The dynamic duo of NRP1 and NRP2 act as co-receptors for a multitude of stimulatory growth factors such as VEGF, PGF, HGF, and PDGF. Alternately, NRPs can bind to ligands of the SEMA3 family of chemorepulsive guidance cues. Consequently, these unique receptors can toggle between opposing pro-tumorigenic and anticancer roles. Their location on the cell surface, tissue specificity patterns, and soluble isoforms make them ideal for targeted therapies, diagnostics, and biomarker analysis in cancer. This chapter focuses on the expression of NRPs in neuronal stem cells and malignant tumors of neuronal origin including gliomas and melanomas. The function of each NRP receptor is cell type specific and ligand dependent.

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References

  1. Takagi S, Hirata T, Agata K, Mochii M, Eguchi G, Fujisawa H. The A5 antigen, a candidate for the neuronal recognition molecule, has homologies to complement components and coagulation factors. Neuron. 1991;7(2):295–307.

    Article  CAS  PubMed  Google Scholar 

  2. Schwarz Q, Ruhrberg C. Neuropilin, you gotta let me know: should I stay or should I go? Cell Adhes Migr. 2010;4(1):61–6.

    Article  Google Scholar 

  3. Prud'homme GJ, Glinka Y. Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity. Oncotarget. 2012;3(9):921–39.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Raimondi C, Ruhrberg C. Neuropilin signalling in vessels, neurons and tumours. Semin Cell Dev Biol. 2013;24(3):172–8.

    Article  CAS  PubMed  Google Scholar 

  5. Djordjevic S, Driscoll PC. Targeting VEGF signalling via the neuropilin co-receptor. Drug Discov Today. 2013;18(9–10):447–55.

    Article  CAS  PubMed  Google Scholar 

  6. Niland S, Eble JA. Neuropilin: handyman and power broker in the tumor microenvironment. Adv Exp Med Biol. 2020;1223:31–67.

    Article  CAS  PubMed  Google Scholar 

  7. Klagsbrun M, Takashima S, Mamluk R. The role of neuropilin in vascular and tumor biology. Adv Exp Med Biol. 2002;515:33–48.

    Article  CAS  PubMed  Google Scholar 

  8. Rossignol M, Beggs AH, Pierce EA, Klagsbrun M. Human neuropilin-1 and neuropilin-2 map to 10p12 and 2q34, respectively. Genomics. 1999;57(3):459–60.

    Article  CAS  PubMed  Google Scholar 

  9. Appleton BA, Wu P, Maloney J, Yin J, Liang WC, Stawicki S, Mortara K, Bowman KK, Elliott JM, Desmarais W, Bazan JF, Bagri A, Tessier-Lavigne M, Koch AW, Wu Y, Watts RJ, Wiesmann C. Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding. EMBO J. 2007;26(23):4902–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Janssen BJ, Malinauskas T, Weir GA, Cader MZ, Siebold C, Jones EY. Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex. Nat Struct Mol Biol. 2012;19(12):1293–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Roth L, Nasarre C, Dirrig-Grosch S, Aunis D, Crémel G, Hubert P, Bagnard D. Transmembrane domain interactions control biological functions of neuropilin-1. Mol Biol Cell. 2008;19(2):646–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Barton R, Driscoll A, Flores S, Mudbhari D, Collins T, Iovine MK, Berger BW. Cysteines in the neuropilin-2 MAM domain modulate receptor homooligomerization and signal transduction. Biopolymers. 2015;104(4):371–8.

    Article  CAS  PubMed  Google Scholar 

  13. Yelland T, Djordjevic S. Crystal structure of the Neuropilin-1 MAM domain: completing the Neuropilin-1 Ectodomain picture. Structure. 2016;24(11):2008–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Puszko AK, Sosnowski P, Raynaud F, Hermine O, Hopfgartner G, Lepelletier Y, Misicka A. Does cysteine rule (CysR) complete the CendR principle? Increase in affinity of peptide ligands for NRP-1 through the presence of N-terminal cysteine. Biomol Ther. 2020;10(3)

    Google Scholar 

  15. Pellet-Many C, Frankel P, Jia H, Zachary I. Neuropilins: structure, function and role in disease. Biochem J. 2008;411(2):211–26.

    Article  CAS  PubMed  Google Scholar 

  16. Rossignol M, Gagnon ML, Klagsbrun M. Genomic organization of human neuropilin-1 and neuropilin-2 genes: identification and distribution of splice variants and soluble isoforms. Genomics. 2000;70(2):211–22.

    Article  CAS  PubMed  Google Scholar 

  17. Tao Q, Spring SC, Terman BI. Characterization of a new alternatively spliced neuropilin-1 isoform. Angiogenesis. 2003;6(1):39–45.

    Article  CAS  PubMed  Google Scholar 

  18. Chen H, Chedotal A, He Z, Goodman CS, 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. 1997;19(3):547–59.

    Article  CAS  PubMed  Google Scholar 

  19. Cai H, Reed RR. 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. 1999;19(15):6519–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang L, Mukhopadhyay D, Xu X. C terminus of RGS-GAIP-interacting protein conveys neuropilin-1-mediated signaling during angiogenesis. FASEB J. 2006;20(9):1513–5.

    Article  CAS  PubMed  Google Scholar 

  21. Prahst C, Héroult M, Lanahan AA, Uziel N, Kessler O, Shraga-Heled N, Simons M, Neufeld G, Augustin HG. Neuropilin-1-VEGFR-2 complexing requires the PDZ-binding domain of neuropilin-1. J Biol Chem. 2008;283(37):25110–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gaur P, Bielenberg DR, Samuel S, Bose D, Zhou Y, Gray MJ, Dallas NA, Fan F, Xia L, Lu J, Ellis LM. Role of class 3 semaphorins and their receptors in tumor growth and angiogenesis. Clin Cancer Res. 2009;15(22):6763–70.

    Article  CAS  PubMed  Google Scholar 

  23. Migliozzi MT, Mucka P, Bielenberg DR. Lymphangiogenesis and metastasis--a closer look at the neuropilin/semaphorin3 axis. Microvasc Res. 2014;96:68–76.

    Article  CAS  PubMed  Google Scholar 

  24. Li X, Bielenberg DR. Neuropilin 1 and Neuropilin 2: cancer progression and biomarker analysis. In: Akslen LA, Watnick RS, editors. Biomarkers of the tumor microenvironment: basic studies and practical applications. Switzerland: Springer; 2017. p. 329–49.

    Chapter  Google Scholar 

  25. He Z, Tessier-Lavigne M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell. 1997;90(4):739–51.

    Article  CAS  PubMed  Google Scholar 

  26. Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD. Neuropilin is a semaphorin III receptor. Cell. 1997;90(4):753–62.

    Article  CAS  PubMed  Google Scholar 

  27. Capparuccia L, Tamagnone L. Semaphorin signaling in cancer cells and in cells of the tumor microenvironment--two sides of a coin. J Cell Sci. 2009;122(Pt 11):1723–36.

    Article  CAS  PubMed  Google Scholar 

  28. 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. Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J Clin Invest. 2010;120(8):2684–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Klagsbrun M, Shimizu A. Semaphorin 3E, an exception to the rule. J Clin Invest. 2010;120(8):2658–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kolodkin AL, Matthes DJ, Goodman CS. The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules. Cell. 1993;75(7):1389–99.

    Article  CAS  PubMed  Google Scholar 

  31. Luo Y, Raible D, Raper JA. Collapsin: a protein in brain that induces the collapse and paralysis of neuronal growth cones. Cell. 1993;75(2):217–27.

    Article  CAS  PubMed  Google Scholar 

  32. Taniguchi M, Masuda T, Fukaya M, Kataoka H, Mishina M, Yaginuma H, Watanabe M, Shimizu T. Identification and characterization of a novel member of murine semaphorin family. Genes Cells. 2005;10(8):785–92.

    Article  CAS  PubMed  Google Scholar 

  33. Kutschera S, Weber H, Weick A, De Smet F, Genove G, Takemoto M, Prahst C, Riedel M, Mikelis C, Baulande S, Champseix C, Kummerer P, Conseiller E, Multon MC, Heroult M, Bicknell R, Carmeliet P, Betsholtz C, Augustin HG. Differential endothelial transcriptomics identifies semaphorin 3G as a vascular class 3 semaphorin. Arterioscler Thromb Vasc Biol. 2011;31(1):151–9.

    Article  CAS  PubMed  Google Scholar 

  34. Liu X, Uemura A, Fukushima Y, Yoshida Y, Hirashima M. Semaphorin 3G provides a repulsive guidance cue to lymphatic endothelial cells via Neuropilin-2/PlexinD1. Cell Rep. 2016;17(9):2299–311.

    Article  CAS  PubMed  Google Scholar 

  35. Chedotal A, Del Rio JA, Ruiz M, He Z, Borrell V, de Castro F, Ezan F, Goodman CS, Tessier-Lavigne M, Sotelo C, Soriano E. Semaphorins III and IV repel hippocampal axons via two distinct receptors. Development. 1998;125(21):4313–23.

    Article  CAS  PubMed  Google Scholar 

  36. Cagnoni G, Tamagnone L. Semaphorin receptors meet receptor tyrosine kinases on the way of tumor progression. Oncogene. 2014;33(40):4795–802.

    Article  CAS  PubMed  Google Scholar 

  37. Pascoe HG, Wang Y, Zhang X. Structural mechanisms of plexin signaling. Prog Biophys Mol Biol. 2015;118(3):161–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wu KY, Hengst U, Cox LJ, Macosko EZ, Jeromin A, Urquhart ER, Jaffrey SR. Local translation of RhoA regulates growth cone collapse. Nature. 2005;436(7053):1020–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Shimizu A, Mammoto A, Italiano JE Jr, Pravda E, Dudley AC, Ingber DE, Klagsbrun M. ABL2/ARG tyrosine kinase mediates SEMA3F-induced RhoA inactivation and cytoskeleton collapse in human glioma cells. J Biol Chem. 2008;283(40):27230–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nakayama H, Bruneau S, Kochupurakkal N, Coma S, Briscoe DM, Klagsbrun M. Regulation of mTOR signaling by Semaphorin 3F-Neuropilin 2 interactions in vitro and in vivo. Sci Rep. 2015;5:11789.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Soker S, Fidder H, Neufeld G, Klagsbrun M. Characterization of novel vascular endothelial growth factor (VEGF) receptors on tumor cells that bind VEGF165 via its exon 7-encoded domain. J Biol Chem. 1996;271(10):5761–7.

    Article  CAS  PubMed  Google Scholar 

  42. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell. 1998;92(6):735–45.

    Article  CAS  PubMed  Google Scholar 

  43. Mamluk R, Gechtman Z, Kutcher ME, Gasiunas N, Gallagher J, Klagsbrun M. Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain. J Biol Chem. 2002;277(27):24818–25.

    Article  CAS  PubMed  Google Scholar 

  44. Klagsbrun M, Eichmann A. A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis. Cytokine Growth Factor Rev. 2005;16(4–5):535–48.

    Article  CAS  PubMed  Google Scholar 

  45. Geretti E, Shimizu A, Kurschat P, Klagsbrun M. Site-directed mutagenesis in the B-neuropilin-2 domain selectively enhances its affinity to VEGF165, but not to semaphorin 3F. J Biol Chem. 2007;282(35):25698–707.

    Article  CAS  PubMed  Google Scholar 

  46. Shraga-Heled N, Kessler O, Prahst C, Kroll J, Augustin H, Neufeld G. Neuropilin-1 and neuropilin-2 enhance VEGF121 stimulated signal transduction by the VEGFR-2 receptor. FASEB J. 2007;21(3):915–26.

    Article  CAS  PubMed  Google Scholar 

  47. Soker S, Miao HQ, 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. 2002;85(2):357–68.

    Article  CAS  PubMed  Google Scholar 

  48. Lee CC, Kreusch A, McMullan D, Ng K, Spraggon G. Crystal structure of the human neuropilin-1 b1 domain. Structure. 2003;11(1):99–108.

    Article  CAS  PubMed  Google Scholar 

  49. Vander Kooi CW, Jusino MA, Perman B, Neau DB, Bellamy HD, Leahy DJ. Structural basis for ligand and heparin binding to neuropilin B domains. Proc Natl Acad Sci U S A. 2007;104(15):6152–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Parker MW, Xu P, Li X, Vander Kooi CW. Structural basis for selective vascular endothelial growth factor-A (VEGF-A) binding to neuropilin-1. J Biol Chem. 2012;287(14):11082–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Gluzman-Poltorak Z, Cohen T, Shibuya M, Neufeld G. Vascular endothelial growth factor receptor-1 and neuropilin-2 form complexes. J Biol Chem. 2001;276(22):18688–94.

    Article  CAS  PubMed  Google Scholar 

  52. Neufeld G, Cohen T, Shraga N, Lange T, Kessler O, Herzog Y. The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc Med. 2002;12(1):13–9.

    Article  CAS  PubMed  Google Scholar 

  53. Shibuya M, Ito N, Claesson-Welsh L. Structure and function of vascular endothelial growth factor receptor-1 and -2. Curr Top Microbiol Immunol. 1999;237:59–83.

    CAS  PubMed  Google Scholar 

  54. Jia H, Bagherzadeh A, Hartzoulakis B, Jarvis A, Löhr M, Shaikh S, Aqil R, Cheng L, Tickner M, Esposito D, Harris R, Driscoll PC, Selwood DL, Zachary IC. Characterization of a bicyclic peptide neuropilin-1 (NP-1) antagonist (EG3287) reveals importance of vascular endothelial growth factor exon 8 for NP-1 binding and role of NP-1 in KDR signaling. J Biol Chem. 2006;281(19):13493–502.

    Article  CAS  PubMed  Google Scholar 

  55. 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. The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. Dev Cell. 2013;25(2):156–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Zhang X, Simons M. Receptor tyrosine kinases endocytosis in endothelium: biology and signaling. Arterioscler Thromb Vasc Biol. 2014;34(9):1831–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kofler NM, Simons M. Angiogenesis versus arteriogenesis: neuropilin 1 modulation of VEGF signaling. F1000Prime Rep. 2015;7:26.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Simons M, Gordon E, Claesson-Welsh L. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol. 2016;17(10):611–25.

    Article  CAS  PubMed  Google Scholar 

  59. Herzog B, Pellet-Many C, Britton G, Hartzoulakis B, Zachary IC. VEGF binding to NRP1 is essential for VEGF stimulation of endothelial cell migration, complex formation between NRP1 and VEGFR2, and signaling via FAK Tyr407 phosphorylation. Mol Biol Cell. 2011;22(15):2766–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Fantin A, Vieira JM, Plein A, Denti L, Fruttiger M, Pollard JW, Ruhrberg C. NRP1 acts cell autonomously in endothelium to promote tip cell function during sprouting angiogenesis. Blood. 2013;121(12):2352–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Dallinga MG, Habani YI, Schimmel AWM, Dallinga-Thie GM, van Noorden CJF, Klaassen I, Schlingemann RO. The role of Heparan sulfate and Neuropilin 2 in VEGFA signaling in human endothelial tip cells and non-tip cells during angiogenesis in vitro. Cell. 2021;10(4)

    Google Scholar 

  62. Kitsukawa T, Shimizu M, Sanbo M, Hirata T, Taniguchi M, Bekku Y, Yagi T, Fujisawa H. Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron. 1997;19(5):995–1005.

    Article  CAS  PubMed  Google Scholar 

  63. Kawasaki T, Kitsukawa T, Bekku Y, Matsuda Y, Sanbo M, Yagi T, Fujisawa H. A requirement for neuropilin-1 in embryonic vessel formation. Development. 1999;126(21):4895–902.

    Article  CAS  PubMed  Google Scholar 

  64. Takashima S, Kitakaze M, Asakura M, Asanuma H, Sanada S, Tashiro F, Niwa H, Miyazaki Ji J, Hirota S, Kitamura Y, Kitsukawa T, Fujisawa H, Klagsbrun M, Hori M. 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. 2002;99(6):3657–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Fantin A, Schwarz Q, Davidson K, Normando EM, Denti L, Ruhrberg C. The cytoplasmic domain of neuropilin 1 is dispensable for angiogenesis, but promotes the spatial separation of retinal arteries and veins. Development. 2011;138(19):4185–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Migdal M, Huppertz B, Tessler S, Comforti A, Shibuya M, Reich R, Baumann H, Neufeld G. Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem. 1998;273(35):22272–8.

    Article  CAS  PubMed  Google Scholar 

  67. Makinen T, Olofsson B, Karpanen T, Hellman U, Soker S, Klagsbrun M, Eriksson U, Alitalo K. Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1. J Biol Chem. 1999;274(30):21217–22.

    Article  CAS  PubMed  Google Scholar 

  68. Sulpice E, Plouët J, Bergé M, Allanic D, Tobelem G, Merkulova-Rainon T. Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity. Blood. 2008;111(4):2036–45.

    Article  CAS  PubMed  Google Scholar 

  69. Glinka Y, Prud'homme GJ. Neuropilin-1 is a receptor for transforming growth factor beta-1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol. 2008;84(1):302–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ball SG, Bayley C, Shuttleworth CA, Kielty CM. Neuropilin-1 regulates platelet-derived growth factor receptor signalling in mesenchymal stem cells. Biochem J. 2010;427(1):29–40.

    Article  CAS  PubMed  Google Scholar 

  71. Pellet-Many C, Frankel P, Evans IM, Herzog B, Jünemann-Ramírez M, Zachary IC. Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas. Biochem J. 2011;435(3):609–18.

    Article  CAS  PubMed  Google Scholar 

  72. Glinka Y, Stoilova S, Mohammed N, Prud'homme GJ. Neuropilin-1 exerts co-receptor function for TGF-beta-1 on the membrane of cancer cells and enhances responses to both latent and active TGF-beta. Carcinogenesis. 2011;32(4):613–21.

    Article  CAS  PubMed  Google Scholar 

  73. Murray-Rust J, McDonald NQ, Blundell TL, Hosang M, Oefner C, Winkler F, Bradshaw RA. Topological similarities in TGF-beta 2, PDGF-BB and NGF define a superfamily of polypeptide growth factors. Structure. 1993;1(2):153–9.

    Article  CAS  PubMed  Google Scholar 

  74. Miao HQ, Soker S, Feiner L, Alonso JL, Raper JA, Klagsbrun M. 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(1):233–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Zhao L, Chen H, Lu L, Wang L, Zhang X, Guo X. New insights into the role of co-receptor neuropilins in tumour angiogenesis and lymphangiogenesis and targeted therapy strategies. J Drug Target. 2021;29(2):155–67.

    Article  CAS  PubMed  Google Scholar 

  76. Niland S, Eble JA. Neuropilins in the context of tumor vasculature. Int J Mol Sci. 2019;20(3)

    Google Scholar 

  77. Lampropoulou A, Ruhrberg C. Neuropilin regulation of angiogenesis. Biochem Soc Trans. 2014;42(6):1623–8.

    Article  CAS  PubMed  Google Scholar 

  78. Squarzoni P, Thion MS, Garel S. Neuronal and microglial regulators of cortical wiring: usual and novel guideposts. Front Neurosci. 2015;9:248.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Huber AB, Kania A, Tran TS, Gu C, De Marco Garcia N, Lieberam I, Johnson D, Jessell TM, Ginty DD, Kolodkin AL. Distinct roles for secreted semaphorin signaling in spinal motor axon guidance. Neuron. 2005;48(6):949–64.

    Article  CAS  PubMed  Google Scholar 

  80. Ulupinar E, Datwani A, Behar O, Fujisawa H, Erzurumlu R. Role of semaphorin III in the developing rodent trigeminal system. Mol Cell Neurosci. 1999;13(4):281–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Tamamaki N, Fujimori K, Nojyo Y, Kaneko T, Takauji R. Evidence that Sema3A and Sema3F regulate the migration of GABAergic neurons in the developing neocortex. J Comp Neurol. 2003;455(2):238–48.

    Article  CAS  PubMed  Google Scholar 

  83. Marín O, Rubenstein JL. Cell migration in the forebrain. Annu Rev Neurosci. 2003;26:441–83.

    Article  PubMed  CAS  Google Scholar 

  84. Marin O, Yaron A, Bagri A, Tessier-Lavigne M, Rubenstein JL. Sorting of striatal and cortical interneurons regulated by semaphorin-neuropilin interactions. Science. 2001;293(5531):872–5.

    Article  CAS  PubMed  Google Scholar 

  85. Ito K, Kawasaki T, Takashima S, Matsuda I, Aiba A, Hirata T. Semaphorin 3F confines ventral tangential migration of lateral olfactory tract neurons onto the telencephalon surface. J Neurosci. 2008;28(17):4414–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Walz A, Rodriguez I, Mombaerts P. Aberrant sensory innervation of the olfactory bulb in neuropilin-2 mutant mice. J Neurosci. 2002;22(10):4025–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Walz A, Feinstein P, Khan M, Mombaerts P. Axonal wiring of guanylate cyclase-D-expressing olfactory neurons is dependent on neuropilin 2 and semaphorin 3F. Development. 2007;134(22):4063–72.

    Article  CAS  PubMed  Google Scholar 

  88. Wray S, Grant P, Gainer H. Evidence that cells expressing luteinizing hormone-releasing hormone mRNA in the mouse are derived from progenitor cells in the olfactory placode. Proc Natl Acad Sci U S A. 1989;86(20):8132–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Cariboni A, Hickok J, Rakic S, Andrews W, Maggi R, Tischkau S, Parnavelas JG. Neuropilins and their ligands are important in the migration of gonadotropin-releasing hormone neurons. J Neurosci. 2007;27(9):2387–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Giger RJ, Cloutier JF, Sahay A, Prinjha RK, Levengood DV, Moore SE, Pickering S, Simmons D, Rastan S, Walsh FS, Kolodkin AL, Ginty DD, Geppert M. Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins. Neuron. 2000;25(1):29–41.

    Article  CAS  PubMed  Google Scholar 

  91. Lumb R, Wiszniak S, Kabbara S, Scherer M, Harvey N, Schwarz Q. Neuropilins define distinct populations of neural crest cells. Neural Dev. 2014;9:24.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Mayor R, Theveneau E. The neural crest. Development. 2013;140(11):2247–51.

    Article  CAS  PubMed  Google Scholar 

  93. Yu HH, Moens CB. Semaphorin signaling guides cranial neural crest cell migration in zebrafish. Dev Biol. 2005;280(2):373–85.

    Article  CAS  PubMed  Google Scholar 

  94. York JR, Yuan T, Lakiza O, McCauley DW. An ancestral role for Semaphorin3F-Neuropilin signaling in patterning neural crest within the new vertebrate head. Development. 2018;145(14)

    Google Scholar 

  95. Gammill LS, Gonzalez C, Bronner-Fraser M. Neuropilin 2/semaphorin 3F signaling is essential for cranial neural crest migration and trigeminal ganglion condensation. Dev Neurobiol. 2007;67(1):47–56.

    Article  CAS  PubMed  Google Scholar 

  96. Gammill LS, Gonzalez C, Bronner-Fraser M. Neuropilin 2/semaphorin 3F signaling is essential for cranial neural crest migration and trigeminal ganglion condensation. J Neurobiol. 2006;67(1):47–56.

    Article  CAS  Google Scholar 

  97. Osborne NJ, Begbie J, Chilton JK, Schmidt H, Eickholt BJ. Semaphorin/neuropilin signaling influences the positioning of migratory neural crest cells within the hindbrain region of the chick. Dev Dyn. 2005;232(4):939–49.

    Article  CAS  PubMed  Google Scholar 

  98. Schwarz Q, Vieira JM, Howard B, Eickholt BJ, Ruhrberg C. Neuropilin 1 and 2 control cranial gangliogenesis and axon guidance through neural crest cells. Development. 2008;135(9):1605–13.

    Article  CAS  PubMed  Google Scholar 

  99. Bielenberg DR, Pettaway CA, Takashima S, Klagsbrun M. Neuropilins in neoplasms: expression, regulation, and function. Exp Cell Res. 2006;312(5):584–93.

    Article  CAS  PubMed  Google Scholar 

  100. Bielenberg DR, Seth A, Shimizu A, Pelton K, Cristofaro V, Ramachandran A, Zwaans BM, Chen C, Krishnan R, Seth M, Huang L, Takashima S, Klagsbrun M, Sullivan MP, Adam RM. Increased smooth muscle contractility in mice deficient for neuropilin 2. Am J Pathol. 2012;181(2):548–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Broholm H, Laursen H. Vascular endothelial growth factor (VEGF) receptor neuropilin-1’s distribution in astrocytic tumors. APMIS. 2004;112(4–5):257–63.

    Article  CAS  PubMed  Google Scholar 

  102. Osada H, Tokunaga T, Nishi M, Hatanaka H, Abe Y, Tsugu A, Kijima H, Yamazaki H, Ueyama Y, Nakamura M. Overexpression of the neuropilin 1 (NRP1) gene correlated with poor prognosis in human glioma. Anticancer Res. 2004;24(2B):547–52.

    CAS  PubMed  Google Scholar 

  103. Frankel P, Pellet-Many C, Lehtolainen P, D'Abaco GM, Tickner ML, Cheng L, Zachary IC. Chondroitin sulphate-modified neuropilin 1 is expressed in human tumour cells and modulates 3D invasion in the U87MG human glioblastoma cell line through a p130Cas-mediated pathway. EMBO Rep. 2008;9(10):983–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Law JW, Lee AY. The role of semaphorins and their receptors in gliomas. J Signal Transduct. 2012;2012:902854.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Friedmann-Morvinski D. Glioblastoma heterogeneity and cancer cell plasticity. Crit Rev Oncog. 2014;19(5):327–36.

    Article  PubMed  Google Scholar 

  106. Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA, Quinn JA, Rich JN, Sathornsumetee S, Gururangan S, Wagner M, Bigner DD, Friedman AH, Friedman HS. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res. 2007;13(4):1253–9.

    Article  CAS  PubMed  Google Scholar 

  107. Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014;370(8):709–22.

    Article  CAS  PubMed  Google Scholar 

  108. Cheray M, Bégaud G, Deluche E, Nivet A, Battu S, Lalloué F, Verdier M, Bessette B. Cancer stem-like cells. In: De Vleeschouwer S, editor. Glioblastoma. Brisbane AU: The Authors; 2017.

    Google Scholar 

  109. Yoshida A, Shimizu A, Asano H, Kadonosono T, Kondoh SK, Geretti E, Mammoto A, Klagsbrun M, Seo MK. VEGF-A/NRP1 stimulates GIPC1 and Syx complex formation to promote RhoA activation and proliferation in skin cancer cells. Biol Open. 2015;4(9):1063–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Migliozzi M, Hida Y, Seth M, Brown G, Kwan J, Coma S, Panigrahy D, Adam RM, Banyard J, Shimizu A, Bielenberg DR. VEGF/VEGFR2 autocrine signaling stimulates metastasis in prostate cancer cells. Curr Angiogen. 2014;3(4):231–44.

    Article  CAS  Google Scholar 

  111. Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, Chung YC, Wu MH, Yang SC, Pan SH, Shih JY, Chan WK, Yang PC. Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res. 2007;13(16):4759–68.

    Article  CAS  PubMed  Google Scholar 

  112. Hamerlik P, Lathia JD, Rasmussen R, Wu Q, Bartkova J, Lee M, Moudry P, Bartek J Jr, Fischer W, Lukas J, Rich JN, Bartek J. Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth. J Exp Med. 2012;209(3):507–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Angom RS, Mondal SK, Wang F, Madamsetty VS, Wang E, Dutta SK, Gulani Y, Sarabia-Estrada R, Sarkaria JN, Quiñones-Hinojosa A, Mukhopadhyay D. Ablation of neuropilin-1 improves the therapeutic response in conventional drug-resistant glioblastoma multiforme. Oncogene. 2020;39(48):7114–26.

    Article  PubMed  Google Scholar 

  114. Hu B, Guo P, Bar-Joseph I, Imanishi Y, Jarzynka MJ, Bogler O, Mikkelsen T, Hirose T, Nishikawa R, Cheng SY. Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway. Oncogene. 2007;26(38):5577–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Bagci T, Wu JK, Pfannl R, Ilag LL, Jay DG. Autocrine semaphorin 3A signaling promotes glioblastoma dispersal. Oncogene. 2009;28(40):3537–50.

    Article  CAS  PubMed  Google Scholar 

  116. Li X, Tang T, Lu X, Zhou H, Huang Y. RNA interference targeting NRP-1 inhibits human glioma cell proliferation and enhances cell apoptosis. Mol Med Rep. 2011;4(6):1261–6.

    CAS  PubMed  Google Scholar 

  117. Wu HB, Wang Z, Wang QS, Han YJ, Wang M, Zhou WL, Li HS. Use of labelled tLyP-1 as a novel ligand targeting the NRP receptor to image glioma. PLoS One. 2015;10(9):e0137676.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Nasarre C, Roth M, Jacob L, Roth L, Koncina E, Thien A, Labourdette G, Poulet P, Hubert P, Crémel G, Roussel G, Aunis D, Bagnard D. Peptide-based interference of the transmembrane domain of neuropilin-1 inhibits glioma growth in vivo. Oncogene. 2010;29(16):2381–92.

    Article  CAS  PubMed  Google Scholar 

  119. Chen L, Miao W, Tang X, Zhang H, Wang S, Luo F, Yan J. Inhibitory effect of neuropilin-1 monoclonal antibody (NRP-1 MAb) on glioma tumor in mice. J Biomed Nanotechnol. 2013;9(4):551–8.

    Article  CAS  PubMed  Google Scholar 

  120. Evans IM, Yamaji M, Britton G, Pellet-Many C, Lockie C, Zachary IC, Frankel P. Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells. Mol Cell Biol. 2011;31(6):1174–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Sun S, Lei Y, Li Q, Wu Y, Zhang L, Mu PP, Ji GQ, Tang CX, Wang YQ, Gao J, Gao J, Li L, Zhuo L, Li YQ, Gao DS. Neuropilin-1 is a glial cell line-derived neurotrophic factor receptor in glioblastoma. Oncotarget. 2017;8(43):74019–35.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC, Anolik R, Huang Y, Martin JD, Kamoun W, Knevels E, Schmidt T, Farrar CT, Vakoc BJ, Mohan N, Chung E, Roberge S, Peterson T, Bais C, Zhelyazkova BH, Yip S, Hasselblatt M, Rossig C, Niemeyer E, Ferrara N, Klagsbrun M, Duda DG, Fukumura D, Xu L, Carmeliet P, Jain RK. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell. 2013;152(5):1065–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Hayden Gephart MG, Su YS, Bandara S, Tsai FC, Hong J, Conley N, Rayburn H, Milenkovic L, Meyer T, Scott MP. Neuropilin-2 contributes to tumorigenicity in a mouse model of hedgehog pathway medulloblastoma. J Neuro-Oncol. 2013;115(2):161–8.

    Article  CAS  Google Scholar 

  124. Zhao H, Hou C, Hou A, Zhu D. Concurrent expression of VEGF-C and Neuropilin-2 is correlated with poor prognosis in glioblastoma. Tohoku J Exp Med. 2016;238(2):85–91.

    Article  CAS  PubMed  Google Scholar 

  125. Karayan-Tapon L, Wager M, Guilhot J, Levillain P, Marquant C, Clarhaut J, Potiron V, Roche J. Semaphorin, neuropilin and VEGF expression in glial tumours: SEMA3G, a prognostic marker? Br J Cancer. 2008;99(7):1153–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Pan Q, Chanthery Y, Liang WC, Stawicki S, Mak J, Rathore N, Tong RK, Kowalski J, Yee SF, Pacheco G, Ross S, Cheng Z, Le Couter J, Plowman G, Peale F, Koch AW, Wu Y, Bagri A, Tessier-Lavigne M, Watts RJ. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell. 2007;11(1):53–67.

    Article  CAS  PubMed  Google Scholar 

  127. Serbedzija GN, Fraser SE, Bronner-Fraser M. Pathways of trunk neural crest cell migration in the mouse embryo as revealed by vital dye labelling. Development. 1990;108(4):605–12.

    Article  CAS  PubMed  Google Scholar 

  128. Eickholt BJ, Mackenzie SL, Graham A, Walsh FS, Doherty P. Evidence for collapsin-1 functioning in the control of neural crest migration in both trunk and hindbrain regions. Development. 1999;126(10):2181–9.

    Article  CAS  PubMed  Google Scholar 

  129. Li A. The biology of melanocyte and melanocyte stem cell. Acta Biochim Biophys Sin Shanghai. 2014;46(4):255–60.

    Article  PubMed  Google Scholar 

  130. Myung P, Ito M. Dissecting the bulge in hair regeneration. J Clin Invest. 2012;122(2):448–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Danen EH, Jansen KF, Klein CE, Smit NP, Ruiter DJ, van Muijen GN. Loss of adhesion to basement membrane components but not to keratinocytes in proliferating melanocytes. Eur J Cell Biol. 1996;70(1):69–75.

    CAS  PubMed  Google Scholar 

  132. Haass NK, Herlyn M. Normal human melanocyte homeostasis as a paradigm for understanding melanoma. J Investig Dermatol Symp Proc. 2005;10(2):153–63.

    Article  CAS  PubMed  Google Scholar 

  133. Tang A, Eller MS, Hara M, Yaar M, Hirohashi S, Gilchrest BA. E-cadherin is the major mediator of human melanocyte adhesion to keratinocytes in vitro. J Cell Sci. 1994;107(Pt 4):983–92.

    Article  CAS  PubMed  Google Scholar 

  134. Hsu MY, Wheelock MJ, Johnson KR, Herlyn M. Shifts in cadherin profiles between human normal melanocytes and melanomas. J Investig Dermatol Symp Proc. 1996;1(2):188–94.

    CAS  PubMed  Google Scholar 

  135. Mucka P, Levonyak N, Geretti E, Zwaans BMM, Li X, Adini I, Klagsbrun M, Adam RM, Bielenberg DR. Inflammation and lymphedema are exacerbated and prolonged by Neuropilin 2 deficiency. Am J Pathol. 2016;186(11):2803–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Uchida Y, James JM, Suto F, Mukouyama YS. Class 3 semaphorins negatively regulate dermal lymphatic network formation. Biol Open. 2015;4(9):1194–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kim EJ, Park HY, Yaar M, Gilchrest BA. Modulation of vascular endothelial growth factor receptors in melanocytes. Exp Dermatol. 2005;14(8):625–33.

    Article  CAS  PubMed  Google Scholar 

  138. Detmar M, Yeo KT, Nagy JA, Van de Water L, Brown LF, Berse B, Elicker BM, Ledbetter S, Dvorak HF. Keratinocyte-derived vascular permeability factor (vascular endothelial growth factor) is a potent mitogen for dermal microvascular endothelial cells. J Invest Dermatol. 1995;105(1):44–50.

    Article  CAS  PubMed  Google Scholar 

  139. Shahrabi-Farahani S, Wang L, Zwaans BM, Santana JM, Shimizu A, Takashima S, Kreuter M, Coultas L, D'Amore PA, Arbeit JM, Akslen LA, Bielenberg DR. Neuropilin 1 expression correlates with differentiation status of epidermal cells and cutaneous squamous cell carcinomas. Lab Investig. 2014;94(7):752–65.

    Article  CAS  PubMed  Google Scholar 

  140. Leonardi GC, Falzone L, Salemi R, Zanghì A, Spandidos DA, McCubrey JA, Candido S, Libra M. Cutaneous melanoma: from pathogenesis to therapy (review). Int J Oncol. 2018;52(4):1071–80.

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Kodet O, Kučera J, Strnadová K, Dvořánková B, Štork J, Lacina L, Smetana K Jr. Cutaneous melanoma dissemination is dependent on the malignant cell properties and factors of intercellular crosstalk in the cancer microenvironment (review). Int J Oncol. 2020;57(3):619–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Damsky WE, Bosenberg M. Melanocytic nevi and melanoma: unraveling a complex relationship. Oncogene. 2017;36(42):5771–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Laga AC, Murphy GF. Cellular heterogeneity in vertical growth phase melanoma. Arch Pathol Lab Med. 2010;134(12):1750–7.

    Article  PubMed  Google Scholar 

  144. Väisänen A, Tuominen H, Kallioinen M, Turpeenniemi-Hujanen T. Matrix metalloproteinase-2 (72 kD type IV collagenase) expression occurs in the early stage of human melanocytic tumour progression and may have prognostic value. J Pathol. 1996;180(3):283–9.

    Article  PubMed  Google Scholar 

  145. Hofmann UB, Westphal JR, Van Muijen GN, Ruiter DJ. Matrix metalloproteinases in human melanoma. J Invest Dermatol. 2000;115(3):337–44.

    Article  CAS  PubMed  Google Scholar 

  146. Streit M, Detmar M. Angiogenesis, lymphangiogenesis, and melanoma metastasis. Oncogene. 2003;22(20):3172–9.

    Article  CAS  PubMed  Google Scholar 

  147. Rajabi P, Neshat A, Mokhtari M, Rajabi MA, Eftekhari M, Tavakoli P. The role of VEGF in melanoma progression. J Res Med Sci. 2012;17(6):534–9.

    PubMed  PubMed Central  Google Scholar 

  148. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.

    Article  PubMed  Google Scholar 

  149. Tawbi HA, Boutros C, Kok D, Robert C, McArthur G. New era in the management of melanoma brain metastases. Am Soc Clin Oncol Educ Book. 2018;38:741–50.

    Article  PubMed  Google Scholar 

  150. Puckett Y, Wilson AM, Farci F, Thevenin C. Melanoma Pathology, in StatPearls2021, ©. Treasure Island FL: StatPearls Publishing LLC; 2021.

    Google Scholar 

  151. Lu J, Cheng Y, Zhang G, Tang Y, Dong Z, McElwee KJ, Li G. Increased expression of neuropilin 1 in melanoma progression and its prognostic significance in patients with melanoma. Mol Med Rep. 2015;12(2):2668–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Ruffini F, D'Atri S, Lacal PM. Neuropilin-1 expression promotes invasiveness of melanoma cells through vascular endothelial growth factor receptor-2-dependent and -independent mechanisms. Int J Oncol. 2013;43(1):297–306.

    Article  CAS  PubMed  Google Scholar 

  153. Pagani E, Ruffini F, Antonini Cappellini GC, Scoppola A, Fortes C, Marchetti P, Graziani G, D'Atri S, Lacal PM. Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness. Int J Oncol. 2016;48(4):1581–9.

    Article  CAS  PubMed  Google Scholar 

  154. Ruffini F, Levati L, Graziani G, Caporali S, Atzori MG, D'Atri S, Lacal PM. Platelet-derived growth factor-C promotes human melanoma aggressiveness through activation of neuropilin-1. Oncotarget. 2017;8(40):66833–48.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Rizzolio S, Cagnoni G, Battistini C, Bonelli S, Isella C, Van Ginderachter JA, Bernards R, Di Nicolantonio F, Giordano S, Tamagnone L. Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies. J Clin Invest. 2018;128(9):3976–90.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Rizzolio S, Corso S, Giordano S, Tamagnone L. Autocrine signaling of NRP1 ligand Galectin-1 elicits resistance to BRAF-targeted therapy in melanoma cells. Cancers (Basel). 2020;12(8)

    Google Scholar 

  158. Rossi M, Tuck J, Kim OJ, Panova I, Symanowski JT, Mahalingam M, Riker AI, Alani RM, Ryu B. Neuropilin-2 gene expression correlates with malignant progression in cutaneous melanoma. Br J Dermatol. 2014;171(2):403–8.

    Article  CAS  PubMed  Google Scholar 

  159. Rushing EC, Stine MJ, Hahn SJ, Shea S, Eller MS, Naif A, Khanna S, Westra WH, Jungbluth AA, Busam KJ, Mahalingam M, Alani RM. Neuropilin-2: a novel biomarker for malignant melanoma? Hum Pathol. 2012;43(3):381–9.

    Article  CAS  PubMed  Google Scholar 

  160. Stine MJ, Wang CJ, Moriarty WF, Ryu B, Cheong R, Westra WH, Levchenko A, Alani RM. Integration of genotypic and phenotypic screening reveals molecular mediators of melanoma-stromal interaction. Cancer Res. 2011;71(7):2433–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Moriarty WF, Kim E, Gerber SA, Hammers H, Alani RM. Neuropilin-2 promotes melanoma growth and progression in vivo. Melanoma Res. 2016;26(4):321–8.

    Article  CAS  PubMed  Google Scholar 

  162. Wititsuwannakul J, Mason AR, Klump VR, Lazova R. Neuropilin-2 as a useful marker in the differentiation between Spitzoid malignant melanoma and Spitz nevus. J Am Acad Dermatol. 2013;68(1):129–37.

    Article  CAS  PubMed  Google Scholar 

  163. Eisenstein A, Panova IP, Chung HJ, Goldberg LJ, Zhang Q, Lazova R, Bhawan J, Busam KJ, Symanowski JT, Alani RM, Ryu B. Quantitative assessment of neuropilin-2 as a simple and sensitive diagnostic assay for spitzoid melanocytic lesions. Melanoma Res. 2018;28(1):71–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Dadras SS, Lange-Asschenfeldt B, Velasco P, Nguyen L, Vora A, Muzikansky A, Jahnke K, Hauschild A, Hirakawa S, Mihm MC, Detmar M. Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol. 2005;18(9):1232–42.

    Article  PubMed  Google Scholar 

  165. Huang R, Andersen LMK, Rofstad EK. Metastatic pathway and the microvascular and physicochemical microenvironments of human melanoma xenografts. J Transl Med. 2017;15(1):203.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  166. Coma S, Shimizu A, Klagsbrun M. Hypoxia induces tumor and endothelial cell migration in a semaphorin 3F- and VEGF-dependent manner via transcriptional repression of their common receptor neuropilin 2. Cell Adhes Migr. 2011;5(3):266–75.

    Article  Google Scholar 

  167. Geretti E, van Meeteren LA, Shimizu A, Dudley AC, Claesson-Welsh L, Klagsbrun M. A mutated soluble neuropilin-2 B domain antagonizes vascular endothelial growth factor bioactivity and inhibits tumor progression. Mol Cancer Res. 2010;8(8):1063–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Bielenberg DR, Hida Y, Shimizu A, Kaipainen A, Kreuter M, Kim CC, Klagsbrun M. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest. 2004;114(9):1260–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Caunt M, Mak J, Liang WC, Stawicki S, Pan Q, Tong RK, Kowalski J, Ho C, Reslan HB, Ross J, Berry L, Kasman I, Zlot C, Cheng Z, Le Couter J, Filvaroff EH, Plowman G, Peale F, French D, Carano R, Koch AW, Wu Y, Watts RJ, Tessier-Lavigne M, Bagri A. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell. 2008;13(4):331–42.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Vascular Biology Program, Boston Children’s Hospital, Karp Family Research Laboratories, 12.213, Boston, MA, USA

    Dakshnapriya Balasubbramanian, Yao Gao & Diane R. Bielenberg

  2. Department of Surgery, Harvard Medical School, Boston, MA, USA

    Dakshnapriya Balasubbramanian, Yao Gao & Diane R. Bielenberg

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  1. Centre for Cancer Biomarkers CCBIO Department of Clinical Medicine, University of Bergen, Bergen, Norway

    Lars A. Akslen

  2. Department of Surgery, Harvard Medical School, Vascular Biology Program, Boston Children’s Hospital, Boston, USA

    Randolph S. Watnick

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Balasubbramanian, D., Gao, Y., Bielenberg, D.R. (2022). Neuropilins as Cancer Biomarkers: A Focus on Neuronal Origin and Specific Cell Functions. In: Akslen, L.A., Watnick, R.S. (eds) Biomarkers of the Tumor Microenvironment. Springer, Cham. https://doi.org/10.1007/978-3-030-98950-7_17

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