Neuropilin 1 and Neuropilin 2: Cancer Progression and Biomarker Analysis

  • Xiaoran Li
  • Diane R. Bielenberg


Neuropilins (NRP, human; Nrp, mouse) are a family of cell surface protein receptors originally named for their role in neuronal guidance during embryonic development. Over the past two decades, the expression, localization, regulation, and function of the NRP family have been intensely studied. The two-member family composed of neuropilin 1 (NRP1) and neuropilin 2 (NRP2) has now been shown to drive diverse processes including neuronal guidance, vasculogenesis, lymphangiogenesis, immunity, smooth muscle tone, epithelial cell migration and branching, epithelial-to-mesenchymal transition, and cancer progression. Although the two receptors share high sequence homology and domain structure, their unique ligand specificity, co-receptor nature, and disparate cell-specific expression patterns mediate pleiotropic functions in multiple tissue systems. Their abundant expression in a myriad of cancers and their location on the cell surface make them prime targets for antitumor therapies and potential use as surrogate biomarkers.


Neuropilin Vascular endothelial growth factor Cancer Tumor Biomarker Angiogenesis Lymphangiogenesis Semaphorin Metastasis Progression 


  1. 1.
    Satoda M, et al. Differential expression of two cell surface proteins, neuropilin and plexin, in Xenopus olfactory axon subclasses. J Neurosci. 1995;15(1 Pt 2):942–55.PubMedGoogle Scholar
  2. 2.
    Neufeld G, et al. The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc Med. 2002;12(1):13–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Bismuth G, Boumsell L. Controlling the immune system through semaphorins. Sci STKE. 2002;2002(128):RE4.PubMedCrossRefGoogle Scholar
  4. 4.
    Bielenberg DR, et al. Neuropilins in neoplasms: expression, regulation, and function. Exp Cell Res. 2006;312(5):584–93.PubMedCrossRefGoogle Scholar
  5. 5.
    Wild JR, et al. Neuropilins: expression and roles in the epithelium. Int J Exp Pathol. 2012;93(2):81–103.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Migliozzi MT, Mucka P, Bielenberg DR. Lymphangiogenesis and metastasis-A closer look at the neuropilin/semaphorin3 axis. Microvasc Res. 2014;96C:68–76.CrossRefGoogle Scholar
  7. 7.
    Rossignol M, et al. Human neuropilin-1 and neuropilin-2 map to 10p12 and 2q34, respectively. Genomics. 1999;57(3):459–60.PubMedCrossRefGoogle Scholar
  8. 8.
    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.PubMedCrossRefGoogle Scholar
  9. 9.
    Klagsbrun M, Takashima S, Mamluk R. The role of neuropilin in vascular and tumor biology. Adv Exp Med Biol. 2002;515:33–48.PubMedCrossRefGoogle Scholar
  10. 10.
    Pellet-Many C, et al. Neuropilins: structure, function and role in disease. Biochem J. 2008;411(2):211–26.PubMedCrossRefGoogle Scholar
  11. 11.
    Roth L, et al. Transmembrane domain interactions control biological functions of neuropilin-1. Mol Biol Cell. 2008;19(2):646–54.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Barton R, et al. Cysteines in the neuropilin-2 MAM domain modulate receptor homooligomerization and signal transduction. Biopolymers. 2015;104(4):371–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Appleton BA, et al. Structural studies of neuropilin/antibody complexes provide insights into semaphorin and VEGF binding. EMBO J. 2007;26(23):4902–12.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Geretti E, et al. 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.PubMedCrossRefGoogle Scholar
  15. 15.
    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. 2002;277(20):18069–76.PubMedCrossRefGoogle Scholar
  16. 16.
    Mamluk R, et al. 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.PubMedCrossRefGoogle Scholar
  17. 17.
    Karpanen T, et al. Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J. 2006;20(9):1462–72.PubMedCrossRefGoogle Scholar
  18. 18.
    Sulpice E, et al. Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity. Blood. 2008;111(4):2036–45.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Tao Q, Spring SC, Terman BI. Characterization of a new alternatively spliced neuropilin-1 isoform. Angiogenesis. 2003;6(1):39–45.PubMedCrossRefGoogle Scholar
  21. 21.
    Chen H, 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(3):547–59.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedGoogle Scholar
  23. 23.
    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.PubMedCrossRefGoogle Scholar
  24. 24.
    Prahst C, et al. Neuropilin-1-VEGFR-2 complexing requires the PDZ-binding domain of neuropilin-1. J Biol Chem. 2008;283(37):25110–4.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Gagnon ML, et al. Identification of a natural soluble neuropilin-1 that binds vascular endothelial growth factor: In vivo expression and antitumor activity. Proc Natl Acad Sci U S A. 2000;97(6):2573–8.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Cackowski FC, et al. Identification of two novel alternatively spliced Neuropilin-1 isoforms. Genomics. 2004;84(1):82–94.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Panigrahy D, Adini I, Mamluk R, Levonyak N, Bruns CJ, D'Amore P, Klagsbrun M, Bielenberg DR. Regulation of soluble Neuropilin 1, an endogenous angiogenesis inhibitor, in liver development and regeneration. Pathology. 2014;46:416–23.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Berge M, et al. Neuropilin-1 is upregulated in hepatocellular carcinoma and contributes to tumour growth and vascular remodelling. J Hepatol. 2011;55(4):866–75.PubMedCrossRefGoogle Scholar
  29. 29.
    Mamluk R, et al. Soluble neuropilin targeted to the skin inhibits vascular permeability. Angiogenesis. 2005;8(3):217–27.PubMedCrossRefGoogle Scholar
  30. 30.
    Parker MW, et al. Structural basis for VEGF-C binding to neuropilin-2 and sequestration by a soluble splice form. Structure. 2015;23(4):677–87.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Geretti E, et al. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Hong TM, et al. Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res. 2007;13(16):4759–68.PubMedCrossRefGoogle Scholar
  33. 33.
    He Z, Tessier-Lavigne M. Neuropilin is a receptor for the axonal chemorepellent Semaphorin III. Cell. 1997;90(4):739–51.PubMedCrossRefGoogle Scholar
  34. 34.
    Kolodkin AL, et al. Neuropilin is a semaphorin III receptor. Cell. 1997;90(4):753–62.PubMedCrossRefGoogle Scholar
  35. 35.
    Soker S, et al. 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.PubMedCrossRefGoogle Scholar
  36. 36.
    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.PubMedCrossRefGoogle Scholar
  37. 37.
    Guo HF, Vander Kooi CW. Neuropilin functions as an essential cell surface receptor. J Biol Chem. 2015;290(49):29120–6.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Raimondi C, Ruhrberg C. Neuropilin signalling in vessels, neurons and tumours. Semin Cell Dev Biol. 2013;24(3):172–8.PubMedCrossRefGoogle Scholar
  39. 39.
    Zachary IC. How neuropilin-1 regulates receptor tyrosine kinase signalling: the knowns and known unknowns. Biochem Soc Trans. 2011;39(6):1583–91.PubMedCrossRefGoogle Scholar
  40. 40.
    Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev. 1997;18(1):4–25.PubMedCrossRefGoogle Scholar
  41. 41.
    Dvorak HF. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol. 2002;20(21):4368–80.PubMedCrossRefGoogle Scholar
  42. 42.
    Soker S, et al. 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.PubMedCrossRefGoogle Scholar
  43. 43.
    Shraga-Heled N, et al. Neuropilin-1 and neuropilin-2 enhance VEGF121 stimulated signal transduction by the VEGFR-2 receptor. FASEB J. 2007;21(3):915–26.PubMedCrossRefGoogle Scholar
  44. 44.
    Nowak DG, et al. Expression of pro- and anti-angiogenic isoforms of VEGF is differentially regulated by splicing and growth factors. J Cell Sci. 2008;121(Pt 20):3487–95.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Soker S, et al. VEGF165 mediates formation of complexes containing VEGFR-2 and neuropilin-1 that enhance VEGF165-receptor binding. J Cell Biochem. 2002;85(2):357–68.PubMedCrossRefGoogle Scholar
  46. 46.
    Lee CC, et al. Crystal structure of the human neuropilin-1 b1 domain. Structure. 2003;11(1):99–108.PubMedCrossRefGoogle Scholar
  47. 47.
    Vander Kooi CW, et al. Structural basis for ligand and heparin binding to neuropilin B domains. Proc Natl Acad Sci U S A. 2007;104(15):6152–7.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Cebe Suarez S, et al. A VEGF-A splice variant defective for heparan sulfate and neuropilin-1 binding shows attenuated signaling through VEGFR-2. Cell Mol Life Sci. 2006;63(17):2067–77.PubMedCrossRefGoogle Scholar
  49. 49.
    Parker MW, et al. Structural basis for selective vascular endothelial growth factor-A (VEGF-A) binding to neuropilin-1. J Biol Chem. 2012;287(14):11082–9.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    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.PubMedGoogle Scholar
  51. 51.
    Gluzman-Poltorak Z, et al. Vascular endothelial growth factor receptor-1 and neuropilin-2 form complexes. J Biol Chem. 2001;276(22):18688–94.PubMedCrossRefGoogle Scholar
  52. 52.
    Migdal M, et al. Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem. 1998;273(35):22272–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Makinen T, et al. Differential binding of vascular endothelial growth factor B splice and proteolytic isoforms to neuropilin-1. J Biol Chem. 1999;274(30):21217–22.PubMedCrossRefGoogle Scholar
  54. 54.
    Yang X, et al. Vascular endothelial growth factor-dependent spatiotemporal dual roles of placental growth factor in modulation of angiogenesis and tumor growth. Proc Natl Acad Sci U S A. 2013;110(34):13932–7.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Favier B, et al. Neuropilin-2 interacts with VEGFR-2 and VEGFR-3 and promotes human endothelial cell survival and migration. Blood. 2006;108(4):1243–50.PubMedCrossRefGoogle Scholar
  56. 56.
    Xu Y, et al. Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J Cell Biol. 2010;188(1):115–30.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Murray-Rust J, et al. Topological similarities in TGF-beta 2, PDGF-BB and NGF define a superfamily of polypeptide growth factors. Structure. 1993;1(2):153–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Ball SG, et al. Neuropilin-1 regulates platelet-derived growth factor receptor signalling in mesenchymal stem cells. Biochem J. 2010;427(1):29–40.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Pellet-Many C, et al. Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas. Biochem J. 2011;435(3):609–18.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Glinka Y, et al. 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.PubMedCrossRefGoogle Scholar
  61. 61.
    Wittmann P, et al. Neuropilin-2 induced by transforming growth factor-beta augments migration of hepatocellular carcinoma cells. BMC Cancer. 2015;15:909.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    West DC, 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. 2005;280(14):13457–64.PubMedCrossRefGoogle Scholar
  63. 63.
    Mizuno K, Nakamura T. Molecular characteristics of HGF and the gene, and its biochemical aspects. EXS. 1993;65:1–29.PubMedGoogle Scholar
  64. 64.
    Zhou H, et al. The solution structure of the N-terminal domain of hepatocyte growth factor reveals a potential heparin-binding site. Structure. 1998;6(1):109–16.PubMedCrossRefGoogle Scholar
  65. 65.
    Matsumoto K, Nakamura T. Hepatocyte growth factor: molecular structure and implications for a central role in liver regeneration. J Gastroenterol Hepatol. 1991;6(5):509–19.PubMedCrossRefGoogle Scholar
  66. 66.
    Kajiya K, et al. Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J. 2005;24(16):2885–95.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Silvagno F, et al. In vivo activation of met tyrosine kinase by heterodimeric hepatocyte growth factor molecule promotes angiogenesis. Arterioscler Thromb Vasc Biol. 1995;15(11):1857–65.PubMedCrossRefGoogle Scholar
  68. 68.
    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.PubMedCrossRefGoogle Scholar
  69. 69.
    Eickholt BJ. Functional diversity and mechanisms of action of the semaphorins. Development. 2008;135(16):2689–94.PubMedCrossRefGoogle Scholar
  70. 70.
    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.PubMedCrossRefGoogle Scholar
  71. 71.
    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.PubMedCrossRefGoogle Scholar
  72. 72.
    Klagsbrun M, Shimizu A. Semaphorin 3E, an exception to the rule. J Clin Invest. 2010;120(8):2658–60.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Casazza A, et al. Sema3E-Plexin D1 signaling drives human cancer cell invasiveness and metastatic spreading in mice. J Clin Invest. 2010;120(8):2684–98.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Taniguchi M, et al. Identification and characterization of a novel member of murine semaphorin family. Genes Cells. 2005;10(8):785–92.PubMedCrossRefGoogle Scholar
  75. 75.
    Gaur P, et al. Role of class 3 semaphorins and their receptors in tumor growth and angiogenesis. Clin Cancer Res. 2009;15(22):6763–70.PubMedCrossRefGoogle Scholar
  76. 76.
    Chedotal A, et al. Semaphorins III and IV repel hippocampal axons via two distinct receptors. Development. 1998;125(21):4313–23.PubMedGoogle Scholar
  77. 77.
    Adams RH, et al. The chemorepulsive activity of secreted semaphorins is regulated by furin-dependent proteolytic processing. EMBO J. 1997;16(20):6077–86.PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Koppel AM, Raper JA. Collapsin-1 covalently dimerizes, and dimerization is necessary for collapsing activity. J Biol Chem. 1998;273(25):15708–13.PubMedCrossRefGoogle Scholar
  79. 79.
    Kutschera S, et al. Differential endothelial transcriptomics identifies semaphorin 3G as a vascular class 3 semaphorin. Arterioscler Thromb Vasc Biol. 2011;31(1):151–9.PubMedCrossRefGoogle Scholar
  80. 80.
    Varshavsky A, et al. Semaphorin-3B is an angiogenesis inhibitor that is inactivated by furin-like pro-protein convertases. Cancer Res. 2008;68(17):6922–31.PubMedCrossRefGoogle Scholar
  81. 81.
    Mumblat Y, et al. Full-Length Semaphorin-3C Is an Inhibitor of Tumor Lymphangiogenesis and Metastasis. Cancer Res. 2015;75(11):2177–86.PubMedCrossRefGoogle Scholar
  82. 82.
    Bassi DE, et al. Proprotein convertases: “master switches” in the regulation of tumor growth and progression. Mol Carcinog. 2005;44(3):151–61.PubMedCrossRefGoogle Scholar
  83. 83.
    Christensen CR, 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(6):1238–44.PubMedGoogle Scholar
  84. 84.
    Christensen C, et al. Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res. 2005;65(14):6167–77.PubMedCrossRefGoogle Scholar
  85. 85.
    Chen H, et al. Semaphorin-neuropilin interactions underlying sympathetic axon responses to class III semaphorins. Neuron. 1998;21(6):1283–90.PubMedCrossRefGoogle Scholar
  86. 86.
    Miao HQ, 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(1):233–42.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Parker MW, et al. Furin processing of semaphorin 3F determines its anti-angiogenic activity by regulating direct binding and competition for neuropilin. Biochemistry. 2010;49(19):4068–75.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Guo HF, et al. Mechanistic basis for the potent anti-angiogenic activity of semaphorin 3F. Biochemistry. 2013;52(43):7551–8.PubMedCrossRefGoogle Scholar
  89. 89.
    Pascoe HG, Wang Y, Zhang X. Structural mechanisms of plexin signaling. Prog Biophys Mol Biol. 2015;118(3):161–8.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Cagnoni G, Tamagnone L. Semaphorin receptors meet receptor tyrosine kinases on the way of tumor progression. Oncogene. 2014;33(40):4795–802.PubMedCrossRefGoogle Scholar
  91. 91.
    Wu KY, et al. Local translation of RhoA regulates growth cone collapse. Nature. 2005;436(7053):1020–4.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Shimizu A, et al. ABL2/ARG tyrosine kinase mediates SEMA3F-induced RhoA inactivation and cytoskeleton collapse in human glioma cells. J Biol Chem. 2008;283(40):27230–8.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Wedel J, et al. Chronic allograft rejection: a fresh look. Curr Opin Organ Transplant. 2015;20(1):13–20.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Lumb R, et al. Neuropilins define distinct populations of neural crest cells. Neural Dev. 2014;9:24.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Rushing EC, et al. Neuropilin-2: a novel biomarker for malignant melanoma? Hum Pathol. 2012;43(3):381–9.PubMedCrossRefGoogle Scholar
  96. 96.
    Moyon D, et al. Plasticity of endothelial cells during arterial-venous differentiation in the avian embryo. Development. 2001;128(17):3359–70.PubMedGoogle Scholar
  97. 97.
    Herzog Y, et al. Differential expression of neuropilin-1 and neuropilin-2 in arteries and veins. Mech Dev. 2001;109(1):115–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Yuan L, et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development. 2002;129(20):4797–806.PubMedGoogle Scholar
  99. 99.
    Kitsukawa T, et al. Overexpression of a membrane protein, neuropilin, in chimeric mice causes anomalies in the cardiovascular system, nervous system and limbs. Development. 1995;121(12):4309–18.PubMedGoogle Scholar
  100. 100.
    Kitsukawa T, et al. Neuropilin-semaphorin III/D-mediated chemorepulsive signals play a crucial role in peripheral nerve projection in mice. Neuron. 1997;19(5):995–1005.PubMedCrossRefGoogle Scholar
  101. 101.
    Kawasaki T, et al. A requirement for neuropilin-1 in embryonic vessel formation. Development. 1999;126(21):4895–902.PubMedGoogle Scholar
  102. 102.
    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 U S A. 2002;99(6):3657–62.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Fantin A, et al. 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.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    le Noble F, et al. Flow regulates arterial-venous differentiation in the chick embryo yolk sac. Development. 2004;131(2):361–75.PubMedCrossRefGoogle Scholar
  105. 105.
    Braet F, et al. Liver sinusoidal endothelial cell modulation upon resection and shear stress in vitro. Comp Hepatol. 2004;3(1):7.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Bielenberg DR, et al. Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest. 2004;114(9):1260–71.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Pan Q, et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell. 2007;11(1):53–67.PubMedCrossRefGoogle Scholar
  108. 108.
    Caunt M, et al. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell. 2008;13(4):331–42.PubMedCrossRefGoogle Scholar
  109. 109.
    Mucka P, et al. Inflammation and lymphedema are exacerbated and prolonged by neuropilin 2 deficiency. Am J Pathol. 2016;186(11):2803–12.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Bielenberg DR, et al. Increased smooth muscle contractility in mice deficient for neuropilin 2. Am J Pathol. 2012;181(2):548–59.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Shahrabi-Farahani S, et al. Neuropilin 1 expression correlates with differentiation status of epidermal cells and cutaneous squamous cell carcinomas. Lab Investig. 2014;94(7):752–65.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Kurschat P, et al. Neuron restrictive silencer factor NRSF/REST is a transcriptional repressor of neuropilin-1 and diminishes the ability of semaphorin 3A to inhibit keratinocyte migration. J Biol Chem. 2006;281(5):2721–9.PubMedCrossRefGoogle Scholar
  113. 113.
    Morris JS, et al. Involvement of axonal guidance proteins and their signaling partners in the developing mouse mammary gland. J Cell Physiol. 2006;206(1):16–24.PubMedCrossRefGoogle Scholar
  114. 114.
    Harper SJ, et al. Expression of neuropilin-1 by human glomerular epithelial cells in vitro and in vivo. Clin Sci (Lond). 2001;101(4):439–46.CrossRefGoogle Scholar
  115. 115.
    Wang HB, et al. Neuropilin 1 is an entry factor that promotes EBV infection of nasopharyngeal epithelial cells. Nat Commun. 2015;6:6240.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Aung NY, et al. Specific Neuropilins Expression in Alveolar Macrophages among Tissue-Specific Macrophages. PLoS One. 2016;11(2):e0147358.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Curreli S, et al. Class 3 semaphorins induce F-actin reorganization in human dendritic cells: role in cell migration. J Leukoc Biol. 2016;100(6):1323–34.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Chaudhary B, Elkord E. Novel expression of Neuropilin 1 on human tumor-infiltrating lymphocytes in colorectal cancer liver metastases. Expert Opin Ther Targets. 2015;19(2):147–61.PubMedCrossRefGoogle Scholar
  119. 119.
    Hansen W, et al. Neuropilin 1 deficiency on CD4+Foxp3+ regulatory T cells impairs mouse melanoma growth. J Exp Med. 2012;209(11):2001–16.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Beck B, et al. A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature. 2011;478(7369):399–403.PubMedCrossRefGoogle Scholar
  121. 121.
    Shahrabi-Farahani S, et al. Neuropilin 1 receptor is up-regulated in dysplastic epithelium and oral squamous cell carcinoma. Am J Pathol. 2016;186(4):1055–64.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Bachelder RE, et al. Vascular endothelial growth factor is an autocrine survival factor for neuropilin-expressing breast carcinoma cells. Cancer Res. 2001;61(15):5736–40.PubMedGoogle Scholar
  123. 123.
    Parikh AA, et al. Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis. Am J Pathol. 2004;164(6):2139–51.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Akagi M, et al. Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells. Br J Cancer. 2003;88(5):796–802.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Okon IS, et al. Aberrant NRP-1 expression serves as predicator of metastatic endometrial and lung cancers. Oncotarget. 2016;7(7):7970–8.PubMedCrossRefGoogle Scholar
  126. 126.
    Baba T, et al. Neuropilin-1 promotes unlimited growth of ovarian cancer by evading contact inhibition. Gynecol Oncol. 2007;105(3):703–11.PubMedCrossRefGoogle Scholar
  127. 127.
    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. 2006;37(11):1414–25.PubMedCrossRefGoogle Scholar
  128. 128.
    Jiang H, et al. Increased expression of neuropilin 1 is associated with epithelial ovarian carcinoma. Mol Med Rep. 2015;12(2):2114–20.PubMedCrossRefGoogle Scholar
  129. 129.
    Latil A, et al. VEGF overexpression in clinically localized prostate tumors and neuropilin-1 overexpression in metastatic forms. Int J Cancer. 2000;89(2):167–71.PubMedCrossRefGoogle Scholar
  130. 130.
    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. Current Angiogenesis. 2014;3(4):231–44.CrossRefGoogle Scholar
  131. 131.
    Hansel DE, et al. Expression of neuropilin-1 in high-grade dysplasia, invasive cancer, and metastases of the human gastrointestinal tract. Am J Surg Pathol. 2004;28(3):347–56.PubMedCrossRefGoogle Scholar
  132. 132.
    Ben Q, et al. High neuropilin 1 expression was associated with angiogenesis and poor overall survival in resected pancreatic ductal adenocarcinoma. Pancreas. 2014;43(5):744–9.PubMedCrossRefGoogle Scholar
  133. 133.
    Cao Y, et al. Neuropilin-1 upholds dedifferentiation and propagation phenotypes of renal cell carcinoma cells by activating Akt and sonic hedgehog axes. Cancer Res. 2008;68(21):8667–72.PubMedPubMedCentralCrossRefGoogle Scholar
  134. 134.
    Roche J, Drabkin H, Brambilla E. Neuropilin and its ligands in normal lung and cancer. Adv Exp Med Biol. 2002;515:103–14.PubMedCrossRefGoogle Scholar
  135. 135.
    Yang S, et al. Circulating soluble neuropilin-1 in patients with early cervical cancer and cervical intraepithelial neoplasia can be used as a valuable diagnostic biomarker. Dis Markers. 2015;2015:506428.PubMedPubMedCentralGoogle Scholar
  136. 136.
    Kawakami T, et al. Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma. Cancer. 2002;95(10):2196–201.PubMedCrossRefGoogle Scholar
  137. 137.
    Sanchez-Carbayo M, et al. Gene discovery in bladder cancer progression using cDNA microarrays. Am J Pathol. 2003;163(2):505–16.PubMedPubMedCentralCrossRefGoogle Scholar
  138. 138.
    Dallas NA, et al. Neuropilin-2-mediated tumor growth and angiogenesis in pancreatic adenocarcinoma. Clin Cancer Res. 2008;14(24):8052–60.PubMedCrossRefGoogle Scholar
  139. 139.
    Fakhari M, et al. Selective upregulation of vascular endothelial growth factor receptors neuropilin-1 and -2 in human neuroblastoma. Cancer. 2002;94(1):258–63.PubMedCrossRefGoogle Scholar
  140. 140.
    Hayden Gephart MG, et al. Neuropilin-2 contributes to tumorigenicity in a mouse model of Hedgehog pathway medulloblastoma. J Neuro-Oncol. 2013;115(2):161–8.CrossRefGoogle Scholar
  141. 141.
    Handa A, et al. Neuropilin-2 expression affects the increased vascularization and is a prognostic factor in osteosarcoma. Int J Oncol. 2000;17(2):291–5.PubMedGoogle Scholar
  142. 142.
    Guttmann-Raviv N, et al. The neuropilins and their role in tumorigenesis and tumor progression. Cancer Lett. 2006;231(1):1–11.PubMedCrossRefGoogle Scholar
  143. 143.
    Ellis LM. The role of neuropilins in cancer. Mol Cancer Ther. 2006;5(5):1099–107.PubMedCrossRefGoogle Scholar
  144. 144.
    Bielenberg DR, Klagsbrun M. Targeting endothelial and tumor cells with semaphorins. Cancer Metastasis Rev. 2007;26(3–4):421–31.PubMedCrossRefGoogle Scholar
  145. 145.
    Bagri A, Tessier-Lavigne M, Watts RJ. Neuropilins in tumor biology. Clin Cancer Res. 2009;15(6):1860–4.PubMedCrossRefGoogle Scholar
  146. 146.
    Grandclement C, Borg C. Neuropilins: a new target for cancer therapy. Cancers (Basel). 2011;3(2):1899–928.CrossRefGoogle Scholar
  147. 147.
    Prud'homme GJ, Glinka Y. Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity. Oncotarget. 2012;3(9):921–39.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Miao HQ, et al. Neuropilin-1 expression by tumor cells promotes tumor angiogenesis and progression. FASEB J. 2000;14(15):2532–9.PubMedCrossRefGoogle Scholar
  149. 149.
    Kigel B, et al. Successful inhibition of tumor development by specific class-3 semaphorins is associated with expression of appropriate semaphorin receptors by tumor cells. PLoS One. 2008;3(9):e3287.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Ji T, et al. Neuropilin-2 expression is inhibited by secreted Wnt antagonists and its down-regulation is associated with reduced tumor growth and metastasis in osteosarcoma. Mol Cancer. 2015;14:86.PubMedPubMedCentralCrossRefGoogle Scholar
  151. 151.
    Barr MP, et al. Vascular endothelial growth factor is an autocrine growth factor, signaling through neuropilin-1 in non-small cell lung cancer. Mol Cancer. 2015;14:45.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013;13(12):871–82.PubMedPubMedCentralCrossRefGoogle Scholar
  153. 153.
    Yoshida A, et al. 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. -76PubMedPubMedCentralCrossRefGoogle Scholar
  154. 154.
    Grun D, Adhikary G, Eckert RL. VEGF-A acts via neuropilin-1 to enhance epidermal cancer stem cell survival and formation of aggressive and highly vascularized tumors. Oncogene. 2016;35(33):4379–87.PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Snuderl M, et al. Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell. 2013;152(5):1065–76.PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Hu B, et al. Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway. Oncogene. 2007;26(38):5577–86.PubMedPubMedCentralCrossRefGoogle Scholar
  157. 157.
    Matsushita A, Gotze T, Korc M. Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res. 2007;67(21):10309–16.PubMedCrossRefGoogle Scholar
  158. 158.
    Li L, et al. Neuropilin-1 is associated with clinicopathology of gastric cancer and contributes to cell proliferation and migration as multifunctional co-receptors. J Exp Clin Cancer Res. 2016;35:16.PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Merkulova-Rainon T, et al. The N-terminal domain of hepatocyte growth factor inhibits the angiogenic behavior of endothelial cells independently from binding to the c-met receptor. J Biol Chem. 2003;278(39):37400–8.PubMedCrossRefGoogle Scholar
  160. 160.
    Ding M, et al. Expression of VEGFR2 and NRP-1 in non-small cell lung cancer and their clinical significance. Chin J Cancer Res. 2014;26(6):669–77.PubMedPubMedCentralGoogle Scholar
  161. 161.
    Zhao J, et al. Investigation of a novel biomarker, neuropilin-1, and its application for poor prognosis in acute myeloid leukemia patients. Tumour Biol. 2014;35(7):6919–24.PubMedCrossRefGoogle Scholar
  162. 162.
    Zhao P, et al. Label-free quantitative proteomic analysis of benzo(a)pyrene-transformed 16HBE cells serum-free culture supernatant and xenografted nude mice sera. Chem Biol Interact. 2016;245:39–49.PubMedCrossRefGoogle Scholar
  163. 163.
    Moriarty WF, et al. Neuropilin-2 promotes melanoma growth and progression in vivo. Melanoma Res. 2016;26(4):321–8.PubMedCrossRefGoogle Scholar
  164. 164.
    Geretti E, Klagsbrun M. Neuropilins: novel targets for anti-angiogenesis therapies. Cell Adhes Migr. 2007;1(2):56–61.CrossRefGoogle Scholar
  165. 165.
    Geretti E, Shimizu A, Klagsbrun M. Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis. Angiogenesis. 2008;11(1):31–9.PubMedCrossRefGoogle Scholar
  166. 166.
    Chaudhary B, et al. Neuropilin 1: function and therapeutic potential in cancer. Cancer Immunol Immunother. 2014;63(2):81–99.PubMedCrossRefGoogle Scholar
  167. 167.
    Patnaik A, et al. A Phase Ib study evaluating MNRP1685A, a fully human anti-NRP1 monoclonal antibody, in combination with bevacizumab and paclitaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol. 2014;73(5):951–60.PubMedCrossRefGoogle Scholar
  168. 168.
    Maru D, Venook AP, Ellis LM. Predictive biomarkers for bevacizumab: are we there yet? Clin Cancer Res. 2013;19(11):2824–7.PubMedCrossRefGoogle Scholar
  169. 169.
    Benson AB 3rd, et al. BATON-CRC: a phase II randomized trial comparing tivozanib plus mFOLFOX6 with bevacizumab plus mFOLFOX6 in stage IV metastatic colorectal cancer. Clin Cancer Res. 2016;22(20):5058–67.PubMedCrossRefGoogle Scholar
  170. 170.
    Jubb AM, et al. Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer. Clin Cancer Res. 2011;17(2):372–81.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Van Cutsem E, et al. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a biomarker evaluation from the AVAGAST randomized phase III trial. J Clin Oncol. 2012;30(17):2119–27.PubMedCrossRefGoogle Scholar
  172. 172.
    Cetin B, et al. The impact of immunohistochemical staining with ezrin-carbonic anhydrase IX and neuropilin-2 on prognosis in patients with metastatic renal cell cancer receiving tyrosine kinase inhibitors. Tumour Biol. 2015;36(11):8471–8.PubMedCrossRefGoogle Scholar
  173. 173.
    Uronis HE, et al. A phase II study of capecitabine, oxaliplatin, and bevacizumab in the treatment of metastatic esophagogastric adenocarcinomas. Oncologist. 2013;18(3):271–2.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Baumgarten P, et al. Differential expression of vascular endothelial growth factor A, its receptors VEGFR-1, −2, and −3 and co-receptors neuropilin-1 and -2 does not predict bevacizumab response in human astrocytomas. Neuro-Oncology. 2016;18(2):173–83.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2017

Authors and Affiliations

  1. 1.Vascular Biology ProgramBoston Children’s HospitalBostonUSA
  2. 2.Department of SurgeryHarvard Medical School and Vascular Biology Program, Boston Children’s HospitalBostonUSA

Personalised recommendations