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.
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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
References
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 92:735–745
Nakamura F, Goshima Y (2002) Structural and functional relation of neuropilins. Adv Exp Med Biol 515:55–69
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.R115.687327
Niland S, Eble JA (2019) Neuropilins in the context of tumor vasculature. Int J Mol Sci 20. https://doi.org/10.3390/ijms20030639
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.1999.5790
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 7:295–307
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-F
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 290:465–470
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 19:547–559
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.2000.6381
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.040337597
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.v97.6.1671
Tao Q, Spring SC, Terman BI (2003) Characterization of a new alternatively spliced neuropilin-1 isoform. Angiogenesis 6:39–45
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.2004.02.001
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.2007.07.007
Lee CC, Kreusch A, McMullan D, Ng K, Spraggon G (2003) Crystal structure of the human neuropilin-1 b1 domain. Structure 11:99–108
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.7601188
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.2008.151
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/BJ20100580
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.M116.714329
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.2017.01228
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.M702965200
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.118.311118
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/s10456-008-9097-1
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.e07-06-0625
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.0097779
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.E09-12-1061
Ellis LM (2006) The role of neuropilins in cancer. Mol Cancer Ther 5:1099–1107. https://doi.org/10.1158/1535-7163.MCT-05-0538
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.M609711200
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 21:1079–1092
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.1105416
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.2007.10.019
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.14405
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.2018.10.004
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/ijms19041264
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:000167569000004
Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9:669–676. https://doi.org/10.1038/nm0603-669
Klagsbrun M, Takashima S, Mamluk R (2002) The role of neuropilin in vascular and tumor biology. Adv Exp Med Biol 515:33–48
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 12:13–19
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.2006.10.018
Sarabipour S, Mac Gabhann F (2018) VEGF-A121a binding to neuropilins—a concept revisited. Cell Adhes Migr 12:204–214. https://doi.org/10.1080/19336918.2017.1372878
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.M909259199
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.94.14.7192
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.2016.87
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.7b00761
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.0908201106
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.2012.11.013
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/BJ20110301
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.M703554200
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.2018.01.040
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/s10555-018-9734-0
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.273.35.22272
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.M200730200
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-07-3256
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-2007-04-084269
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.M410924200
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/10.1155/2018/1075156
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.18706
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.2015.02.124
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.200493
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.0208090
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/bgq281
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.2018.01.014
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-12-0995
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-2011-03-341388
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 39:589–598
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_1
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-09-1810
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.12017
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/ijms20030556
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/JCI36308
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.111600
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.S37744
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.2014.10.007
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.2006.11.021
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-X
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/nrc2404
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.1000025
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.23332
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-11-3907
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.201202078
Campbell ID, Humphries MJ (2011) Integrin structure, activation, and interactions. Cold Spring Harb Perspect Biol 3. https://doi.org/10.1101/cshperspect.a004994
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.25.022106.141618
Humphries JD, Byron A, Humphries MJ (2006) Integrin ligands at a glance. J Cell Sci 119:3901–3903. https://doi.org/10.1242/jcs.03098
Hynes RO (2009) The extracellular matrix: not just pretty fibrils. Science 326:1216–1219. https://doi.org/10.1126/science.1176009
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.x
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.2018.08.004
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.192054
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.2011.11.010
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/nature09621
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.22419
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.2014.12.046
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-13-0529
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-y
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-y
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.019927
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.M109.030700
Castellani V (2002) The function of neuropilin/L1 complex. Adv Exp Med Biol 515:91–102
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.2004.01.010
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.2008.86
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-18-0289
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.3373-07.2007
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.4.12.1317
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.272.39.24203
Stringer SE (2006) The role of heparan sulphate proteoglycans in angiogenesis. Biochem Soc Trans 34:451–453. https://doi.org/10.1042/BST0340451
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.a006502
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.2013.11.002
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.112.00006
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.25032
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.1801346
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.5141
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.2014.02.010
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.2013.00405
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/nature12428
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.177.3.1460
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-12-0085
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.010918
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-09-2797
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.626
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 99:59–69
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/10.1159/000485455
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/s13046-017-0577-2
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/ijms19041203
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.2010.04.003
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.2015.10.003
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.0800835105
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.114.304881
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)63772-8
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 88:584–592
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.6600811
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.16.10.5276
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/ncomms12038
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-17-2020
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/BJ20091512
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.20248
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/JCI41203
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/10.1186/1476-4598-9-209
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.00903-10
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.d4
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.1653708
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.1509384113
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.1210348
Weinstein IB (2002) Cancer. Addiction to oncogenes—the Achilles heal of cancer. Science 297:63–64. https://doi.org/10.1126/science.1073096
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/s13046-016-0291-5
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/JCI99257
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-w
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.2009.12.046
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/nature13121
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.2014.418
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.M110.151696
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.113746
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/ncomms8264
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/s41598-017-12992-2
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.8233
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.16308
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.a006718
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.2011.198
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.201404922
Hao J, Yu JS (2018) Semaphorin 3C and its receptors in cancer and cancer stem-like cells. Biomedicine 6. https://doi.org/10.3390/biomedicines6020042
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/ijms20030774
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/JCI21378
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 64:1008–1015
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-08-1520
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.2005.06.004
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.2009.03.025
Armulik A, Abramsson A, Betsholtz C (2005) Endothelial/pericyte interactions. Circ Res 97:512–523. https://doi.org/10.1161/01.RES.0000182903.16652.d7
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.2005.10.019
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.107.161521
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.2013.02.003
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-z
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/JCI25705
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.0033633
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.6.8.4363
Goel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13:871–882. https://doi.org/10.1038/nrc3627
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 6:851–860
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/nature01784
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/10.1080/19336918.2016.1212805
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.094433
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-09-0552
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.2008.120
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 19:6519–6527
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.C800137200
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/s13277-016-5138-3
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/ncomms5904
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.1183057
Horowitz A, Seerapu HR (2012) Regulation of VEGF signaling by membrane traffic. Cell Signal 24:1810–1820. https://doi.org/10.1016/j.cellsig.2012.05.007
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.2010.02.016
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.2013.03.019
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-2007-12-125856
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.0067029
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/10.1155/2018/2175927
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.1211029
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-11-4058
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 25:43–56
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.M804777200
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-08-2614
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.173054.111
Mercurio AM (2019) VEGF/neuropilin signaling in cancer stem cells. Int J Mol Sci 20. https://doi.org/10.3390/ijms20030490
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
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.2017.91
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.2013.01.036
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.137
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.2017.0240
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 8:2–15
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.x
Rizzolio S, Tamagnone L (2011) Multifaceted role of neuropilins in cancer. Curr Med Chem 18:3563–3575
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.0023208
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.0020444
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/s12943-015-0359-4
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.2015.01.018
Bartel DP (2018) Metazoan MicroRNAs. Cell 173:20–51. https://doi.org/10.1016/j.cell.2018.03.006
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.10929
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.22691
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.2018.4451
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.2014.10.014
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.0094422
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/s11010-014-2211-3
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.22990
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 8:14235–14240
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.13495
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.28093
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.27679
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.S173416
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.2019.108772
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.31329
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/s11060-013-1271-7
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.2012.10.026
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.S103460
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.2016.3362
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/BJ20071639
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.2416
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.2017.05.012
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.0101931
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-13-1755
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.aag0528
Hirata E, Sahai E (2017) Tumor microenvironment and differential responses to therapy. Cold Spring Harb Perspect Med 7. https://doi.org/10.1101/cshperspect.a026781
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/ijms18112355
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/s13045-017-0448-5
Kalluri R (2016) The biology and function of fibroblasts in cancer. Nat Rev Cancer 16:582–598. https://doi.org/10.1038/nrc.2016.73
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.2703
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.20377
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/nrc1477
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.24347
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/BST20160387
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-x
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.2005.08.010
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.2017.00003
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.2012.02.004
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/NEJM198612253152606
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.2013.768
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-y
Mohammadi H, Sahai E (2018) Mechanisms and impact of altered tumour mechanics. Nat Cell Biol 20:766–774. https://doi.org/10.1038/s41556-018-0131-2
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.13402
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-x
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/ncb1658
Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8:464–478. https://doi.org/10.1038/nrm2183
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-x
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/s12015-010-9169-7
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/10.1186/1756-9966-31-16
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.2013.1948
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-2012-05-424713
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.2012.02.005
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.2004.12.047
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.2014.07.006
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.112.269399
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.201505551
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-14-2464
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.12003
Herman JG, Meadows GG (2007) Increased class 3 semaphorin expression modulates the invasive and adhesive properties of prostate cancer cells. Int J Oncol 30:1231–1238
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.2014.10.055
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.20134
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.2014.00075
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.M109.055129
Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62. https://doi.org/10.1126/science.1104819
Jain RK (2014) Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26:605–622. https://doi.org/10.1016/j.ccell.2014.10.006
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/JCI58976
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-2007-08-110205
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.2013.09.003
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.aah4807
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.2012.120
Franzolin G, Tamagnone L (2019) Semaphorin signaling in cancer-associated inflammation. Int J Mol Sci 20. https://doi.org/10.3390/ijms20020377
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.2017.08.010
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-18-0562
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.22936
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.15-18598
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.2001.0286
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.05-5646com
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.10936
Shevach EM (2009) Mechanisms of foxp3+ T regulatory cell-mediated suppression. Immunity 30:636–645. https://doi.org/10.1016/j.immuni.2009.04.010
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.2017.01578
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.2018.9219
Napolitano V, Tamagnone L (2019) Neuropilins controlling cancer therapy responsiveness. Int J Mol Sci 20. https://doi.org/10.3390/ijms20082049
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.201100176
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.20166796
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/nature11249
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/s00262-013-1500-0
Graziani G, Lacal PM (2015) Neuropilin-1 as therapeutic target for malignant melanoma. Front Oncol 5:125. https://doi.org/10.3389/fonc.2015.00125
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 15:369–373
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-04-2229
Jamil MO, Hathaway A, Mehta A (2015) Tivozanib: status of development. Curr Oncol Rep 17:24. https://doi.org/10.1007/s11912-015-0451-3
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.2012.46.2762
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/nov288
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
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.V100.13.4622
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.2015.06.009
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.2016.07.023
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.2015.03.043
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.x
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.2008.19.0108
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/nrd4591
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-z
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/s00280-014-2426-8
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.2017.042.02.2564106
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/jm901755g
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/19.7.1525
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.6602308
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.aac4882
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-07-0001
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.201300658
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.8b00210
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.2013.02.006
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-12-3015
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.M203658200
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)63206-3
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.2015.08.016
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.2018.08.083
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/molecules24091756
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.2010.9
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.10101
Simon-Gracia L, Hunt H, Teesalu T (2018) Peritoneal carcinomatosis targeting with tumor homing peptides. Molecules 23. https://doi.org/10.3390/molecules23051190
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/ncomms7240
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-07-6752
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.201500564
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.6b03815
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.2017.06.005
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/JCI92284
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.2016.03.008
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/c8ob00669e
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
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.2017.05.022
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 21:5434–5449
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/biom9050172
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.S141559
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.2011.537
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-14-0366
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-x
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.22470
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The author’s scientific work on NRP1 is financially supported by Deutsche Forschungs gemeinschaft (grant: SFB1009 A09).
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Niland, S., Eble, J.A. (2020). Neuropilin: Handyman and Power Broker in the Tumor Microenvironment. In: Birbrair, A. (eds) Tumor Microenvironment. Advances in Experimental Medicine and Biology, vol 1223. Springer, Cham. https://doi.org/10.1007/978-3-030-35582-1_3
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