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Neuropilin: Handyman and Power Broker in the Tumor Microenvironment

  • Stephan NilandEmail author
  • Johannes A. Eble
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1223)

Abstract

Neuropilin-1 and neuropilin-2 form a small family of transmembrane receptors, which, due to the lack of a cytosolic protein kinase domain, act primarily as co-receptors for various ligands. Performing at the molecular level both the executive and organizing functions of a handyman as well as of a power broker, they are instrumental in controlling the signaling of various receptor tyrosine kinases, integrins, and other molecules involved in the regulation of physiological and pathological angiogenic processes. In this setting, the various neuropilin ligands and interaction partners on various cells of the tumor microenvironment, such as cancer cells, endothelial cells, cancer-associated fibroblasts, and immune cells, are surveyed. The suitability of various neuropilin-targeting substances and the intervention in neuropilin-mediated interactions is considered as a possible building block of tumor therapy.

Keywords

Cancer cell Endothelial cell Neuropilin interacting partners Neuropilin ligands Neuropilin signaling Semaphorin Tumor-penetrating peptides Tumor angiogenesis Tumor microenvironment Tumor stromal cell Vascular endothelial growth factor 

Abbreviations

3′-UTR

3′-Untranslated region

ADAM

A disintegrin and metalloproteinase domain containing protein

ADAMTS

A disintegrin and metalloproteinase with thrombospondin motifs

AGO

Argonaute

AKT

Protein kinase B

ALK

Anaplastic lymphoma kinase

ALK1

Activin receptor-like kinase; serine/threonine-protein kinase receptor R3

ALK5

Activin receptor-like kinase; TGF-β receptor 1

BMP

Bone morphogenetic protein

BRAF

Rat/rapidly accelerated fibrosarcoma, isoform B

CAF

Cancer-associated fibroblasts

CD

Cluster of differentiation

CendR

Carboxy-terminal end rule

CSC

Cancer stem cell

CUB domain

Cubilin homology domain

DDR

Discoidin domain receptor

Dlg domain

Discs large domain

EC

Endothelial cell

ECM

Extracellular matrix

EGF(R)

Epidermal growth factor (receptor)

EMT

Epithelial to mesenchymal transition

EphA2

Erythropoietin-producing human hepatocellular (EPH) receptor A2

ER

Endoplasmic reticulum

ErbB

Erythroblastosis oncogene B

ERK

Extracellular-signal-regulated kinase

FAK

Focal adhesion kinase

FGF(R)

Fibroblast growth factor (receptor)

Frzb

Frizzled-related protein

GAIP

G alpha interacting protein

GAP

GTPase activation protein

gC1qR

Globular head of complement factor C1q binding protein/receptor

GEF

Guanine nucleotide exchange factor

GIPC

GAIP interacting protein, C-terminus

GIPC1

GIPC PDZ domain containing family member 1, synectin

GLI1

Glioma-associated oncogene homolog 1

GLUT1CBP

Glucose transporter 1 C-terminal binding protein

Her2

Human epidermal growth factor receptor 2

HGF(R)

Hepatocyte growth factor (receptor)

HH

Hedgehog

IGF1R

Insulin-like growth factor 1 (IGF-1) receptor

IIP1

Insulin-like growth factor-1 receptor-interacting protein 1

Jnk

c-Jun N-terminal kinase

KRAS

Kirsten rat sarcoma

L1CAM

L1 cell adhesion molecule

LAMC2

Laminin subunit γ2

lncRNA

Long noncoding RNA

LRP5

Low-density lipoprotein receptor related protein 5

MAM domain

Meprin/A5-protein/PTPmu

MAP(K)

Mitogen-activated protein (kinase)

MET

Mesenchymal-epithelial transition factor (MET) proto-oncogene

miR

microRNA

MMP

Matrix metalloproteinase

NIP

Neuropilin-1 interacting protein

NRP

Neuropilin

p130Cas

CRK-associated substrate

PDGF(R)

Platelet-derived growth factor (receptor)

PDZ

Postsynaptic density/discs large/zonula occludens-1

PI3K

Phosphoinositide 3-kinase

PKC

Protein kinase C

PlGF(R)

Placenta growth factor (receptor)

PSD-95 domain

Postsynaptic density protein 95 domain

PTEN

Phosphatase and tensin homolog

PTPmu

Protein tyrosine phosphatase μ

RAS

Rat sarcoma

RhoGEF

Rho guanine nucleotide exchange factor 1

RTK

Receptor-type tyrosine kinase

SAPK1

Stress-activated protein kinase 1

SEMA

Semaphorin

SEMCAP1

Semaphorin 4C (SEMA4C)-interacting protein 1

SMAD

sma(ll) and Daf-4 homolog

sNRP

Soluble neuropilin

Src

Sarcoma

Syx

Synectin-binding GEF

TAM

Tumor-associated macrophage

TEC

Tumor endothelial cell

TFPI1

Tissue factor pathway inhibitor

TGF-β(R)

Transforming growth factor-β (receptor)

TIE

Tyrosine kinase with immunoglobulin-like and EGF-like domains

TIP2

Tax-interacting protein 2

TORC2

Rapamycin-sensitive TOR complex 2

Treg

Regulatory T cell

uPA

Urokinase plasminogen activator

VCAM-1

Vascular adhesion protein-1

VEGF(R)

Vascular endothelial growth factor (receptor)

VM

Vasculogenic mimicry

WIF1

Wnt inhibitory factor 1

Wnt

Wingless-related integration site

YAP1

Yes-associated protein 1

ZO-1 domain

Zonula occludens-1 domain

Notes

Acknowledgment

The author’s scientific work on NRP1 is financially supported by Deutsche Forschungs gemeinschaft (grant: SFB1009 A09).

References

  1. 1.
    Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735–745PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Nakamura F, Goshima Y (2002) Structural and functional relation of neuropilins. Adv Exp Med Biol 515:55–69PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Guo HF, Vander Kooi CW (2015) Neuropilin functions as an essential cell surface receptor. J Biol Chem 290:29120–29126.  https://doi.org/10.1074/jbc.R115.687327CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Niland S, Eble JA (2019) Neuropilins in the context of tumor vasculature. Int J Mol Sci 20.  https://doi.org/10.3390/ijms20030639PubMedCentralCrossRefGoogle Scholar
  5. 5.
    Rossignol M, Beggs AH, Pierce EA, Klagsbrun M (1999) Human neuropilin-1 and neuropilin-2 map to 10p12 and 2q34, respectively. Genomics 57:459–460.  https://doi.org/10.1006/geno.1999.5790CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Takagi S, Hirata T, Agata K, Mochii M, Eguchi G, Fujisawa H (1991) The A5 antigen, a candidate for the neuronal recognition molecule, has homologies to complement components and coagulation factors. Neuron 7:295–307PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Kawakami A, Kitsukawa T, Takagi S, Fujisawa H (1996) Developmentally regulated expression of a cell surface protein, neuropilin, in the mouse nervous system. J Neurobiol 29:1–17.  https://doi.org/10.1002/(SICI)1097-4695(199601)29:1<1::AID-NEU1>3.0.CO;2-FCrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Fujisawa H, Kitsukawa T, Kawakami A, Takagi S, Shimizu M, Hirata T (1997) Roles of a neuronal cell-surface molecule, neuropilin, in nerve fiber fasciculation and guidance. Cell Tissue Res 290:465–470PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Chen H, Chedotal A, He Z, Goodman CS, Tessier-Lavigne M (1997) Neuropilin-2, a novel member of the neuropilin family, is a high affinity receptor for the semaphorins Sema E and Sema IV but not Sema III. Neuron 19:547–559PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Rossignol M, Gagnon ML, Klagsbrun M (2000) Genomic organization of human neuropilin-1 and neuropilin-2 genes: identification and distribution of splice variants and soluble isoforms. Genomics 70:211–222.  https://doi.org/10.1006/geno.2000.6381CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Gagnon ML, Bielenberg DR, Gechtman Z, Miao HQ, Takashima S, Soker S, Klagsbrun M (2000) 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 97:2573–2578.  https://doi.org/10.1073/pnas.040337597CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Yamada Y, Takakura N, Yasue H, Ogawa H, Fujisawa H, Suda T (2001) Exogenous clustered neuropilin 1 enhances vasculogenesis and angiogenesis. Blood 97:1671–1678.  https://doi.org/10.1182/blood.v97.6.1671CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Tao Q, Spring SC, Terman BI (2003) Characterization of a new alternatively spliced neuropilin-1 isoform. Angiogenesis 6:39–45PubMedCrossRefPubMedCentralGoogle Scholar
  14. 14.
    Cackowski FC, Xu L, Hu B, Cheng SY (2004) Identification of two novel alternatively spliced neuropilin-1 isoforms. Genomics 84:82–94.  https://doi.org/10.1016/j.ygeno.2004.02.001CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kiedzierska A, Smietana K, Czepczynska H, Otlewski J (2007) Structural similarities and functional diversity of eukaryotic discoidin-like domains. Biochim Biophys Acta 1774:1069–1078.  https://doi.org/10.1016/j.bbapap.2007.07.007CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lee CC, Kreusch A, McMullan D, Ng K, Spraggon G (2003) Crystal structure of the human neuropilin-1 b1 domain. Structure 11:99–108PubMedCrossRefPubMedCentralGoogle Scholar
  17. 17.
    Shintani Y, Takashima S, Asano Y, Kato H, Liao Y, Yamazaki S, Tsukamoto O, Seguchi O, Yamamoto H, Fukushima T et al (2006) Glycosaminoglycan modification of neuropilin-1 modulates VEGFR2 signaling. EMBO J 25:3045–3055.  https://doi.org/10.1038/sj.emboj.7601188CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Frankel P, Pellet-Many C, Lehtolainen P, D’Abaco GM, Tickner ML, Cheng L, Zachary IC (2008) 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 9:983–989.  https://doi.org/10.1038/embor.2008.151CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Pellet-Many C, Frankel P, Evans IM, Herzog B, Junemann-Ramirez M, Zachary IC (2011) Neuropilin-1 mediates PDGF stimulation of vascular smooth muscle cell migration and signalling via p130Cas. Biochem J 435:609–618.  https://doi.org/10.1042/BJ20100580CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Bhide GP, Fernandes NR, Colley KJ (2016) Sequence requirements for neuropilin-2 recognition by ST8SiaIV and polysialylation of its O-glycans. J Biol Chem 291:9444–9457.  https://doi.org/10.1074/jbc.M116.714329CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Roy S, Bag AK, Singh RK, Talmadge JE, Batra SK, Datta K (2017) Multifaceted role of neuropilins in the immune system: potential targets for immunotherapy. Front Immunol 8:1228.  https://doi.org/10.3389/fimmu.2017.01228CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Curreli S, Arany Z, Gerardy-Schahn R, Mann D, Stamatos NM (2007) Polysialylated neuropilin-2 is expressed on the surface of human dendritic cells and modulates dendritic cell-T lymphocyte interactions. J Biol Chem 282:30346–30356.  https://doi.org/10.1074/jbc.M702965200CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mehta V, Fields L, Evans IM, Yamaji M, Pellet-Many C, Jones T, Mahmoud M, Zachary I (2018) VEGF (vascular endothelial growth factor) induces NRP1 (neuropilin-1) cleavage via ADAMs (a disintegrin and metalloproteinase) 9 and 10 to generate novel carboxy-terminal NRP1 fragments that regulate angiogenic signaling. Arterioscler Thromb Vasc Biol 38:1845–1858.  https://doi.org/10.1161/ATVBAHA.118.311118CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Geretti E, Shimizu A, Klagsbrun M (2008) Neuropilin structure governs VEGF and semaphorin binding and regulates angiogenesis. Angiogenesis 11:31–39.  https://doi.org/10.1007/s10456-008-9097-1CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Roth L, Nasarre C, Dirrig-Grosch S, Aunis D, Cremel G, Hubert P, Bagnard D (2008) Transmembrane domain interactions control biological functions of neuropilin-1. Mol Biol Cell 19:646–654.  https://doi.org/10.1091/mbc.e07-06-0625CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Aci-Seche S, Sawma P, Hubert P, Sturgis JN, Bagnard D, Jacob L, Genest M, Garnier N (2014) Transmembrane recognition of the semaphorin co-receptors neuropilin 1 and plexin A1: coarse-grained simulations. PLoS One 9:e97779.  https://doi.org/10.1371/journal.pone.0097779CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Herzog B, Pellet-Many C, Britton G, Hartzoulakis B, Zachary IC (2011) 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 22:2766–2776.  https://doi.org/10.1091/mbc.E09-12-1061CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Ellis LM (2006) The role of neuropilins in cancer. Mol Cancer Ther 5:1099–1107.  https://doi.org/10.1158/1535-7163.MCT-05-0538CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Guttmann-Raviv N, Shraga-Heled N, Varshavsky A, Guimaraes-Sternberg C, Kessler O, Neufeld G (2007) Semaphorin-3A and semaphorin-3F work together to repel endothelial cells and to inhibit their survival by induction of apoptosis. J Biol Chem 282:26294–26305.  https://doi.org/10.1074/jbc.M609711200CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Giger RJ, Urquhart ER, Gillespie SK, Levengood DV, Ginty DD, Kolodkin AL (1998) Neuropilin-2 is a receptor for semaphorin IV: insight into the structural basis of receptor function and specificity. Neuron 21:1079–1092PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Gu C, Yoshida Y, Livet J, Reimert DV, Mann F, Merte J, Henderson CE, Jessell TM, Kolodkin AL, Ginty DD (2005) Semaphorin 3E and plexin-D1 control vascular pattern independently of neuropilins. Science 307:265–268.  https://doi.org/10.1126/science.1105416CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Chauvet S, Cohen S, Yoshida Y, Fekrane L, Livet J, Gayet O, Segu L, Buhot MC, Jessell TM, Henderson CE et al (2007) Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development. Neuron 56:807–822.  https://doi.org/10.1016/j.neuron.2007.10.019CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Mota F, Fotinou C, Rana RR, Chan AWE, Yelland T, Arooz MT, O’Leary AP, Hutton J, Frankel P, Zachary I et al (2018) Architecture and hydration of the arginine-binding site of neuropilin-1. FEBS J 285:1290–1304.  https://doi.org/10.1111/febs.14405CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Peng K, Bai Y, Zhu Q, Hu B, Xu Y (2019) Targeting VEGF-neuropilin interactions: a promising antitumor strategy. Drug Discov Today 24:656–664.  https://doi.org/10.1016/j.drudis.2018.10.004CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Peach CJ, Mignone VW, Arruda MA, Alcobia DC, Hill SJ, Kilpatrick LE, Woolard J (2018) Molecular pharmacology of VEGF-A isoforms: binding and signalling at VEGFR2. Int J Mol Sci 19.  https://doi.org/10.3390/ijms19041264PubMedCentralCrossRefGoogle Scholar
  36. 36.
    Robinson CJ, Stringer SE (2001) The splice variants of vascular endothelial growth factor (VEGF) and their receptors. J Cell Sci 114:853–865. PMID: WOS:000167569000004PubMedPubMedCentralGoogle Scholar
  37. 37.
    Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676.  https://doi.org/10.1038/nm0603-669CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Klagsbrun M, Takashima S, Mamluk R (2002) The role of neuropilin in vascular and tumor biology. Adv Exp Med Biol 515:33–48PubMedCrossRefPubMedCentralGoogle Scholar
  39. 39.
    Neufeld G, Cohen T, Shraga N, Lange T, Kessler O, Herzog Y (2002) The neuropilins: multifunctional semaphorin and VEGF receptors that modulate axon guidance and angiogenesis. Trends Cardiovasc Med 12:13–19PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Pan Q, Chanthery Y, Liang WC, Stawicki S, Mak J, Rathore N, Tong RK, Kowalski J, Yee SF, Pacheco G et al (2007) Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11:53–67.  https://doi.org/10.1016/j.ccr.2006.10.018CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Sarabipour S, Mac Gabhann F (2018) VEGF-A121a binding to neuropilins—a concept revisited. Cell Adhes Migr 12:204–214.  https://doi.org/10.1080/19336918.2017.1372878CrossRefGoogle Scholar
  42. 42.
    Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G (2000) Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected]. J Biol Chem 275:18040–18045.  https://doi.org/10.1074/jbc.M909259199CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Muller YA, Li B, Christinger HW, Wells JA, Cunningham BC, de Vos AM (1997) Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding site. Proc Natl Acad Sci U S A 94:7192–7197.  https://doi.org/10.1073/pnas.94.14.7192CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Simons M, Gordon E, Claesson-Welsh L (2016) Mechanisms and regulation of endothelial VEGF receptor signalling. Nat Rev Mol Cell Biol 17:611–625.  https://doi.org/10.1038/nrm.2016.87CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Baek DS, Kim JH, Kim YJ, Kim YS (2018) Immunoglobulin Fc-fused peptide without C-terminal Arg or Lys residue augments neuropilin-1-dependent tumor vascular permeability. Mol Pharm 15:394–402.  https://doi.org/10.1021/acs.molpharmaceut.7b00761CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Teesalu T, Sugahara KN, Kotamraju VR, Ruoslahti E (2009) C-end rule peptides mediate neuropilin-1-dependent cell, vascular, and tissue penetration. Proc Natl Acad Sci U S A 106:16157–16162.  https://doi.org/10.1073/pnas.0908201106CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Djordjevic S, Driscoll PC (2013) Targeting VEGF signalling via the neuropilin co-receptor. Drug Discov Today 18:447–455.  https://doi.org/10.1016/j.drudis.2012.11.013CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Koch S, Tugues S, Li X, Gualandi L, Claesson-Welsh L (2011) Signal transduction by vascular endothelial growth factor receptors. Biochem J 437:169–183.  https://doi.org/10.1042/BJ20110301CrossRefGoogle Scholar
  49. 49.
    Pan Q, Chathery Y, Wu Y, Rathore N, Tong RK, Peale F, Bagri A, Tessier-Lavigne M, Koch AW, Watts RJ (2007) Neuropilin-1 binds to VEGF121 and regulates endothelial cell migration and sprouting. J Biol Chem 282:24049–24056.  https://doi.org/10.1074/jbc.M703554200CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Wang J, Huang Y, Zhang J, Xing B, Xuan W, Wang H, Huang H, Yang J, Tang J (2018) NRP-2 in tumor lymphangiogenesis and lymphatic metastasis. Cancer Lett 418:176–184.  https://doi.org/10.1016/j.canlet.2018.01.040CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Lala PK, Nandi P, Majumder M (2018) Roles of prostaglandins in tumor-associated lymphangiogenesis with special reference to breast cancer. Cancer Metastasis Rev 37:369–384.  https://doi.org/10.1007/s10555-018-9734-0CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Migdal M, Huppertz B, Tessler S, Comforti A, Shibuya M, Reich R, Baumann H, Neufeld G (1998) Neuropilin-1 is a placenta growth factor-2 receptor. J Biol Chem 273:22272–22278.  https://doi.org/10.1074/jbc.273.35.22272CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Mamluk R, Gechtman Z, Kutcher ME, Gasiunas N, Gallagher J, Klagsbrun M (2002) Neuropilin-1 binds vascular endothelial growth factor 165, placenta growth factor-2, and heparin via its b1b2 domain. J Biol Chem 277:24818–24825.  https://doi.org/10.1074/jbc.M200730200CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Matsushita A, Gotze T, Korc M (2007) Hepatocyte growth factor-mediated cell invasion in pancreatic cancer cells is dependent on neuropilin-1. Cancer Res 67:10309–10316.  https://doi.org/10.1158/0008-5472.CAN-07-3256CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Sulpice E, Plouet J, Berge M, Allanic D, Tobelem G, Merkulova-Rainon T (2008) Neuropilin-1 and neuropilin-2 act as coreceptors, potentiating proangiogenic activity. Blood 111:2036–2045.  https://doi.org/10.1182/blood-2007-04-084269CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    West DC, Rees CG, Duchesne L, Patey SJ, Terry CJ, Turnbull JE, Delehedde M, Heegaard CW, Allain F, Vanpouille C et al (2005) Interactions of multiple heparin binding growth factors with neuropilin-1 and potentiation of the activity of fibroblast growth factor-2. J Biol Chem 280:13457–13464.  https://doi.org/10.1074/jbc.M410924200CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Ceccarelli S, Nodale C, Vescarelli E, Pontecorvi P, Manganelli V, Casella G, Onesti MG, Sorice M, Romano F, Angeloni A et al (2018) Neuropilin 1 mediates keratinocyte growth factor signaling in adipose-derived stem cells: potential involvement in adipogenesis. Stem Cells Int 2018:1075156.  https://doi.org/10.1155/2018/1075156CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Ruffini F, Levati L, Graziani G, Caporali S, Atzori MG, D’Atri S, Lacal PM (2017) Platelet-derived growth factor-C promotes human melanoma aggressiveness through activation of neuropilin-1. Oncotarget 8:66833–66848.  https://doi.org/10.18632/oncotarget.18706CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Ohsaka A, Hirota-Komatsu S, Araki M, Komatsu N (2015) Platelet-derived growth factor receptors form complexes with neuropilin-1 during megakaryocytic differentiation of thrombopoietin-dependent UT-7/TPO cells. Biochem Biophys Res Commun 459:443–449.  https://doi.org/10.1016/j.bbrc.2015.02.124CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Muhl L, Folestad EB, Gladh H, Wang Y, Moessinger C, Jakobsson L, Eriksson U (2017) Neuropilin 1 binds PDGF-D and is a co-receptor in PDGF-D-PDGFRbeta signaling. J Cell Sci 130:1365–1378.  https://doi.org/10.1242/jcs.200493CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Glinka Y, Prud’homme GJ (2008) Neuropilin-1 is a receptor for transforming growth factor beta-1, activates its latent form, and promotes regulatory T cell activity. J Leukoc Biol 84:302–310.  https://doi.org/10.1189/jlb.0208090CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Glinka Y, Stoilova S, Mohammed N, Prud’homme GJ (2011) 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 32:613–621.  https://doi.org/10.1093/carcin/bgq281CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Vivekanandhan S, Mukhopadhyay D (2019) Genetic status of KRAS influences transforming growth factor-beta (TGF-beta) signaling: an insight into neuropilin-1 (NRP1) mediated tumorigenesis. Semin Cancer Biol 54:72–79.  https://doi.org/10.1016/j.semcancer.2018.01.014CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Rizzolio S, Rabinowicz N, Rainero E, Lanzetti L, Serini G, Norman J, Neufeld G, Tamagnone L (2012) Neuropilin-1-dependent regulation of EGF-receptor signaling. Cancer Res 72:5801–5811.  https://doi.org/10.1158/0008-5472.CAN-12-0995CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Kigel B, Rabinowicz N, Varshavsky A, Kessler O, Neufeld G (2011) Plexin-A4 promotes tumor progression and tumor angiogenesis by enhancement of VEGF and bFGF signaling. Blood 118:4285–4296.  https://doi.org/10.1182/blood-2011-03-341388CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Antipenko A, Himanen JP, van Leyen K, Nardi-Dei V, Lesniak J, Barton WA, Rajashankar KR, Lu M, Hoemme C, Puschel AW et al (2003) Structure of the semaphorin-3A receptor binding module. Neuron 39:589–598PubMedCrossRefPubMedCentralGoogle Scholar
  67. 67.
    Alto LT, Terman JR (2017) Semaphorins and their signaling mechanisms. Methods Mol Biol 1493:1–25.  https://doi.org/10.1007/978-1-4939-6448-2_1CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    Gaur P, Bielenberg DR, Samuel S, Bose D, Zhou Y, Gray MJ, Dallas NA, Fan F, Xia L, Lu J et al (2009) Role of class 3 semaphorins and their receptors in tumor growth and angiogenesis. Clin Cancer Res 15:6763–6770.  https://doi.org/10.1158/1078-0432.CCR-09-1810CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Serini G, Bussolino F, Maione F, Giraudo E (2013) Class 3 semaphorins: physiological vascular normalizing agents for anti-cancer therapy. J Intern Med 273:138–155.  https://doi.org/10.1111/joim.12017CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Toledano S, Nir-Zvi I, Engelman R, Kessler O, Neufeld G (2019) Class-3 semaphorins and their receptors: potent multifunctional modulators of tumor progression. Int J Mol Sci 20.  https://doi.org/10.3390/ijms20030556PubMedCentralCrossRefGoogle Scholar
  71. 71.
    Maione F, Molla F, Meda C, Latini R, Zentilin L, Giacca M, Seano G, Serini G, Bussolino F, Giraudo E (2009) Semaphorin 3A is an endogenous angiogenesis inhibitor that blocks tumor growth and normalizes tumor vasculature in transgenic mouse models. J Clin Invest 119:3356–3372.  https://doi.org/10.1172/JCI36308CrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Wong HK, Shimizu A, Kirkpatrick ND, Garkavtsev I, Chan AW, di Tomaso E, Klagsbrun M, Jain RK (2012) Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism. Neoplasia 14:84–94.  https://doi.org/10.1593/neo.111600CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Nasarre P, Gemmill RM, Drabkin HA (2014) The emerging role of class-3 semaphorins and their neuropilin receptors in oncology. Onco Targets Ther 7:1663–1687.  https://doi.org/10.2147/OTT.S37744CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Sawma P, Roth L, Blanchard C, Bagnard D, Cremel G, Bouveret E, Duneau JP, Sturgis JN, Hubert P (2014) Evidence for new homotypic and heterotypic interactions between transmembrane helices of proteins involved in receptor tyrosine kinase and neuropilin signaling. J Mol Biol 426:4099–4111.  https://doi.org/10.1016/j.jmb.2014.10.007CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Liang WC, Dennis MS, Stawicki S, Chanthery Y, Pan Q, Chen Y, Eigenbrot C, Yin J, Koch AW, Wu X et al (2007) Function blocking antibodies to neuropilin-1 generated from a designed human synthetic antibody phage library. J Mol Biol 366:815–829.  https://doi.org/10.1016/j.jmb.2006.11.021CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Barton WA, Himanen JP, Antipenko A, Nikolov DB (2004) Structures of axon guidance molecules and their neuronal receptors. Adv Protein Chem 68:65–106.  https://doi.org/10.1016/S0065-3233(04)68003-XCrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Neufeld G, Kessler O (2008) The semaphorins: versatile regulators of tumour progression and tumour angiogenesis. Nat Rev Cancer 8:632–645.  https://doi.org/10.1038/nrc2404CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Valdembri D, Caswell PT, Anderson KI, Schwarz JP, Konig I, Astanina E, Caccavari F, Norman JC, Humphries MJ, Bussolino F et al (2009) Neuropilin-1/GIPC1 signaling regulates alpha5beta1 integrin traffic and function in endothelial cells. PLoS Biol 7:e25.  https://doi.org/10.1371/journal.pbio.1000025CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Perrot-Applanat M, Di Benedetto M (2012) Autocrine functions of VEGF in breast tumor cells: adhesion, survival, migration and invasion. Cell Adhes Migr 6:547–553.  https://doi.org/10.4161/cam.23332CrossRefGoogle Scholar
  80. 80.
    Yaqoob U, Cao S, Shergill U, Jagavelu K, Geng Z, Yin M, de Assuncao TM, Cao Y, Szabolcs A, Thorgeirsson S et al (2012) Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment. Cancer Res 72:4047–4059.  https://doi.org/10.1158/0008-5472.CAN-11-3907CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Goel HL, Pursell B, Chang C, Shaw LM, Mao J, Simin K, Kumar P, Vander Kooi CW, Shultz LD, Greiner DL et al (2013) GLI1 regulates a novel neuropilin-2/alpha6beta1 integrin based autocrine pathway that contributes to breast cancer initiation. EMBO Mol Med 5:488–508.  https://doi.org/10.1002/emmm.201202078CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Campbell ID, Humphries MJ (2011) Integrin structure, activation, and interactions. Cold Spring Harb Perspect Biol 3.  https://doi.org/10.1101/cshperspect.a004994PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Luo BH, Carman CV, Springer TA (2007) Structural basis of integrin regulation and signaling. Annu Rev Immunol 25:619–647.  https://doi.org/10.1146/annurev.immunol.25.022106.141618CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Humphries JD, Byron A, Humphries MJ (2006) Integrin ligands at a glance. J Cell Sci 119:3901–3903.  https://doi.org/10.1242/jcs.03098CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Hynes RO (2009) The extracellular matrix: not just pretty fibrils. Science 326:1216–1219.  https://doi.org/10.1126/science.1176009CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Singh B, Fleury C, Jalalvand F, Riesbeck K (2012) Human pathogens utilize host extracellular matrix proteins laminin and collagen for adhesion and invasion of the host. FEMS Microbiol Rev 36:1122–1180.  https://doi.org/10.1111/j.1574-6976.2012.00340.xCrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Humphries JD, Chastney MR, Askari JA, Humphries MJ (2019) Signal transduction via integrin adhesion complexes. Curr Opin Cell Biol 56:14–21.  https://doi.org/10.1016/j.ceb.2018.08.004CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Horton ER, Humphries JD, James J, Jones MC, Askari JA, Humphries MJ (2016) The integrin adhesome network at a glance. J Cell Sci 129:4159–4163.  https://doi.org/10.1242/jcs.192054CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Kanchanawong P, Waterman CM (2012) Advances in light-based imaging of three-dimensional cellular ultrastructure. Curr Opin Cell Biol 24:125–133.  https://doi.org/10.1016/j.ceb.2011.11.010CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Kanchanawong P, Shtengel G, Pasapera AM, Ramko EB, Davidson MW, Hess HF, Waterman CM (2010) Nanoscale architecture of integrin-based cell adhesions. Nature 468:580–584.  https://doi.org/10.1038/nature09621CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Goel HL, Mercurio AM (2012) Enhancing integrin function by VEGF/neuropilin signaling: implications for tumor biology. Cell Adhes Migr 6:554–560.  https://doi.org/10.4161/cam.22419CrossRefGoogle Scholar
  92. 92.
    Ou JJ, Wei X, Peng Y, Zha L, Zhou RB, Shi H, Zhou Q, Liang HJ (2015) Neuropilin-2 mediates lymphangiogenesis of colorectal carcinoma via a VEGFC/VEGFR3 independent signaling. Cancer Lett 358:200–209.  https://doi.org/10.1016/j.canlet.2014.12.046CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Cao Y, Hoeppner LH, Bach SEG, Guo Y, Wang E, Wu J, Cowley MJ, Chang DK, Waddell N et al (2013) Neuropilin-2 promotes extravasation and metastasis by interacting with endothelial alpha5 integrin. Cancer Res 73:4579–4590.  https://doi.org/10.1158/0008-5472.CAN-13-0529CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Pan H, Wanami LS, Dissanayake TR, Bachelder RE (2009) Autocrine semaphorin3A stimulates alpha2 beta1 integrin expression/function in breast tumor cells. Breast Cancer Res Treat 118:197–205.  https://doi.org/10.1007/s10549-008-0179-yCrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Naik A, Al-Yahyaee A, Abdullah N, Sam JE, Al-Zeheimi N, Yaish MW, Adham SA (2018) Neuropilin-1 promotes the oncogenic tenascin-C/integrin beta3 pathway and modulates chemoresistance in breast cancer cells. BMC Cancer 18:533.  https://doi.org/10.1186/s12885-018-4446-yCrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Ellison TS, Atkinson SJ, Steri V, Kirkup BM, Preedy ME, Johnson RT, Ruhrberg C, Edwards DR, Schneider JG, Weilbaecher K et al (2015) Suppression of beta3-integrin in mice triggers a neuropilin-1-dependent change in focal adhesion remodelling that can be targeted to block pathological angiogenesis. Dis Model Mech 8:1105–1119.  https://doi.org/10.1242/dmm.019927CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Robinson SD, Reynolds LE, Kostourou V, Reynolds AR, da Silva RG, Tavora B, Baker M, Marshall JF, Hodivala-Dilke KM (2009) Alphav beta3 integrin limits the contribution of neuropilin-1 to vascular endothelial growth factor-induced angiogenesis. J Biol Chem 284:33966–33981.  https://doi.org/10.1074/jbc.M109.030700CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Castellani V (2002) The function of neuropilin/L1 complex. Adv Exp Med Biol 515:91–102PubMedCrossRefPubMedCentralGoogle Scholar
  99. 99.
    Castellani V, Falk J, Rougon G (2004) Semaphorin3A-induced receptor endocytosis during axon guidance responses is mediated by L1 CAM. Mol Cell Neurosci 26:89–100.  https://doi.org/10.1016/j.mcn.2004.01.010CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Bechara A, Nawabi H, Moret F, Yaron A, Weaver E, Bozon M, Abouzid K, Guan JL, Tessier-Lavigne M, Lemmon V et al (2008) FAK-MAPK-dependent adhesion disassembly downstream of L1 contributes to semaphorin3A-induced collapse. EMBO J 27:1549–1562.  https://doi.org/10.1038/emboj.2008.86CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Dallatomasina A, Gasparri AM, Colombo B, Sacchi A, Bianco M, Daniele T, Esposito A, Pastorino F, Ponzoni M, Marcucci F et al (2019) Spatiotemporal regulation of tumor angiogenesis by circulating chromogranin a cleavage and neuropilin-1 engagement. Cancer Res 79:1925–1937.  https://doi.org/10.1158/0008-5472.CAN-18-0289CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Ben-Zvi A, Ben-Gigi L, Klein H, Behar O (2007) Modulation of semaphorin3A activity by p75 neurotrophin receptor influences peripheral axon patterning. J Neurosci 27:13000–13011.  https://doi.org/10.1523/JNEUROSCI.3373-07.2007CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Park JE, Keller GA, Ferrara N (1993) The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell 4:1317–1326.  https://doi.org/10.1091/mbc.4.12.1317CrossRefPubMedPubMedCentralGoogle Scholar
  104. 104.
    Jonca F, Ortega N, Gleizes PE, Bertrand N, Plouet J (1997) Cell release of bioactive fibroblast growth factor 2 by exon 6-encoded sequence of vascular endothelial growth factor. J Biol Chem 272:24203–24209.  https://doi.org/10.1074/jbc.272.39.24203CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Stringer SE (2006) The role of heparan sulphate proteoglycans in angiogenesis. Biochem Soc Trans 34:451–453.  https://doi.org/10.1042/BST0340451CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Koch S, Claesson-Welsh L (2012) Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb Perspect Med 2:a006502.  https://doi.org/10.1101/cshperspect.a006502CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Vempati P, Popel AS, Mac Gabhann F (2014) Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning. Cytokine Growth Factor Rev 25:1–19.  https://doi.org/10.1016/j.cytogfr.2013.11.002CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Niland S, Ditkowski B, Parrandier D, Roth L, Augustin H, Eble JA (2013) Rhodocetin-alphabeta-induced neuropilin-1-cMet association triggers restructuring of matrix contacts in endothelial cells. Arterioscler Thromb Vasc Biol 33:544–554.  https://doi.org/10.1161/ATVBAHA.112.00006CrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Niland S, Komljenovic D, Macas J, Bracht T, Bauerle T, Liebner S, Eble JA (2018) Rhodocetin-alphabeta selectively breaks the endothelial barrier of the tumor vasculature in HT1080 fibrosarcoma and A431 epidermoid carcinoma tumor models. Oncotarget 9:22406–22422.  https://doi.org/10.18632/oncotarget.25032CrossRefPubMedPubMedCentralGoogle Scholar
  110. 110.
    Rezaei M, Martins Cavaco AC, Seebach J, Niland S, Zimmermann J, Hanschmann EM, Hallmann R, Schillers H, Eble JA (2019) Signals of the neuropilin-1-MET Axis and cues of mechanical force exertion converge to elicit inflammatory activation in coherent endothelial cells. J Immunol 202:1559–1572.  https://doi.org/10.4049/jimmunol.1801346CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Morin E, Sjoberg E, Tjomsland V, Testini C, Lindskog C, Franklin O, Sund M, Ohlund D, Kiflemariam S, Sjoblom T et al (2018) VEGF receptor-2/neuropilin 1 trans-complex formation between endothelial and tumor cells is an independent predictor of pancreatic cancer survival. J Pathol 246:311–322.  https://doi.org/10.1002/path.5141CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Koch S, van Meeteren LA, Morin E, Testini C, Westrom S, Bjorkelund H, Le Jan S, Adler J, Berger P, Claesson-Welsh L (2014) NRP1 presented in trans to the endothelium arrests VEGFR2 endocytosis, preventing angiogenic signaling and tumor initiation. Dev Cell 28:633–646.  https://doi.org/10.1016/j.devcel.2014.02.010CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Campos-Mora M, Morales RA, Gajardo T, Catalan D, Pino-Lagos K (2013) Neuropilin-1 in transplantation tolerance. Front Immunol 4:405.  https://doi.org/10.3389/fimmu.2013.00405CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Delgoffe GM, Woo SR, Turnis ME, Gravano DM, Guy C, Overacre AE, Bettini ML, Vogel P, Finkelstein D, Bonnevier J et al (2013) Stability and function of regulatory T cells is maintained by a neuropilin-1-semaphorin-4A axis. Nature 501:252–256.  https://doi.org/10.1038/nature12428CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Bourbie-Vaudaine S, Blanchard N, Hivroz C, Romeo PH (2006) Dendritic cells can turn CD4+ T lymphocytes into vascular endothelial growth factor-carrying cells by intercellular neuropilin-1 transfer. J Immunol 177:1460–1469.  https://doi.org/10.4049/jimmunol.177.3.1460CrossRefPubMedPubMedCentralGoogle Scholar
  116. 116.
    Goel HL, Chang C, Pursell B, Leav I, Lyle S, Xi HS, Hsieh CC, Adisetiyo H, Roy-Burman P, Coleman IM et al (2012) VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer. Cancer Discov 2:906–921.  https://doi.org/10.1158/2159-8290.CD-12-0085CrossRefPubMedPubMedCentralGoogle Scholar
  117. 117.
    Yoshida A, Shimizu A, Asano H, Kadonosono T, Kondoh SK, Geretti E, Mammoto A, Klagsbrun M, Seo MK (2015) VEGF-A/NRP1 stimulates GIPC1 and Syx complex formation to promote RhoA activation and proliferation in skin cancer cells. Biol Open 4:1063–1076.  https://doi.org/10.1242/bio.010918CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Smith NR, Baker D, James NH, Ratcliffe K, Jenkins M, Ashton SE, Sproat G, Swann R, Gray N, Ryan A et al (2010) Vascular endothelial growth factor receptors VEGFR-2 and VEGFR-3 are localized primarily to the vasculature in human primary solid cancers. Clin Cancer Res 16:3548–3561.  https://doi.org/10.1158/1078-0432.CCR-09-2797CrossRefPubMedPubMedCentralGoogle Scholar
  119. 119.
    Prud’homme GJ, Glinka Y (2012) Neuropilins are multifunctional coreceptors involved in tumor initiation, growth, metastasis and immunity. Oncotarget 3:921–939.  https://doi.org/10.18632/oncotarget.626CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Takahashi T, Fournier A, Nakamura F, Wang LH, Murakami Y, Kalb RG, Fujisawa H, Strittmatter SM (1999) Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors. Cell 99:59–69PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Zhang L, Wang H, Li C, Zhao Y, Wu L, Du X, Han Z (2017) VEGF-A/neuropilin 1 pathway confers cancer stemness via activating Wnt/beta-catenin axis in breast cancer cells. Cell Physiol Biochem 44:1251–1262.  https://doi.org/10.1159/000485455CrossRefPubMedPubMedCentralGoogle Scholar
  122. 122.
    Atzori MG, Tentori L, Ruffini F, Ceci C, Lisi L, Bonanno E, Scimeca M, Eskilsson E, Daubon T, Miletic H et al (2017) The anti-vascular endothelial growth factor receptor-1 monoclonal antibody D16F7 inhibits invasiveness of human glioblastoma and glioblastoma stem cells. J Exp Clin Cancer Res 36:106.  https://doi.org/10.1186/s13046-017-0577-2CrossRefPubMedPubMedCentralGoogle Scholar
  123. 123.
    Shimizu A, Zankov DP, Kurokawa-Seo M, Ogita H (2018) Vascular endothelial growth factor-A exerts diverse cellular effects via small G proteins, Rho and Rap. Int J Mol Sci 19.  https://doi.org/10.3390/ijms19041203PubMedCentralCrossRefGoogle Scholar
  124. 124.
    Wang Z, Ahmad A, Li Y, Kong D, Azmi AS, Banerjee S, Sarkar FH (2010) Emerging roles of PDGF-D signaling pathway in tumor development and progression. Biochim Biophys Acta 1806:122–130.  https://doi.org/10.1016/j.bbcan.2010.04.003CrossRefPubMedPubMedCentralGoogle Scholar
  125. 125.
    Hernandez-Garcia R, Iruela-Arispe ML, Reyes-Cruz G, Vazquez-Prado J (2015) Endothelial RhoGEFs: a systematic analysis of their expression profiles in VEGF-stimulated and tumor endothelial cells. Vasc Pharmacol 74:60–72.  https://doi.org/10.1016/j.vph.2015.10.003CrossRefGoogle Scholar
  126. 126.
    Ghosh K, Thodeti CK, Dudley AC, Mammoto A, Klagsbrun M, Ingber DE (2008) Tumor-derived endothelial cells exhibit aberrant Rho-mediated mechanosensing and abnormal angiogenesis in vitro. Proc Natl Acad Sci U S A 105:11305–11310.  https://doi.org/10.1073/pnas.0800835105CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Deng Y, Zhang X, Simons M (2015) Molecular controls of lymphatic VEGFR3 signaling. Arterioscler Thromb Vasc Biol 35:421–429.  https://doi.org/10.1161/ATVBAHA.114.304881CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Parikh AA, Fan F, Liu WB, Ahmad SA, Stoeltzing O, Reinmuth N, Bielenberg D, Bucana CD, Klagsbrun M, Ellis LM (2004) Neuropilin-1 in human colon cancer: expression, regulation, and role in induction of angiogenesis. Am J Pathol 164:2139–2151.  https://doi.org/10.1016/S0002-9440(10)63772-8CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Ding H, Wu X, Roncari L, Lau N, Shannon P, Nagy A, Guha A (2000) Expression and regulation of neuropilin-1 in human astrocytomas. Int J Cancer 88:584–592PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Akagi M, Kawaguchi M, Liu W, McCarty MF, Takeda A, Fan F, Stoeltzing O, Parikh AA, Jung YD, Bucana CD et al (2003) Induction of neuropilin-1 and vascular endothelial growth factor by epidermal growth factor in human gastric cancer cells. Br J Cancer 88:796–802.  https://doi.org/10.1038/sj.bjc.6600811CrossRefPubMedPubMedCentralGoogle Scholar
  131. 131.
    Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y (1996) A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol 16:5276–5287.  https://doi.org/10.1128/mcb.16.10.5276CrossRefPubMedPubMedCentralGoogle Scholar
  132. 132.
    Aghajanian H, Cho YK, Manderfield LJ, Herling MR, Gupta M, Ho VC, Li L, Degenhardt K, Aharonov A, Tzahor E et al (2016) Coronary vasculature patterning requires a novel endothelial ErbB2 holoreceptor. Nat Commun 7:12038.  https://doi.org/10.1038/ncomms12038CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Rizzolio S, Battistini C, Cagnoni G, Apicella M, Vella V, Giordano S, Tamagnone L (2018) Downregulating neuropilin-2 triggers a novel mechanism enabling EGFR-dependent resistance to oncogene-targeted therapies. Cancer Res 78:1058–1068.  https://doi.org/10.1158/0008-5472.CAN-17-2020CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Ball SG, Bayley C, Shuttleworth CA, Kielty CM (2010) Neuropilin-1 regulates platelet-derived growth factor receptor signalling in mesenchymal stem cells. Biochem J 427:29–40.  https://doi.org/10.1042/BJ20091512CrossRefPubMedPubMedCentralGoogle Scholar
  135. 135.
    Banerjee S, Sengupta K, Dhar K, Mehta S, D’Amore PA, Dhar G, Banerjee SK (2006) Breast cancer cells secreted platelet-derived growth factor-induced motility of vascular smooth muscle cells is mediated through neuropilin-1. Mol Carcinog 45:871–880.  https://doi.org/10.1002/mc.20248CrossRefPubMedPubMedCentralGoogle Scholar
  136. 136.
    Cao S, Yaqoob U, Das A, Shergill U, Jagavelu K, Huebert RC, Routray C, Abdelmoneim S, Vasdev M, Leof E et al (2010) Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-beta signaling in hepatic stellate cells. J Clin Invest 120:2379–2394.  https://doi.org/10.1172/JCI41203CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Dhar K, Dhar G, Majumder M, Haque I, Mehta S, Van Veldhuizen PJ, Banerjee SK, Banerjee S (2010) Tumor cell-derived PDGF-B potentiates mouse mesenchymal stem cells-pericytes transition and recruitment through an interaction with NRP-1. Mol Cancer 9:209.  https://doi.org/10.1186/1476-4598-9-209CrossRefPubMedPubMedCentralGoogle Scholar
  138. 138.
    Evans IM, Yamaji M, Britton G, Pellet-Many C, Lockie C, Zachary IC, Frankel P (2011) Neuropilin-1 signaling through p130Cas tyrosine phosphorylation is essential for growth factor-dependent migration of glioma and endothelial cells. Mol Cell Biol 31:1174–1185.  https://doi.org/10.1128/MCB.00903-10CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Ponten A, Folestad EB, Pietras K, Eriksson U (2005) Platelet-derived growth factor D induces cardiac fibrosis and proliferation of vascular smooth muscle cells in heart-specific transgenic mice. Circ Res 97:1036–1045.  https://doi.org/10.1161/01.RES.0000190590.31545.d4CrossRefPubMedPubMedCentralGoogle Scholar
  140. 140.
    Andrae J, Gallini R, Betsholtz C (2008) Role of platelet-derived growth factors in physiology and medicine. Genes Dev 22:1276–1312.  https://doi.org/10.1101/gad.1653708CrossRefPubMedPubMedCentralGoogle Scholar
  141. 141.
    Cortez E, Gladh H, Braun S, Bocci M, Cordero E, Bjorkstrom NK, Miyazaki H, Michael IP, Eriksson U, Folestad E et al (2016) Functional malignant cell heterogeneity in pancreatic neuroendocrine tumors revealed by targeting of PDGF-DD. Proc Natl Acad Sci U S A 113:E864–E873.  https://doi.org/10.1073/pnas.1509384113CrossRefPubMedPubMedCentralGoogle Scholar
  142. 142.
    Hu B, Guo P, Bar-Joseph I, Imanishi Y, Jarzynka MJ, Bogler O, Mikkelsen T, Hirose T, Nishikawa R, Cheng SY (2007) Neuropilin-1 promotes human glioma progression through potentiating the activity of the HGF/SF autocrine pathway. Oncogene 26:5577–5586.  https://doi.org/10.1038/sj.onc.1210348CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Weinstein IB (2002) Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 297:63–64.  https://doi.org/10.1126/science.1073096CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Li L, Jiang X, Zhang Q, Dong X, Gao Y, He Y, Qiao H, Xie F, Xie X, Sun X (2016) 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 35:16.  https://doi.org/10.1186/s13046-016-0291-5CrossRefPubMedPubMedCentralGoogle Scholar
  145. 145.
    Rizzolio S, Cagnoni G, Battistini C, Bonelli S, Isella C, Van Ginderachter JA, Bernards R, Di Nicolantonio F, Giordano S, Tamagnone L (2018) Neuropilin-1 upregulation elicits adaptive resistance to oncogene-targeted therapies. J Clin Invest 128:3976–3990.  https://doi.org/10.1172/JCI99257CrossRefPubMedPubMedCentralGoogle Scholar
  146. 146.
    Liu W, Wu T, Dong X, Zeng YA (2017) Neuropilin-1 is upregulated by Wnt/beta-catenin signaling and is important for mammary stem cells. Sci Rep 7:10941.  https://doi.org/10.1038/s41598-017-11287-wCrossRefPubMedPubMedCentralGoogle Scholar
  147. 147.
    Lichtenberger BM, Tan PK, Niederleithner H, Ferrara N, Petzelbauer P, Sibilia M (2010) Autocrine VEGF signaling synergizes with EGFR in tumor cells to promote epithelial cancer development. Cell 140:268–279.  https://doi.org/10.1016/j.cell.2009.12.046CrossRefPubMedPubMedCentralGoogle Scholar
  148. 148.
    Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, Haanen J, Blank C, Wesseling J, Willems SM et al (2014) Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508:118–122.  https://doi.org/10.1038/nature13121CrossRefPubMedPubMedCentralGoogle Scholar
  149. 149.
    Wang J, Huang SK, Marzese DM, Hsu SC, Kawas NP, Chong KK, Long GV, Menzies AM, Scolyer RA, Izraely S et al (2015) Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas. J Invest Dermatol 135:532–541.  https://doi.org/10.1038/jid.2014.418CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Cao Y, Szabolcs A, Dutta SK, Yaqoob U, Jagavelu K, Wang L, Leof EB, Urrutia RA, Shah VH, Mukhopadhyay D (2010) Neuropilin-1 mediates divergent R-Smad signaling and the myofibroblast phenotype. J Biol Chem 285:31840–31848.  https://doi.org/10.1074/jbc.M110.151696CrossRefPubMedPubMedCentralGoogle Scholar
  151. 151.
    Hirota S, Clements TP, Tang LK, Morales JE, Lee HS, Oh SP, Rivera GM, Wagner DS, McCarty JH (2015) Neuropilin 1 balances beta8 integrin-activated TGFbeta signaling to control sprouting angiogenesis in the brain. Development 142:4363–4373.  https://doi.org/10.1242/dev.113746CrossRefPubMedPubMedCentralGoogle Scholar
  152. 152.
    Aspalter IM, Gordon E, Dubrac A, Ragab A, Narloch J, Vizan P, Geudens I, Collins RT, Franco CA, Abrahams CL et al (2015) Alk1 and Alk5 inhibition by Nrp1 controls vascular sprouting downstream of Notch. Nat Commun 6:7264.  https://doi.org/10.1038/ncomms8264CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Vivekanandhan S, Yang L, Cao Y, Wang E, Dutta SK, Sharma AK, Mukhopadhyay D (2017) Genetic status of KRAS modulates the role of neuropilin-1 in tumorigenesis. Sci Rep 7:12877.  https://doi.org/10.1038/s41598-017-12992-2CrossRefPubMedPubMedCentralGoogle Scholar
  154. 154.
    Yin K, Yin W, Wang Y, Zhou L, Liu Y, Yang G, Wang J, Lu J (2016) MiR-206 suppresses epithelial mesenchymal transition by targeting TGF-beta signaling in estrogen receptor positive breast cancer cells. Oncotarget 7:24537–24548.  https://doi.org/10.18632/oncotarget.8233CrossRefPubMedPubMedCentralGoogle Scholar
  155. 155.
    Chen Y, Huang S, Wu B, Fang J, Zhu M, Sun L, Zhang L, Zhang Y, Sun M, Guo L et al (2017) Transforming growth factor-beta1 promotes breast cancer metastasis by downregulating miR-196a-3p expression. Oncotarget 8:49110–49122.  https://doi.org/10.18632/oncotarget.16308CrossRefPubMedPubMedCentralGoogle Scholar
  156. 156.
    Neufeld G, Sabag AD, Rabinovicz N, Kessler O (2012) Semaphorins in angiogenesis and tumor progression. Cold Spring Harb Perspect Med 2:a006718.  https://doi.org/10.1101/cshperspect.a006718CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Sakurai A, Doci CL, Gutkind JS (2012) Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer. Cell Res 22:23–32.  https://doi.org/10.1038/cr.2011.198CrossRefPubMedPubMedCentralGoogle Scholar
  158. 158.
    Yang WJ, Hu J, Uemura A, Tetzlaff F, Augustin HG, Fischer A (2015) Semaphorin-3C signals through neuropilin-1 and PlexinD1 receptors to inhibit pathological angiogenesis. EMBO Mol Med 7:1267–1284.  https://doi.org/10.15252/emmm.201404922CrossRefPubMedPubMedCentralGoogle Scholar
  159. 159.
    Hao J, Yu JS (2018) Semaphorin 3C and its receptors in cancer and cancer stem-like cells. Biomedicine 6.  https://doi.org/10.3390/biomedicines6020042PubMedCentralCrossRefPubMedGoogle Scholar
  160. 160.
    Hui DHF, Tam KJ, Jiao IZF, Ong CJ (2019) Semaphorin 3C as a therapeutic target in prostate and other cancers. Int J Mol Sci 20.  https://doi.org/10.3390/ijms20030774PubMedCentralCrossRefGoogle Scholar
  161. 161.
    Bielenberg DR, Hida Y, Shimizu A, Kaipainen A, Kreuter M, Kim CC, Klagsbrun M (2004) Semaphorin 3F, a chemorepulsant for endothelial cells, induces a poorly vascularized, encapsulated, nonmetastatic tumor phenotype. J Clin Invest 114:1260–1271.  https://doi.org/10.1172/JCI21378CrossRefPubMedPubMedCentralGoogle Scholar
  162. 162.
    Kessler O, Shraga-Heled N, Lange T, Gutmann-Raviv N, Sabo E, Baruch L, Machluf M, Neufeld G (2004) Semaphorin-3F is an inhibitor of tumor angiogenesis. Cancer Res 64:1008–1015PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Dallas NA, Gray MJ, Xia L, Fan F, van Buren G 2nd, Gaur P, Samuel S, Lim SJ, Arumugam T, Ramachandran V et al (2008) Neuropilin-2-mediated tumor growth and angiogenesis in pancreatic adenocarcinoma. Clin Cancer Res 14:8052–8060.  https://doi.org/10.1158/1078-0432.CCR-08-1520CrossRefPubMedPubMedCentralGoogle Scholar
  164. 164.
    Zeng Q, Li S, Chepeha DB, Giordano TJ, Li J, Zhang H, Polverini PJ, Nor J, Kitajewski J, Wang CY (2005) Crosstalk between tumor and endothelial cells promotes tumor angiogenesis by MAPK activation of Notch signaling. Cancer Cell 8:13–23.  https://doi.org/10.1016/j.ccr.2005.06.004CrossRefPubMedPubMedCentralGoogle Scholar
  165. 165.
    Benedito R, Roca C, Sorensen I, Adams S, Gossler A, Fruttiger M, Adams RH (2009) The Notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137:1124–1135.  https://doi.org/10.1016/j.cell.2009.03.025CrossRefPubMedPubMedCentralGoogle Scholar
  166. 166.
    Armulik A, Abramsson A, Betsholtz C (2005) Endothelial/pericyte interactions. Circ Res 97:512–523.  https://doi.org/10.1161/01.RES.0000182903.16652.d7CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    von Tell D, Armulik A, Betsholtz C (2006) Pericytes and vascular stability. Exp Cell Res 312:623–629.  https://doi.org/10.1016/j.yexcr.2005.10.019CrossRefGoogle Scholar
  168. 168.
    Gaengel K, Genove G, Armulik A, Betsholtz C (2009) Endothelial-mural cell signaling in vascular development and angiogenesis. Arterioscler Thromb Vasc Biol 29:630–638.  https://doi.org/10.1161/ATVBAHA.107.161521CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Gu C, Giraudo E (2013) The role of semaphorins and their receptors in vascular development and cancer. Exp Cell Res 319:1306–1316.  https://doi.org/10.1016/j.yexcr.2013.02.003CrossRefPubMedPubMedCentralGoogle Scholar
  170. 170.
    Aguilera KY, Brekken RA (2014) Recruitment and retention: factors that affect pericyte migration. Cell Mol Life Sci 71:299–309.  https://doi.org/10.1007/s00018-013-1432-zCrossRefPubMedPubMedCentralGoogle Scholar
  171. 171.
    Xian X, Hakansson J, Stahlberg A, Lindblom P, Betsholtz C, Gerhardt H, Semb H (2006) Pericytes limit tumor cell metastasis. J Clin Invest 116:642–651.  https://doi.org/10.1172/JCI25705CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Chakraborty G, Kumar S, Mishra R, Patil TV, Kundu GC (2012) Semaphorin 3A suppresses tumor growth and metastasis in mice melanoma model. PLoS One 7:e33633.  https://doi.org/10.1371/journal.pone.0033633CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Fukasawa M, Matsushita A, Korc M (2007) Neuropilin-1 interacts with integrin beta1 and modulates pancreatic cancer cell growth, survival and invasion. Cancer Biol Ther 6:1173–1180.  https://doi.org/10.4161/cbt.6.8.4363CrossRefPubMedPubMedCentralGoogle Scholar
  174. 174.
    Goel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13:871–882.  https://doi.org/10.1038/nrc3627CrossRefPubMedPubMedCentralGoogle Scholar
  175. 175.
    Byzova TV, Goldman CK, Pampori N, Thomas KA, Bett A, Shattil SJ, Plow EF (2000) A mechanism for modulation of cellular responses to VEGF: activation of the integrins. Mol Cell 6:851–860PubMedPubMedCentralGoogle Scholar
  176. 176.
    Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F, Zammataro L, Primo L, Tamagnone L, Logan M et al (2003) Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424:391–397.  https://doi.org/10.1038/nature01784CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Valdembri D, Regano D, Maione F, Giraudo E, Serini G (2016) Class 3 semaphorins in cardiovascular development. Cell Adhes Migr 10:641–651.  https://doi.org/10.1080/19336918.2016.1212805CrossRefGoogle Scholar
  178. 178.
    Goel HL, Pursell B, Standley C, Fogarty K, Mercurio AM (2012) Neuropilin-2 regulates alpha6beta1 integrin in the formation of focal adhesions and signaling. J Cell Sci 125:497–506.  https://doi.org/10.1242/jcs.094433CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Muders MH, Zhang H, Wang E, Tindall DJ, Datta K (2009) Vascular endothelial growth factor-C protects prostate cancer cells from oxidative stress by the activation of mammalian target of rapamycin complex-2 and AKT-1. Cancer Res 69:6042–6048.  https://doi.org/10.1158/0008-5472.CAN-09-0552CrossRefPubMedPubMedCentralGoogle Scholar
  180. 180.
    Facchinetti V, Ouyang W, Wei H, Soto N, Lazorchak A, Gould C, Lowry C, Newton AC, Mao Y, Miao RQ et al (2008) The mammalian target of rapamycin complex 2 controls folding and stability of Akt and protein kinase C. EMBO J 27:1932–1943.  https://doi.org/10.1038/emboj.2008.120CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Cai H, Reed RR (1999) Cloning and characterization of neuropilin-1-interacting protein: a PSD-95/Dlg/ZO-1 domain-containing protein that interacts with the cytoplasmic domain of neuropilin-1. J Neurosci 19:6519–6527PubMedPubMedCentralCrossRefGoogle Scholar
  182. 182.
    Prahst C, Heroult M, Lanahan AA, Uziel N, Kessler O, Shraga-Heled N, Simons M, Neufeld G, Augustin HG (2008) Neuropilin-1-VEGFR-2 complexing requires the PDZ-binding domain of neuropilin-1. J Biol Chem 283:25110–25114.  https://doi.org/10.1074/jbc.C800137200CrossRefPubMedPubMedCentralGoogle Scholar
  183. 183.
    Zhang G, Chen L, Sun K, Khan AA, Yan J, Liu H, Lu A, Gu N (2016) Neuropilin-1 (NRP-1)/GIPC1 pathway mediates glioma progression. Tumour Biol 37:13777–13788.  https://doi.org/10.1007/s13277-016-5138-3CrossRefPubMedPubMedCentralGoogle Scholar
  184. 184.
    Pang HB, Braun GB, Friman T, Aza-Blanc P, Ruidiaz ME, Sugahara KN, Teesalu T, Ruoslahti E (2014) An endocytosis pathway initiated through neuropilin-1 and regulated by nutrient availability. Nat Commun 5:4904.  https://doi.org/10.1038/ncomms5904CrossRefPubMedPubMedCentralGoogle Scholar
  185. 185.
    Sugahara KN, Teesalu T, Karmali PP, Kotamraju VR, Agemy L, Greenwald DR, Ruoslahti E (2010) Coadministration of a tumor-penetrating peptide enhances the efficacy of cancer drugs. Science 328:1031–1035.  https://doi.org/10.1126/science.1183057CrossRefPubMedPubMedCentralGoogle Scholar
  186. 186.
    Horowitz A, Seerapu HR (2012) Regulation of VEGF signaling by membrane traffic. Cell Signal 24:1810–1820.  https://doi.org/10.1016/j.cellsig.2012.05.007CrossRefPubMedPubMedCentralGoogle Scholar
  187. 187.
    Lanahan AA, Hermans K, Claes F, Kerley-Hamilton JS, Zhuang ZW, Giordano FJ, Carmeliet P, Simons M (2010) VEGF receptor 2 endocytic trafficking regulates arterial morphogenesis. Dev Cell 18:713–724.  https://doi.org/10.1016/j.devcel.2010.02.016CrossRefPubMedPubMedCentralGoogle Scholar
  188. 188.
    Lanahan A, Zhang X, Fantin A, Zhuang Z, Rivera-Molina F, Speichinger K, Prahst C, Zhang J, Wang Y, Davis G et al (2013) The neuropilin 1 cytoplasmic domain is required for VEGF-A-dependent arteriogenesis. Dev Cell 25:156–168.  https://doi.org/10.1016/j.devcel.2013.03.019CrossRefPubMedPubMedCentralGoogle Scholar
  189. 189.
    Kawamura H, Li X, Goishi K, van Meeteren LA, Jakobsson L, Cebe-Suarez S, Shimizu A, Edholm D, Ballmer-Hofer K, Kjellen L et al (2008) Neuropilin-1 in regulation of VEGF-induced activation of p38MAPK and endothelial cell organization. Blood 112:3638–3649.  https://doi.org/10.1182/blood-2007-12-125856CrossRefPubMedPubMedCentralGoogle Scholar
  190. 190.
    D’Haene N, Sauvage S, Maris C, Adanja I, Le Mercier M, Decaestecker C, Baum L, Salmon I (2013) VEGFR1 and VEGFR2 involvement in extracellular galectin-1- and galectin-3-induced angiogenesis. PLoS One 8:e67029.  https://doi.org/10.1371/journal.pone.0067029CrossRefPubMedPubMedCentralGoogle Scholar
  191. 191.
    Wang L, Zhao Y, Wang Y, Wu X (2018) The role of Galectins in cervical cancer biology and progression. Biomed Res Int 2018:2175927.  https://doi.org/10.1155/2018/2175927CrossRefPubMedPubMedCentralGoogle Scholar
  192. 192.
    Hsieh SH, Ying NW, Wu MH, Chiang WF, Hsu CL, Wong TY, Jin YT, Hong TM, Chen YL (2008) Galectin-1, a novel ligand of neuropilin-1, activates VEGFR-2 signaling and modulates the migration of vascular endothelial cells. Oncogene 27:3746–3753.  https://doi.org/10.1038/sj.onc.1211029CrossRefPubMedPubMedCentralGoogle Scholar
  193. 193.
    Cao YEG, Wang E, Pal K, Dutta SK, Bar-Sagi D, Mukhopadhyay D (2012) VEGF exerts an angiogenesis-independent function in cancer cells to promote their malignant progression. Cancer Res 72:3912–3918.  https://doi.org/10.1158/0008-5472.CAN-11-4058PubMedPubMedCentralCrossRefGoogle Scholar
  194. 194.
    Chen H, Bagri A, Zupicich JA, Zou Y, Stoeckli E, Pleasure SJ, Lowenstein DH, Skarnes WC, Chedotal A, Tessier-Lavigne M (2000) Neuropilin-2 regulates the development of selective cranial and sensory nerves and hippocampal mossy fiber projections. Neuron 25:43–56PubMedCrossRefPubMedCentralGoogle Scholar
  195. 195.
    Horiguchi K, Shirakihara T, Nakano A, Imamura T, Miyazono K, Saitoh M (2009) Role of Ras signaling in the induction of Snail by transforming growth factor-beta. J Biol Chem 284:245–253.  https://doi.org/10.1074/jbc.M804777200CrossRefPubMedPubMedCentralGoogle Scholar
  196. 196.
    Cao Y, Wang L, Nandy D, Zhang Y, Basu A, Radisky D, Mukhopadhyay D (2008) Neuropilin-1 upholds dedifferentiation and propagation phenotypes of renal cell carcinoma cells by activating Akt and Sonic hedgehog axes. Cancer Res 68:8667–8672.  https://doi.org/10.1158/0008-5472.CAN-08-2614CrossRefPubMedPubMedCentralGoogle Scholar
  197. 197.
    Hillman RT, Feng BY, Ni J, Woo WM, Milenkovic L, Hayden Gephart MG, Teruel MN, Oro AE, Chen JK, Scott MP (2011) Neuropilins are positive regulators of Hedgehog signal transduction. Genes Dev 25:2333–2346.  https://doi.org/10.1101/gad.173054.111CrossRefPubMedPubMedCentralGoogle Scholar
  198. 198.
    Mercurio AM (2019) VEGF/neuropilin signaling in cancer stem cells. Int J Mol Sci 20.  https://doi.org/10.3390/ijms20030490PubMedCentralCrossRefGoogle Scholar
  199. 199.
    Ge X, Milenkovic L, Suyama K, Hartl T, Purzner T, Winans A, Meyer T, Scott MP (2015) Phosphodiesterase 4D acts downstream of neuropilin to control Hedgehog signal transduction and the growth of medulloblastoma. Elife 4.  https://doi.org/10.7554/eLife.07068
  200. 200.
    Po A, Silvano M, Miele E, Capalbo C, Eramo A, Salvati V, Todaro M, Besharat ZM, Catanzaro G, Cucchi D et al (2017) Noncanonical GLI1 signaling promotes stemness features and in vivo growth in lung adenocarcinoma. Oncogene 36:4641–4652.  https://doi.org/10.1038/onc.2017.91CrossRefPubMedPubMedCentralGoogle Scholar
  201. 201.
    Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC, Anolik R, Huang Y, Martin JD, Kamoun W et al (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152:1065–1076.  https://doi.org/10.1016/j.cell.2013.01.036CrossRefPubMedPubMedCentralGoogle Scholar
  202. 202.
    Yogi K, Sridhar E, Goel N, Jalali R, Goel A, Moiyadi A, Thorat R, Panwalkar P, Khire A, Dasgupta A et al (2015) MiR-148a, a microRNA upregulated in the WNT subgroup tumors, inhibits invasion and tumorigenic potential of medulloblastoma cells by targeting neuropilin 1. Oncoscience 2:334–348.  https://doi.org/10.18632/oncoscience.137CrossRefPubMedPubMedCentralGoogle Scholar
  203. 203.
    Kim D, Lee V, Dorsey TB, Niklason LE, Gui L, Dai G (2018) Neuropilin-1 mediated arterial differentiation of murine pluripotent stem cells. Stem Cells Dev 27:441–455.  https://doi.org/10.1089/scd.2017.0240CrossRefPubMedPubMedCentralGoogle Scholar
  204. 204.
    Papadopoulou K, Murray S, Manousou K, Tikas I, Dervenis C, Sgouros J, Rontogianni D, Lakis S, Bobos M, Poulios C et al (2018) Genotyping and mRNA profiling reveal actionable molecular targets in biliary tract cancers. Am J Cancer Res 8:2–15PubMedPubMedCentralGoogle Scholar
  205. 205.
    Takakura N (2012) Formation and regulation of the cancer stem cell niche. Cancer Sci 103:1177–1181.  https://doi.org/10.1111/j.1349-7006.2012.02270.xCrossRefPubMedPubMedCentralGoogle Scholar
  206. 206.
    Rizzolio S, Tamagnone L (2011) Multifaceted role of neuropilins in cancer. Curr Med Chem 18:3563–3575PubMedCrossRefPubMedCentralGoogle Scholar
  207. 207.
    Samuel S, Gaur P, Fan F, Xia L, Gray MJ, Dallas NA, Bose D, Rodriguez-Aguayo C, Lopez-Berestein G, Plowman G et al (2011) Neuropilin-2 mediated beta-catenin signaling and survival in human gastro-intestinal cancer cell lines. PLoS One 6:e23208.  https://doi.org/10.1371/journal.pone.0023208CrossRefPubMedPubMedCentralGoogle Scholar
  208. 208.
    Grandclement C, Pallandre JR, Valmary Degano S, Viel E, Bouard A, Balland J, Remy-Martin JP, Simon B, Rouleau A, Boireau W et al (2011) Neuropilin-2 expression promotes TGF-beta1-mediated epithelial to mesenchymal transition in colorectal cancer cells. PLoS One 6:e20444.  https://doi.org/10.1371/journal.pone.0020444CrossRefPubMedPubMedCentralGoogle Scholar
  209. 209.
    Ji T, Guo Y, Kim K, McQueen P, Ghaffar S, Christ A, Lin C, Eskander R, Zi X, Hoang BH (2015) 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 14:86.  https://doi.org/10.1186/s12943-015-0359-4CrossRefPubMedPubMedCentralGoogle Scholar
  210. 210.
    Parker MW, Linkugel AD, Goel HL, Wu T, Mercurio AM, Vander Kooi CW (2015) Structural basis for VEGF-C binding to neuropilin-2 and sequestration by a soluble splice form. Structure 23:677–687.  https://doi.org/10.1016/j.str.2015.01.018CrossRefPubMedPubMedCentralGoogle Scholar
  211. 211.
    Bartel DP (2018) Metazoan MicroRNAs. Cell 173:20–51.  https://doi.org/10.1016/j.cell.2018.03.006CrossRefPubMedPubMedCentralGoogle Scholar
  212. 212.
    Prud’homme GJ, Glinka Y, Lichner Z, Yousef GM (2016) Neuropilin-1 is a receptor for extracellular miRNA and AGO2/miRNA complexes and mediates the internalization of miRNAs that modulate cell function. Oncotarget 7:68057–68071.  https://doi.org/10.18632/oncotarget.10929CrossRefPubMedPubMedCentralGoogle Scholar
  213. 213.
    Li Y, Egranov SD, Yang L, Lin C (2019) Molecular mechanisms of long noncoding RNAs-mediated cancer metastasis. Genes Chromosomes Cancer 58:200–207.  https://doi.org/10.1002/gcc.22691CrossRefPubMedPubMedCentralGoogle Scholar
  214. 214.
    Chen ZP, Wei JC, Wang Q, Yang P, Li WL, He F, Chen HC, Hu H, Zhong JB, Cao J (2018) Long noncoding RNA 00152 functions as a competing endogenous RNA to regulate NRP1 expression by sponging with miRNA206 in colorectal cancer. Int J Oncol 53:1227–1236.  https://doi.org/10.3892/ijo.2018.4451CrossRefPubMedPubMedCentralGoogle Scholar
  215. 215.
    Zhou J, Zhang M, Huang Y, Feng L, Chen H, Hu Y, Chen H, Zhang K, Zheng L, Zheng S (2015) MicroRNA-320b promotes colorectal cancer proliferation and invasion by competing with its homologous microRNA-320a. Cancer Lett 356:669–675.  https://doi.org/10.1016/j.canlet.2014.10.014CrossRefPubMedPubMedCentralGoogle Scholar
  216. 216.
    Peng Y, Liu YM, Li LC, Wang LL, Wu XL (2014) MicroRNA-338 inhibits growth, invasion and metastasis of gastric cancer by targeting NRP1 expression. PLoS One 9:e94422.  https://doi.org/10.1371/journal.pone.0094422CrossRefPubMedPubMedCentralGoogle Scholar
  217. 217.
    Liu C, Wang Z, Wang Y, Gu W (2015) MiR-338 suppresses the growth and metastasis of OSCC cells by targeting NRP1. Mol Cell Biochem 398:115–122.  https://doi.org/10.1007/s11010-014-2211-3CrossRefPubMedPubMedCentralGoogle Scholar
  218. 218.
    Ding Z, Zhu J, Zeng Y, Du W, Zhang Y, Tang H, Zheng Y, Qin H, Liu Z, Huang JA (2019) The regulation of neuropilin 1 expression by miR-338-3p promotes non-small cell lung cancer via changes in EGFR signaling. Mol Carcinog 58:1019–1032.  https://doi.org/10.1002/mc.22990CrossRefPubMedPubMedCentralGoogle Scholar
  219. 219.
    Zhang YJ, Liu XC, Du J, Zhang YJ (2015) MiR-152 regulates metastases of non-small cell lung cancer cells by targeting neuropilin-1. Int J Clin Exp Pathol 8:14235–14240PubMedPubMedCentralGoogle Scholar
  220. 220.
    Zhu H, Jiang X, Zhou X, Dong X, Xie K, Yang C, Jiang H, Sun X, Lu J (2018) Neuropilin-1 regulated by miR-320 contributes to the growth and metastasis of cholangiocarcinoma cells. Liver Int 38:125–135.  https://doi.org/10.1111/liv.13495CrossRefPubMedPubMedCentralGoogle Scholar
  221. 221.
    Li H, Zhao J, Liu B, Luo J, Li Z, Qin X, Wei Y (2019) MicroRNA-320 targeting neuropilin 1 inhibits proliferation and migration of vascular smooth muscle cells and neointimal formation. Int J Med Sci 16:106–114.  https://doi.org/10.7150/ijms.28093CrossRefPubMedPubMedCentralGoogle Scholar
  222. 222.
    Taddei ML, Cavallini L, Ramazzotti M, Comito G, Pietrovito L, Morandi A, Giannoni E, Raugei G, Chiarugi P (2019) Stromal-induced downregulation of miR-1247 promotes prostate cancer malignancy. J Cell Physiol 234:8274–8285.  https://doi.org/10.1002/jcp.27679CrossRefPubMedPubMedCentralGoogle Scholar
  223. 223.
    Zhang L, Chen Y, Wang H, Zheng X, Li C, Han Z (2018) miR-376a inhibits breast cancer cell progression by targeting neuropilin-1 NR. Onco Targets Ther 11:5293–5302.  https://doi.org/10.2147/OTT.S173416CrossRefPubMedPubMedCentralGoogle Scholar
  224. 224.
    Zhang L, Chen Y, Li C, Liu J, Ren H, Li L, Zheng X, Wang H, Han Z (2019) RNA binding protein PUM2 promotes the stemness of breast cancer cells via competitively binding to neuropilin-1 (NRP-1) mRNA with miR-376a. Biomed Pharmacother 114:108772.  https://doi.org/10.1016/j.biopha.2019.108772CrossRefPubMedPubMedCentralGoogle Scholar
  225. 225.
    Zhang G, Chen L, Khan AA, Li B, Gu B, Lin F, Su X, Yan J (2018) miRNA-124-3p/neuropilin-1(NRP-1) axis plays an important role in mediating glioblastoma growth and angiogenesis. Int J Cancer 143:635–644.  https://doi.org/10.1002/ijc.31329CrossRefPubMedPubMedCentralGoogle Scholar
  226. 226.
    Epis MR, Giles KM, Candy PA, Webster RJ, Leedman PJ (2014) miR-331-3p regulates expression of neuropilin-2 in glioblastoma. J Neuro-Oncol 116:67–75.  https://doi.org/10.1007/s11060-013-1271-7CrossRefGoogle Scholar
  227. 227.
    Zheng X, Chopp M, Lu Y, Buller B, Jiang F (2013) MiR-15b and miR-152 reduce glioma cell invasion and angiogenesis via NRP-2 and MMP-3. Cancer Lett 329:146–154.  https://doi.org/10.1016/j.canlet.2012.10.026CrossRefPubMedPubMedCentralGoogle Scholar
  228. 228.
    Liu C, Li M, Hu Y, Shi N, Yu H, Liu H, Lian H (2016) miR-486-5p attenuates tumor growth and lymphangiogenesis by targeting neuropilin-2 in colorectal carcinoma. Onco Targets Ther 9:2865–2871.  https://doi.org/10.2147/OTT.S103460CrossRefPubMedPubMedCentralGoogle Scholar
  229. 229.
    Pagani E, Ruffini F, Antonini Cappellini GC, Scoppola A, Fortes C, Marchetti P, Graziani G, D’Atri S, Lacal PM (2016) Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness. Int J Oncol 48:1581–1589.  https://doi.org/10.3892/ijo.2016.3362CrossRefPubMedPubMedCentralGoogle Scholar
  230. 230.
    Pellet-Many C, Frankel P, Jia H, Zachary I (2008) Neuropilins: structure, function and role in disease. Biochem J 411:211–226.  https://doi.org/10.1042/BJ20071639CrossRefPubMedPubMedCentralGoogle Scholar
  231. 231.
    Janssen BJ, Malinauskas T, Weir GA, Cader MZ, Siebold C, Jones EY (2012) Neuropilins lock secreted semaphorins onto plexins in a ternary signaling complex. Nat Struct Mol Biol 19:1293–1299.  https://doi.org/10.1038/nsmb.2416CrossRefPubMedPubMedCentralGoogle Scholar
  232. 232.
    Palodetto B, da Silva Santos Duarte A, Rodrigues Lopes M, Adolfo Corrocher F, Marconi Roversi F, Soares Niemann F, Priscila Vieira Ferro K, Leda Figueiredo Longhini A, Melo Campos P, Favaro P et al (2017) SEMA3A partially reverses VEGF effects through binding to neuropilin-1. Stem Cell Res 22:70–78.  https://doi.org/10.1016/j.scr.2017.05.012CrossRefPubMedPubMedCentralGoogle Scholar
  233. 233.
    Chu W, Song X, Yang X, Ma L, Zhu J, He M, Wang Z, Wu Y (2014) Neuropilin-1 promotes epithelial-to-mesenchymal transition by stimulating nuclear factor-kappa B and is associated with poor prognosis in human oral squamous cell carcinoma. PLoS One 9:e101931.  https://doi.org/10.1371/journal.pone.0101931CrossRefPubMedPubMedCentralGoogle Scholar
  234. 234.
    Nasarre P, Gemmill RM, Potiron VA, Roche J, Lu X, Baron AE, Korch C, Garrett-Mayer E, Lagana A, Howe PH et al (2013) Neuropilin-2 is upregulated in lung cancer cells during TGF-beta1-induced epithelial-mesenchymal transition. Cancer Res 73:7111–7121.  https://doi.org/10.1158/0008-5472.CAN-13-1755CrossRefPubMedPubMedCentralGoogle Scholar
  235. 235.
    Gemmill RM, Nasarre P, Nair-Menon J, Cappuzzo F, Landi L, D’Incecco A, Uramoto H, Yoshida T, Haura EB, Armeson K et al (2017) The neuropilin 2 isoform NRP2b uniquely supports TGFbeta-mediated progression in lung cancer. Sci Signal 10.  https://doi.org/10.1126/scisignal.aag0528PubMedPubMedCentralCrossRefGoogle Scholar
  236. 236.
    Hirata E, Sahai E (2017) Tumor microenvironment and differential responses to therapy. Cold Spring Harb Perspect Med 7.  https://doi.org/10.1101/cshperspect.a026781PubMedPubMedCentralCrossRefGoogle Scholar
  237. 237.
    Cavaco A, Rezaei M, Niland S, Eble JA (2017) Collateral damage intended—cancer-associated fibroblasts and vasculature are potential targets in cancer therapy. Int J Mol Sci 18.  https://doi.org/10.3390/ijms18112355PubMedCentralCrossRefGoogle Scholar
  238. 238.
    von Ahrens D, Bhagat TD, Nagrath D, Maitra A, Verma A (2017) The role of stromal cancer-associated fibroblasts in pancreatic cancer. J Hematol Oncol 10:76.  https://doi.org/10.1186/s13045-017-0448-5CrossRefGoogle Scholar
  239. 239.
    Kalluri R (2016) The biology and function of fibroblasts in cancer. Nat Rev Cancer 16:582–598.  https://doi.org/10.1038/nrc.2016.73CrossRefGoogle Scholar
  240. 240.
    Gajewski TF, Schreiber H, Fu YX (2013) Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol 14:1014–1022.  https://doi.org/10.1038/ni.2703CrossRefPubMedPubMedCentralGoogle Scholar
  241. 241.
    Otranto M, Sarrazy V, Bonte F, Hinz B, Gabbiani G, Desmouliere A (2012) The role of the myofibroblast in tumor stroma remodeling. Cell Adhes Migr 6:203–219.  https://doi.org/10.4161/cam.20377CrossRefGoogle Scholar
  242. 242.
    Mueller MM, Fusenig NE (2004) Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer 4:839–849.  https://doi.org/10.1038/nrc1477CrossRefPubMedPubMedCentralGoogle Scholar
  243. 243.
    Polanska UM, Orimo A (2013) Carcinoma-associated fibroblasts: non-neoplastic tumour-promoting mesenchymal cells. J Cell Physiol 228:1651–1657.  https://doi.org/10.1002/jcp.24347CrossRefPubMedPubMedCentralGoogle Scholar
  244. 244.
    Erdogan B, Webb DJ (2017) Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans 45:229–236.  https://doi.org/10.1042/BST20160387CrossRefPubMedPubMedCentralGoogle Scholar
  245. 245.
    Kuzet SE, Gaggioli C (2016) Fibroblast activation in cancer: when seed fertilizes soil. Cell Tissue Res 365:607–619.  https://doi.org/10.1007/s00441-016-2467-xCrossRefPubMedPubMedCentralGoogle Scholar
  246. 246.
    Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, Reinhart-King CA, Margulies SS, Dembo M, Boettiger D et al (2005) Tensional homeostasis and the malignant phenotype. Cancer Cell 8:241–254.  https://doi.org/10.1016/j.ccr.2005.08.010CrossRefPubMedPubMedCentralGoogle Scholar
  247. 247.
    Ramamonjisoa N, Ackerstaff E (2017) Characterization of the tumor microenvironment and tumor-stroma interaction by non-invasive preclinical imaging. Front Oncol 7:3.  https://doi.org/10.3389/fonc.2017.00003CrossRefPubMedPubMedCentralGoogle Scholar
  248. 248.
    Hinz B, Phan SH, Thannickal VJ, Prunotto M, Desmouliere A, Varga J, De Wever O, Mareel M, Gabbiani G (2012) Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am J Pathol 180:1340–1355.  https://doi.org/10.1016/j.ajpath.2012.02.004CrossRefPubMedPubMedCentralGoogle Scholar
  249. 249.
    Dvorak HF (1986) Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med 315:1650–1659.  https://doi.org/10.1056/NEJM198612253152606CrossRefGoogle Scholar
  250. 250.
    Yu Y, Xiao CH, Tan LD, Wang QS, Li XQ, Feng YM (2014) Cancer-associated fibroblasts induce epithelial-mesenchymal transition of breast cancer cells through paracrine TGF-beta signalling. Br J Cancer 110:724–732.  https://doi.org/10.1038/bjc.2013.768CrossRefPubMedPubMedCentralGoogle Scholar
  251. 251.
    Khan Z, Marshall JF (2016) The role of integrins in TGFbeta activation in the tumour stroma. Cell Tissue Res 365:657–673.  https://doi.org/10.1007/s00441-016-2474-yCrossRefPubMedPubMedCentralGoogle Scholar
  252. 252.
    Mohammadi H, Sahai E (2018) Mechanisms and impact of altered tumour mechanics. Nat Cell Biol 20:766–774.  https://doi.org/10.1038/s41556-018-0131-2CrossRefPubMedPubMedCentralGoogle Scholar
  253. 253.
    Xing Y, Zhao S, Zhou BP, Mi J (2015) Metabolic reprogramming of the tumour microenvironment. FEBS J 282:3892–3898.  https://doi.org/10.1111/febs.13402CrossRefPubMedPubMedCentralGoogle Scholar
  254. 254.
    Marchiq I, Pouyssegur J (2016) Hypoxia, cancer metabolism and the therapeutic benefit of targeting lactate/H(+) symporters. J Mol Med (Berl) 94:155–171.  https://doi.org/10.1007/s00109-015-1307-xCrossRefGoogle Scholar
  255. 255.
    Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, Sahai E (2007) Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol 9:1392–1400.  https://doi.org/10.1038/ncb1658CrossRefPubMedPubMedCentralGoogle Scholar
  256. 256.
    Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478.  https://doi.org/10.1038/nrm2183CrossRefPubMedPubMedCentralGoogle Scholar
  257. 257.
    Delgado-Bellido D, Serrano-Saenz S, Fernandez-Cortes M, Oliver FJ (2017) Vasculogenic mimicry signaling revisited: focus on non-vascular VE-cadherin. Mol Cancer 16:65.  https://doi.org/10.1186/s12943-017-0631-xCrossRefPubMedPubMedCentralGoogle Scholar
  258. 258.
    Dong J, Zhao Y, Huang Q, Fei X, Diao Y, Shen Y, Xiao H, Zhang T, Lan Q, Gu X (2011) Glioma stem/progenitor cells contribute to neovascularization via transdifferentiation. Stem Cell Rev 7:141–152.  https://doi.org/10.1007/s12015-010-9169-7CrossRefGoogle Scholar
  259. 259.
    Xu Y, Li Q, Li XY, Yang QY, Xu WW, Liu GL (2012) Short-term anti-vascular endothelial growth factor treatment elicits vasculogenic mimicry formation of tumors to accelerate metastasis. J Exp Clin Cancer Res 31:16.  https://doi.org/10.1186/1756-9966-31-16CrossRefPubMedPubMedCentralGoogle Scholar
  260. 260.
    Ruffini F, D’Atri S, Lacal PM (2013) Neuropilin-1 expression promotes invasiveness of melanoma cells through vascular endothelial growth factor receptor-2-dependent and -independent mechanisms. Int J Oncol 43:297–306.  https://doi.org/10.3892/ijo.2013.1948CrossRefPubMedPubMedCentralGoogle Scholar
  261. 261.
    Fantin A, Vieira JM, Plein A, Denti L, Fruttiger M, Pollard JW, Ruhrberg C (2013) NRP1 acts cell autonomously in endothelium to promote tip cell function during sprouting angiogenesis. Blood 121:2352–2362.  https://doi.org/10.1182/blood-2012-05-424713CrossRefPubMedPubMedCentralGoogle Scholar
  262. 262.
    Larrivee B, Prahst C, Gordon E, del Toro R, Mathivet T, Duarte A, Simons M, Eichmann A (2012) ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway. Dev Cell 22:489–500.  https://doi.org/10.1016/j.devcel.2012.02.005CrossRefPubMedPubMedCentralGoogle Scholar
  263. 263.
    Guttmann-Raviv N, Kessler O, Shraga-Heled N, Lange T, Herzog Y, Neufeld G (2006) The neuropilins and their role in tumorigenesis and tumor progression. Cancer Lett 231:1–11.  https://doi.org/10.1016/j.canlet.2004.12.047CrossRefPubMedPubMedCentralGoogle Scholar
  264. 264.
    Migliozzi MT, Mucka P, Bielenberg DR (2014) Lymphangiogenesis and metastasis--a closer look at the neuropilin/semaphorin3 axis. Microvasc Res 96:68–76.  https://doi.org/10.1016/j.mvr.2014.07.006CrossRefPubMedPubMedCentralGoogle Scholar
  265. 265.
    Jurisic G, Maby-El Hajjami H, Karaman S, Ochsenbein AM, Alitalo A, Siddiqui SS, Ochoa Pereira C, Petrova TV, Detmar M (2012) An unexpected role of semaphorin3a-neuropilin-1 signaling in lymphatic vessel maturation and valve formation. Circ Res 111:426–436.  https://doi.org/10.1161/CIRCRESAHA.112.269399CrossRefPubMedPubMedCentralGoogle Scholar
  266. 266.
    Serini G, Tamagnone L (2015) Bad vessels beware! Semaphorins will sort you out! EMBO Mol Med 7:1251–1253.  https://doi.org/10.15252/emmm.201505551CrossRefPubMedPubMedCentralGoogle Scholar
  267. 267.
    Mumblat Y, Kessler O, Ilan N, Neufeld G (2015) Full-length semaphorin-3C is an inhibitor of tumor lymphangiogenesis and metastasis. Cancer Res 75:2177–2186.  https://doi.org/10.1158/0008-5472.CAN-14-2464CrossRefPubMedPubMedCentralGoogle Scholar
  268. 268.
    Miyato H, Tsuno NH, Kitayama J (2012) Semaphorin 3C is involved in the progression of gastric cancer. Cancer Sci 103:1961–1966.  https://doi.org/10.1111/cas.12003CrossRefPubMedPubMedCentralGoogle Scholar
  269. 269.
    Herman JG, Meadows GG (2007) Increased class 3 semaphorin expression modulates the invasive and adhesive properties of prostate cancer cells. Int J Oncol 30:1231–1238PubMedPubMedCentralGoogle Scholar
  270. 270.
    Man J, Shoemake J, Zhou W, Fang X, Wu Q, Rizzo A, Prayson R, Bao S, Rich JN, Yu JS (2014) Sema3C promotes the survival and tumorigenicity of glioma stem cells through Rac1 activation. Cell Rep 9:1812–1826.  https://doi.org/10.1016/j.celrep.2014.10.055CrossRefPubMedPubMedCentralGoogle Scholar
  271. 271.
    Bassi DE, Fu J, Lopez de Cicco R, Klein-Szanto AJ (2005) Proprotein convertases: “master switches” in the regulation of tumor growth and progression. Mol Carcinog 44:151–161.  https://doi.org/10.1002/mc.20134CrossRefPubMedPubMedCentralGoogle Scholar
  272. 272.
    Riabov V, Gudima A, Wang N, Mickley A, Orekhov A, Kzhyshkowska J (2014) Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front Physiol 5:75.  https://doi.org/10.3389/fphys.2014.00075CrossRefPubMedPubMedCentralGoogle Scholar
  273. 273.
    Esselens C, Malapeira J, Colome N, Casal C, Rodriguez-Manzaneque JC, Canals F, Arribas J (2010) The cleavage of semaphorin 3C induced by ADAMTS1 promotes cell migration. J Biol Chem 285:2463–2473.  https://doi.org/10.1074/jbc.M109.055129CrossRefPubMedPubMedCentralGoogle Scholar
  274. 274.
    Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62.  https://doi.org/10.1126/science.1104819CrossRefPubMedPubMedCentralGoogle Scholar
  275. 275.
    Jain RK (2014) Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26:605–622.  https://doi.org/10.1016/j.ccell.2014.10.006CrossRefPubMedPubMedCentralGoogle Scholar
  276. 276.
    Maione F, Capano S, Regano D, Zentilin L, Giacca M, Casanovas O, Bussolino F, Serini G, Giraudo E (2012) Semaphorin 3A overcomes cancer hypoxia and metastatic dissemination induced by antiangiogenic treatment in mice. J Clin Invest 122:1832–1848.  https://doi.org/10.1172/JCI58976CrossRefPubMedPubMedCentralGoogle Scholar
  277. 277.
    Acevedo LM, Barillas S, Weis SM, Gothert JR, Cheresh DA (2008) Semaphorin 3A suppresses VEGF-mediated angiogenesis yet acts as a vascular permeability factor. Blood 111:2674–2680.  https://doi.org/10.1182/blood-2007-08-110205CrossRefPubMedPubMedCentralGoogle Scholar
  278. 278.
    Cerani A, Tetreault N, Menard C, Lapalme E, Patel C, Sitaras N, Beaudoin F, Leboeuf D, De Guire V, Binet F et al (2013) Neuron-derived semaphorin 3A is an early inducer of vascular permeability in diabetic retinopathy via neuropilin-1. Cell Metab 18:505–518.  https://doi.org/10.1016/j.cmet.2013.09.003CrossRefPubMedPubMedCentralGoogle Scholar
  279. 279.
    Gioelli N, Maione F, Camillo C, Ghitti M, Valdembri D, Morello N, Darche M, Zentilin L, Cagnoni G, Qiu Y et al (2018) A rationally designed NRP1-independent superagonist SEMA3A mutant is an effective anticancer agent. Sci Transl Med 10.  https://doi.org/10.1126/scitranslmed.aah4807PubMedCrossRefPubMedCentralGoogle Scholar
  280. 280.
    Albini A, Tosetti F, Li VW, Noonan DM, Li WW (2012) Cancer prevention by targeting angiogenesis. Nat Rev Clin Oncol 9:498–509.  https://doi.org/10.1038/nrclinonc.2012.120CrossRefPubMedPubMedCentralGoogle Scholar
  281. 281.
    Franzolin G, Tamagnone L (2019) Semaphorin signaling in cancer-associated inflammation. Int J Mol Sci 20.  https://doi.org/10.3390/ijms20020377PubMedCentralCrossRefPubMedGoogle Scholar
  282. 282.
    Schellenburg S, Schulz A, Poitz DM, Muders MH (2017) Role of neuropilin-2 in the immune system. Mol Immunol 90:239–244.  https://doi.org/10.1016/j.molimm.2017.08.010CrossRefPubMedGoogle Scholar
  283. 283.
    Roy S, Bag AK, Dutta S, Polavaram NS, Islam R, Schellenburg S, Banwait J, Guda C, Ran S, Hollingsworth MA et al (2018) Macrophage-derived neuropilin-2 exhibits novel tumor-promoting functions. Cancer Res 78:5600–5617.  https://doi.org/10.1158/0008-5472.CAN-18-0562CrossRefPubMedPubMedCentralGoogle Scholar
  284. 284.
    Chen XJ, Wu S, Yan RM, Fan LS, Yu L, Zhang YM, Wei WF, Zhou CF, Wu XG, Zhong M et al (2019) The role of the hypoxia-Nrp-1 axis in the activation of M2-like tumor-associated macrophages in the tumor microenvironment of cervical cancer. Mol Carcinog 58:388–397.  https://doi.org/10.1002/mc.22936CrossRefPubMedGoogle Scholar
  285. 285.
    Dejda A, Mawambo G, Daudelin JF, Miloudi K, Akla N, Patel C, Andriessen EM, Labrecque N, Sennlaub F, Sapieha P (2016) Neuropilin-1-expressing microglia are associated with nascent retinal vasculature yet dispensable for developmental angiogenesis. Invest Ophthalmol Vis Sci 57:1530–1536.  https://doi.org/10.1167/iovs.15-18598CrossRefPubMedPubMedCentralGoogle Scholar
  286. 286.
    Karkkainen MJ, Alitalo K (2002) Lymphatic endothelial regulation, lymphoedema, and lymph node metastasis. Semin Cell Dev Biol 13:9–18.  https://doi.org/10.1006/scdb.2001.0286CrossRefPubMedPubMedCentralGoogle Scholar
  287. 287.
    Karpanen T, Heckman CA, Keskitalo S, Jeltsch M, Ollila H, Neufeld G, Tamagnone L, Alitalo K (2006) Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J 20:1462–1472.  https://doi.org/10.1096/fj.05-5646comCrossRefPubMedPubMedCentralGoogle Scholar
  288. 288.
    Kawakami T, Tokunaga T, Hatanaka H, Kijima H, Yamazaki H, Abe Y, Osamura Y, Inoue H, Ueyama Y, Nakamura M (2002) Neuropilin 1 and neuropilin 2 co-expression is significantly correlated with increased vascularity and poor prognosis in nonsmall cell lung carcinoma. Cancer 95:2196–2201.  https://doi.org/10.1002/cncr.10936CrossRefPubMedPubMedCentralGoogle Scholar
  289. 289.
    Shevach EM (2009) Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30:636–645.  https://doi.org/10.1016/j.immuni.2009.04.010CrossRefPubMedPubMedCentralGoogle Scholar
  290. 290.
    Zhao H, Liao X, Kang Y (2017) Tregs: where we are and what comes next? Front Immunol 8:1578.  https://doi.org/10.3389/fimmu.2017.01578CrossRefPubMedPubMedCentralGoogle Scholar
  291. 291.
    Yu Y, Cui J (2018) Present and future of cancer immunotherapy: a tumor microenvironmental perspective. Oncol Lett 16:4105–4113.  https://doi.org/10.3892/ol.2018.9219CrossRefPubMedPubMedCentralGoogle Scholar
  292. 292.
    Napolitano V, Tamagnone L (2019) Neuropilins controlling cancer therapy responsiveness. Int J Mol Sci 20.  https://doi.org/10.3390/ijms20082049PubMedCentralCrossRefGoogle Scholar
  293. 293.
    Torti D, Trusolino L (2011) Oncogene addiction as a foundational rationale for targeted anti-cancer therapy: promises and perils. EMBO Mol Med 3:623–636.  https://doi.org/10.1002/emmm.201100176CrossRefPubMedPubMedCentralGoogle Scholar
  294. 294.
    Fallahi-Sichani M, Becker V, Izar B, Baker GJ, Lin JR, Boswell SA, Shah P, Rotem A, Garraway LA, Sorger PK (2017) Adaptive resistance of melanoma cells to RAF inhibition via reversible induction of a slowly dividing de-differentiated state. Mol Syst Biol 13:905.  https://doi.org/10.15252/msb.20166796CrossRefPubMedPubMedCentralGoogle Scholar
  295. 295.
    Wilson TR, Fridlyand J, Yan Y, Penuel E, Burton L, Chan E, Peng J, Lin E, Wang Y, Sosman J et al (2012) Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature 487:505–509.  https://doi.org/10.1038/nature11249CrossRefPubMedPubMedCentralGoogle Scholar
  296. 296.
    Chaudhary B, Khaled YS, Ammori BJ, Elkord E (2014) Neuropilin 1: function and therapeutic potential in cancer. Cancer Immunol Immunother 63:81–99.  https://doi.org/10.1007/s00262-013-1500-0CrossRefPubMedPubMedCentralGoogle Scholar
  297. 297.
    Graziani G, Lacal PM (2015) Neuropilin-1 as therapeutic target for malignant melanoma. Front Oncol 5:125.  https://doi.org/10.3389/fonc.2015.00125CrossRefPubMedPubMedCentralGoogle Scholar
  298. 298.
    Kamiya T, Kawakami T, Abe Y, Nishi M, Onoda N, Miyazaki N, Oida Y, Yamazaki H, Ueyama Y, Nakamura M (2006) The preserved expression of neuropilin (NRP) 1 contributes to a better prognosis in colon cancer. Oncol Rep 15:369–373PubMedPubMedCentralGoogle Scholar
  299. 299.
    Gray MJ, Wey JS, Belcheva A, McCarty MF, Trevino JG, Evans DB, Ellis LM, Gallick GE (2005) Neuropilin-1 suppresses tumorigenic properties in a human pancreatic adenocarcinoma cell line lacking neuropilin-1 coreceptors. Cancer Res 65:3664–3670.  https://doi.org/10.1158/0008-5472.CAN-04-2229CrossRefPubMedPubMedCentralGoogle Scholar
  300. 300.
    Jamil MO, Hathaway A, Mehta A (2015) Tivozanib: status of development. Curr Oncol Rep 17:24.  https://doi.org/10.1007/s11912-015-0451-3CrossRefPubMedPubMedCentralGoogle Scholar
  301. 301.
    Lambrechts D, Lenz HJ, de Haas S, Carmeliet P, Scherer SJ (2013) Markers of response for the antiangiogenic agent bevacizumab. J Clin Oncol 31:1219–1230.  https://doi.org/10.1200/JCO.2012.46.2762CrossRefPubMedPubMedCentralGoogle Scholar
  302. 302.
    Baumgarten P, Blank AE, Franz K, Hattingen E, Dunst M, Zeiner P, Hoffmann K, Bahr O, Mader L, Goeppert B et al (2016) 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 18:173–183.  https://doi.org/10.1093/neuonc/nov288CrossRefPubMedPubMedCentralGoogle Scholar
  303. 303.
    Bais C, Mueller B, Brady MF, Mannel RS, Burger RA, Wei W, Marien KM, Kockx MM, Husain A, Birrer MJ et al (2017) Tumor microvessel density as a potential predictive marker for Bevacizumab benefit: GOG-0218 biomarker analyses. J Natl Cancer Inst 109.  https://doi.org/10.1093/jnci/djx066
  304. 304.
    Schuch G, Machluf M, Bartsch G Jr, Nomi M, Richard H, Atala A, Soker S (2002) In vivo administration of vascular endothelial growth factor (VEGF) and its antagonist, soluble neuropilin-1, predicts a role of VEGF in the progression of acute myeloid leukemia in vivo. Blood 100:4622–4628.  https://doi.org/10.1182/blood.V100.13.4622CrossRefPubMedPubMedCentralGoogle Scholar
  305. 305.
    Sugahara KN, Scodeller P, Braun GB, de Mendoza TH, Yamazaki CM, Kluger MD, Kitayama J, Alvarez E, Howell SB, Teesalu T et al (2015) A tumor-penetrating peptide enhances circulation-independent targeting of peritoneal carcinomatosis. J Control Release 212:59–69.  https://doi.org/10.1016/j.jconrel.2015.06.009CrossRefPubMedPubMedCentralGoogle Scholar
  306. 306.
    Simon-Gracia L, Hunt H, Scodeller P, Gaitzsch J, Kotamraju VR, Sugahara KN, Tammik O, Ruoslahti E, Battaglia G, Teesalu T (2016) iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes. Biomaterials 104:247–257.  https://doi.org/10.1016/j.biomaterials.2016.07.023CrossRefPubMedPubMedCentralGoogle Scholar
  307. 307.
    Zhang H, Tam S, Ingham ES, Mahakian LM, Lai CY, Tumbale SK, Teesalu T, Hubbard NE, Borowsky AD, Ferrara KW (2015) Ultrasound molecular imaging of tumor angiogenesis with a neuropilin-1-targeted microbubble. Biomaterials 56:104–113.  https://doi.org/10.1016/j.biomaterials.2015.03.043CrossRefPubMedPubMedCentralGoogle Scholar
  308. 308.
    Bumbaca D, Xiang H, Boswell CA, Port RE, Stainton SL, Mundo EE, Ulufatu S, Bagri A, Theil FP, Fielder PJ et al (2012) Maximizing tumour exposure to anti-neuropilin-1 antibody requires saturation of non-tumour tissue antigenic sinks in mice. Br J Pharmacol 166:368–377.  https://doi.org/10.1111/j.1476-5381.2011.01777.xCrossRefPubMedPubMedCentralGoogle Scholar
  309. 309.
    Feldman DR, Baum MS, Ginsberg MS, Hassoun H, Flombaum CD, Velasco S, Fischer P, Ronnen E, Ishill N, Patil S et al (2009) Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 27:1432–1439.  https://doi.org/10.1200/JCO.2008.19.0108CrossRefPubMedPubMedCentralGoogle Scholar
  310. 310.
    Mahoney KM, Rennert PD, Freeman GJ (2015) Combination cancer immunotherapy and new immunomodulatory targets. Nat Rev Drug Discov 14:561–584.  https://doi.org/10.1038/nrd4591CrossRefPubMedPubMedCentralGoogle Scholar
  311. 311.
    Weekes CD, Beeram M, Tolcher AW, Papadopoulos KP, Gore L, Hegde P, Xin Y, Yu R, Shih LM, Xiang H et al (2014) A phase I study of the human monoclonal anti-NRP1 antibody MNRP1685A in patients with advanced solid tumors. Investig New Drugs 32:653–660.  https://doi.org/10.1007/s10637-014-0071-zCrossRefGoogle Scholar
  312. 312.
    Patnaik A, LoRusso PM, Messersmith WA, Papadopoulos KP, Gore L, Beeram M, Ramakrishnan V, Kim AH, Beyer JC, Mason Shih L et al (2014) 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 73:951–960.  https://doi.org/10.1007/s00280-014-2426-8CrossRefPubMedPubMedCentralGoogle Scholar
  313. 313.
    Leng Q, Woodle MC, Mixson AJ (2017) NRP1 transport of cancer therapeutics mediated by tumor-penetrating peptides. Drugs Future 42:95–104.  https://doi.org/10.1358/dof.2017.042.02.2564106CrossRefPubMedPubMedCentralGoogle Scholar
  314. 314.
    Jarvis A, Allerston CK, Jia H, Herzog B, Garza-Garcia A, Winfield N, Ellard K, Aqil R, Lynch R, Chapman C et al (2010) Small molecule inhibitors of the neuropilin-1 vascular endothelial growth factor A (VEGF-A) interaction. J Med Chem 53:2215–2226.  https://doi.org/10.1021/jm901755gCrossRefPubMedPubMedCentralGoogle Scholar
  315. 315.
    Binetruy-Tournaire R, Demangel C, Malavaud B, Vassy R, Rouyre S, Kraemer M, Plouet J, Derbin C, Perret G, Mazie JC (2000) Identification of a peptide blocking vascular endothelial growth factor (VEGF)-mediated angiogenesis. EMBO J 19:1525–1533.  https://doi.org/10.1093/emboj/19.7.1525CrossRefPubMedPubMedCentralGoogle Scholar
  316. 316.
    Barr MP, Byrne AM, Duffy AM, Condron CM, Devocelle M, Harriott P, Bouchier-Hayes DJ, Harmey JH (2005) A peptide corresponding to the neuropilin-1-binding site on VEGF(165) induces apoptosis of neuropilin-1-expressing breast tumour cells. Br J Cancer 92:328–333.  https://doi.org/10.1038/sj.bjc.6602308CrossRefPubMedPubMedCentralGoogle Scholar
  317. 317.
    Sidman RL, Li J, Lawrence M, Hu W, Musso GF, Giordano RJ, Cardo-Vila M, Pasqualini R, Arap W (2015) The peptidomimetic Vasotide targets two retinal VEGF receptors and reduces pathological angiogenesis in murine and nonhuman primate models of retinal disease. Sci Transl Med 7:309ra165.  https://doi.org/10.1126/scitranslmed.aac4882CrossRefPubMedPubMedCentralGoogle Scholar
  318. 318.
    Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, Chung YC, Wu MH, Yang SC, Pan SH, Shih JY et al (2007) Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res 13:4759–4768.  https://doi.org/10.1158/1078-0432.CCR-07-0001CrossRefPubMedPubMedCentralGoogle Scholar
  319. 319.
    Jia H, Aqil R, Cheng L, Chapman C, Shaikh S, Jarvis A, Chan AW, Hartzoulakis B, Evans IM, Frolov A et al (2014) N-terminal modification of VEGF-A C terminus-derived peptides delineates structural features involved in neuropilin-1 binding and functional activity. Chembiochem 15:1161–1170.  https://doi.org/10.1002/cbic.201300658CrossRefPubMedPubMedCentralGoogle Scholar
  320. 320.
    Powell J, Mota F, Steadman D, Soudy C, Miyauchi JT, Crosby S, Jarvis A, Reisinger T, Winfield N, Evans G et al (2018) Small molecule neuropilin-1 antagonists combine antiangiogenic and antitumor activity with immune modulation through reduction of transforming growth factor beta (TGFbeta) production in regulatory T-cells. J Med Chem 61:4135–4154.  https://doi.org/10.1021/acs.jmedchem.8b00210CrossRefPubMedPubMedCentralGoogle Scholar
  321. 321.
    Zanuy D, Kotla R, Nussinov R, Teesalu T, Sugahara KN, Aleman C, Haspel N (2013) Sequence dependence of C-end rule peptides in binding and activation of neuropilin-1 receptor. J Struct Biol 182:78–86.  https://doi.org/10.1016/j.jsb.2013.02.006CrossRefPubMedPubMedCentralGoogle Scholar
  322. 322.
    Zhang L, Parry GC, Levin EG (2013) Inhibition of tumor cell migration by LD22-4, an N-terminal fragment of 24-kDa FGF2, is mediated by neuropilin 1. Cancer Res 73:3316–3325.  https://doi.org/10.1158/0008-5472.CAN-12-3015CrossRefPubMedPubMedCentralGoogle Scholar
  323. 323.
    Ding L, Donate F, Parry GC, Guan X, Maher P, Levin EG (2002) Inhibition of cell migration and angiogenesis by the amino-terminal fragment of 24kD basic fibroblast growth factor. J Biol Chem 277:31056–31061.  https://doi.org/10.1074/jbc.M203658200CrossRefPubMedPubMedCentralGoogle Scholar
  324. 324.
    Levin EG, Sikora L, Ding L, Rao SP, Sriramarao P (2004) Suppression of tumor growth and angiogenesis in vivo by a truncated form of 24-kd fibroblast growth factor (FGF)-2. Am J Pathol 164:1183–1190.  https://doi.org/10.1016/S0002-9440(10)63206-3CrossRefPubMedPubMedCentralGoogle Scholar
  325. 325.
    Kim YJ, Bae J, Shin TH, Kang SH, Jeong M, Han Y, Park JH, Kim SK, Kim YS (2015) Immunoglobulin Fc-fused, neuropilin-1-specific peptide shows efficient tumor tissue penetration and inhibits tumor growth via anti-angiogenesis. J Control Release 216:56–68.  https://doi.org/10.1016/j.jconrel.2015.08.016CrossRefPubMedPubMedCentralGoogle Scholar
  326. 326.
    Tymecka D, Puszko AK, Lipinski PFJ, Fedorczyk B, Wilenska B, Sura K, Perret GY, Misicka A (2018) Branched pentapeptides as potent inhibitors of the vascular endothelial growth factor 165 binding to neuropilin-1: design, synthesis and biological activity. Eur J Med Chem 158:453–462.  https://doi.org/10.1016/j.ejmech.2018.08.083CrossRefPubMedPubMedCentralGoogle Scholar
  327. 327.
    Fedorczyk B, Lipinski PFJ, Puszko AK, Tymecka D, Wilenska B, Dudka W, Perret GY, Wieczorek R, Misicka A (2019) Triazolopeptides inhibiting the interaction between neuropilin-1 and vascular endothelial growth factor-165. Molecules 24.  https://doi.org/10.3390/molecules24091756PubMedCentralCrossRefGoogle Scholar
  328. 328.
    Nasarre C, Roth M, Jacob L, Roth L, Koncina E, Thien A, Labourdette G, Poulet P, Hubert P, Cremel G et al (2010) Peptide-based interference of the transmembrane domain of neuropilin-1 inhibits glioma growth in vivo. Oncogene 29:2381–2392.  https://doi.org/10.1038/onc.2010.9CrossRefPubMedPubMedCentralGoogle Scholar
  329. 329.
    Arpel A, Gamper C, Spenle C, Fernandez A, Jacob L, Baumlin N, Laquerriere P, Orend G, Cremel G, Bagnard D (2016) Inhibition of primary breast tumor growth and metastasis using a neuropilin-1 transmembrane domain interfering peptide. Oncotarget 7:54723–54732.  https://doi.org/10.18632/oncotarget.10101CrossRefPubMedPubMedCentralGoogle Scholar
  330. 330.
    Simon-Gracia L, Hunt H, Teesalu T (2018) Peritoneal carcinomatosis targeting with tumor homing peptides. Molecules 23.  https://doi.org/10.3390/molecules23051190PubMedCentralCrossRefGoogle Scholar
  331. 331.
    Wang HB, Zhang H, Zhang JP, Li Y, Zhao B, Feng GK, Du Y, Xiong D, Zhong Q, Liu WL et al (2015) Neuropilin 1 is an entry factor that promotes EBV infection of nasopharyngeal epithelial cells. Nat Commun 6:6240.  https://doi.org/10.1038/ncomms7240CrossRefPubMedPubMedCentralGoogle Scholar
  332. 332.
    Fogal V, Zhang L, Krajewski S, Ruoslahti E (2008) Mitochondrial/cell-surface protein p32/gC1qR as a molecular target in tumor cells and tumor stroma. Cancer Res 68:7210–7218.  https://doi.org/10.1158/0008-5472.CAN-07-6752CrossRefPubMedPubMedCentralGoogle Scholar
  333. 333.
    Paasonen L, Sharma S, Braun GB, Kotamraju VR, Chung TD, She ZG, Sugahara KN, Yliperttula M, Wu B, Pellecchia M et al (2016) New p32/gC1qR ligands for targeted tumor drug delivery. Chembiochem 17:570–575.  https://doi.org/10.1002/cbic.201500564CrossRefPubMedPubMedCentralGoogle Scholar
  334. 334.
    Sharma S, Kotamraju VR, Molder T, Tobi A, Teesalu T, Ruoslahti E (2017) Tumor-penetrating nanosystem strongly suppresses breast tumor growth. Nano Lett 17:1356–1364.  https://doi.org/10.1021/acs.nanolett.6b03815CrossRefPubMedPubMedCentralGoogle Scholar
  335. 335.
    Hunt H, Simon-Gracia L, Tobi A, Kotamraju VR, Sharma S, Nigul M, Sugahara KN, Ruoslahti E, Teesalu T (2017) Targeting of p32 in peritoneal carcinomatosis with intraperitoneal linTT1 peptide-guided pro-apoptotic nanoparticles. J Control Release 260:142–153.  https://doi.org/10.1016/j.jconrel.2017.06.005CrossRefPubMedPubMedCentralGoogle Scholar
  336. 336.
    Liu X, Lin P, Perrett I, Lin J, Liao YP, Chang CH, Jiang J, Wu N, Donahue T, Wainberg Z et al (2017) Tumor-penetrating peptide enhances transcytosis of silicasome-based chemotherapy for pancreatic cancer. J Clin Invest 127:2007–2018.  https://doi.org/10.1172/JCI92284CrossRefPubMedPubMedCentralGoogle Scholar
  337. 337.
    Ruoslahti E (2017) Tumor penetrating peptides for improved drug delivery. Adv Drug Deliv Rev 110-111:3–12.  https://doi.org/10.1016/j.addr.2016.03.008CrossRefPubMedPubMedCentralGoogle Scholar
  338. 338.
    Thoreau F, Vanwonterghem L, Henry M, Coll JL, Boturyn D (2018) Design of RGD-ATWLPPR peptide conjugates for the dual targeting of alphaVbeta3 integrin and neuropilin-1. Org Biomol Chem 16:4101–4107.  https://doi.org/10.1039/c8ob00669eCrossRefPubMedPubMedCentralGoogle Scholar
  339. 339.
    CEND-1 in combination with nanoparticle albumin bound-paclitaxel (Abraxane) and gemcitabine in metastatic pancreatic cancer, 27 May 2018 [cited 5 Dec 2018], 1 p. ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US), 31 Jul 2018. Identifier: NCT03517176. Available from: https://www.clinicaltrials.gov/ct2/show/NCT03517176?term=Cend-1&cond=cancer&rank=1
  340. 340.
    Liang DS, Zhang WJ, Wang AT, Su HT, Zhong HJ, Qi XR (2017) Treating metastatic triple negative breast cancer with CD44/neuropilin dual molecular targets of multifunctional nanoparticles. Biomaterials 137:23–36.  https://doi.org/10.1016/j.biomaterials.2017.05.022CrossRefPubMedPubMedCentralGoogle Scholar
  341. 341.
    Chen L, Zhang G, Shi Y, Qiu R, Khan AA (2015) Neuropilin-1 (NRP-1) and magnetic nanoparticles, a potential combination for diagnosis and therapy of gliomas. Curr Pharm Des 21:5434–5449PubMedCrossRefPubMedCentralGoogle Scholar
  342. 342.
    Xiang Z, Jiang G, Yang X, Fan D, Nan X, Li D, Hu Z, Fang Q (2019) Peptosome coadministration improves nanoparticle delivery to tumors through NRP1-mediated co-endocytosis. Biomol Ther 9.  https://doi.org/10.3390/biom9050172PubMedCentralCrossRefGoogle Scholar
  343. 343.
    Thomas E, Colombeau L, Gries M, Peterlini T, Mathieu C, Thomas N, Boura C, Frochot C, Vanderesse R, Lux F et al (2017) Ultrasmall AGuIX theranostic nanoparticles for vascular-targeted interstitial photodynamic therapy of glioblastoma. Int J Nanomedicine 12:7075–7088.  https://doi.org/10.2147/IJN.S141559CrossRefPubMedPubMedCentralGoogle Scholar
  344. 344.
    Roth L, Agemy L, Kotamraju VR, Braun G, Teesalu T, Sugahara KN, Hamzah J, Ruoslahti E (2012) Transtumoral targeting enabled by a novel neuropilin-binding peptide. Oncogene 31:3754–3763.  https://doi.org/10.1038/onc.2011.537CrossRefPubMedPubMedCentralGoogle Scholar
  345. 345.
    Sugahara KN, Braun GB, de Mendoza TH, Kotamraju VR, French RP, Lowy AM, Teesalu T, Ruoslahti E (2015) Tumor-penetrating iRGD peptide inhibits metastasis. Mol Cancer Ther 14:120–128.  https://doi.org/10.1158/1535-7163.MCT-14-0366CrossRefPubMedPubMedCentralGoogle Scholar
  346. 346.
    Hamilton AM, Aidoudi-Ahmed S, Sharma S, Kotamraju VR, Foster PJ, Sugahara KN, Ruoslahti E, Rutt BK (2015) Nanoparticles coated with the tumor-penetrating peptide iRGD reduce experimental breast cancer metastasis in the brain. J Mol Med (Berl) 93:991–1001.  https://doi.org/10.1007/s00109-015-1279-xCrossRefGoogle Scholar
  347. 347.
    Zakraoui O, Marcinkiewicz C, Aloui Z, Othman H, Grepin R, Haoues M, Essafi M, Srairi-Abid N, Gasmi A, Karoui H et al (2017) Lebein, a snake venom disintegrin, suppresses human colon cancer cells proliferation and tumor-induced angiogenesis through cell cycle arrest, apoptosis induction and inhibition of VEGF expression. Mol Carcinog 56:18–35.  https://doi.org/10.1002/mc.22470CrossRefPubMedPubMedCentralGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Institute of Physiological Chemistry and PathobiochemistryUniversity of MünsterMünsterGermany

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