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Neuropilin-1-Expressing Monocytes: Implications for Therapeutic Angiogenesis and Cancer Therapy

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Abstract

Besides acting as a common receptor for both vascular endothelial growth factors and semaphorins on the endothelial cell surface, neuropilin-1 is also expressed by a variety of circulating immune cells. We have characterized a population of circulating myeloid cells, characterized by the expression of neuropilin-1, able to promote vessel maturation and contributing to cancer vessel normalization. These neuropilin-1-expressing monocytes (NEMs) represent a specific subset of CD11b+NRP1+Gr1-resident monocytes, producing several factors involved in vessel maturation, including PDGF-B, TGF-β, and thrombospondin-1, acting as chemoattractant for vascular smooth muscle cells. NEMs can be isolated from either the bone marrow or Sema3A-expressing muscles. Their direct injection at sites of neoangiogenesis results in the maturation of growing capillaries into functional arterial vessels. When directly injected into growing tumors, NEMs exert potent antitumor activity despite having no effect on cancer cell proliferation. Instead, NEMs promote mural cell coverage of tumor vessels and reduce vascular leakiness, resulting in smaller, better perfused, and less hypoxic tumors. We conclude that NEMs represent a novel, unique population of myeloid cells that can be exploited for multiple therapeutic applications. On the one hand, they can improve functional maturation of neo-vessels for the induction of therapeutic angiogenesis, while, on the other hand, they promote tumor vessel normalization, thereby inhibiting tumor growth.

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References

  1. Zacchigna S, Zentilin L, Giacca M (2014) Adeno-associated virus vectors as therapeutic and investigational tools in the cardiovascular system. Circ Res 114(11):1827–1846. doi:10.1161/CIRCRESAHA.114.302331

    Article  CAS  PubMed  Google Scholar 

  2. Lovric J, Mano M, Zentilin L, Eulalio A, Zacchigna S, Giacca M (2012) Terminal differentiation of cardiac and skeletal myocytes induces permissivity to AAV transduction by relieving inhibition imposed by DNA damage response proteins. Mol Ther 20(11):2087–2097. doi:10.1038/mt.2012.144 mt2012144 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Arsic N, Zentilin L, Zacchigna S, Santoro D, Stanta G, Salvi S, Sinagra G, Giacca M (2003) Induction of functional neovascularization by combined VEGF and angiopoietin-1 gene transfer using AAV vectors. Mol Ther 7:450–459

    Article  CAS  PubMed  Google Scholar 

  4. Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF (1983) Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219(4587):983–985

    Article  CAS  PubMed  Google Scholar 

  5. Ferrara N, Henzel WJ (1989) Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun 161(2):851–858 doi:0006-291X(89)92678-8 [pii]

    Article  CAS  PubMed  Google Scholar 

  6. Giacca M, Zacchigna S (2012) VEGF gene therapy: therapeutic angiogenesis in the clinic and beyond. Gene Ther 19(6):622–629. doi:10.1038/gt.2012.17 gt201217 [pii]

    Article  CAS  PubMed  Google Scholar 

  7. Deodato B, Arsic N, Zentilin L, Galeano M, Santoro D, Torre V, Altavilla D, Valdembri D, Bussolino F, Squadrito F, Giacca M (2002) Recombinant AAV vector encoding human VEGF165 enhances wound healing. Gene Ther 9:777–785

    Article  CAS  PubMed  Google Scholar 

  8. Moimas S, Novati F, Ronchi G, Zacchigna S, Fregnan F, Zentilin L, Papa G, Giacca M, Geuna S, Perroteau I, Arnez ZM, Raimondo S (2013) Effect of vascular endothelial growth factor gene therapy on post-traumatic peripheral nerve regeneration and denervation-related muscle atrophy. Gene Ther 20(10):1014–1021. doi:10.1038/gt.2013.26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Arsic N, Zacchigna S, Zentilin L, Ramirez-Correa G, Pattarini L, Salvi A, Sinagra G, Giacca M (2004) Vascular endothelial growth factor stimulates skeletal muscle regeneration in vivo. Mol Ther 10(5):844–854

    Article  CAS  PubMed  Google Scholar 

  10. Ferrarini M, Arsic N, Recchia FA, Zentilin L, Zacchigna S, Xu X, Linke A, Giacca M, Hintze TH (2006) Adeno-Associated Virus-mediated transduction of VEGF165 improves cardiac tissue viability and functional recovery after permanent coronary occlusion in conscious dogs. Circ Res 98:954–961

    Article  CAS  PubMed  Google Scholar 

  11. Tafuro S, Ayuso E, Zacchigna S, Zentilin L, Moimas S, Dore F, Giacca M (2009) Inducible adeno-associated virus vectors promote functional angiogenesis in adult organisms via regulated vascular endothelial growth factor expression. Cardiovasc Res 83(4):663–671. doi:10.1093/cvr/cvp152 cvp152 [pii]

    Article  CAS  PubMed  Google Scholar 

  12. Zacchigna S, Papa G, Antonini A, Novati F, Moimas S, Carrer A, Arsic N, Zentilin L, Visintini V, Pascone M, Giacca M (2005) Improved survival of ischemic cutaneous and musculocutaneous flaps after vascular endothelial growth factor gene transfer using adeno-associated virus vectors. Am J Pathol 167(4):981–991

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zacchigna S, Tasciotti E, Kusmic C, Arsic N, Sorace O, Marini C, Marzullo P, Pardini S, Petroni D, Pattarini L, Moimas S, Giacca M, Sambuceti G (2007) In vivo imaging shows abnormal function of vascular endothelial growth factor-induced vasculature. Hum Gene Ther 18(6):515–524

    Article  CAS  PubMed  Google Scholar 

  14. Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini L, Chorianopoulos E, Liesenborghs L, Koch M, De Mol M, Autiero M, Wyns S, Plaisance S, Moons L, van Rooijen N, Giacca M, Stassen JM, Dewerchin M, Collen D, Carmeliet P (2007) Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131(3):463–475

    Article  CAS  PubMed  Google Scholar 

  15. Macedo A, Moriggi M, Vasso M, De Palma S, Sturnega M, Friso G, Gelfi C, Giacca M, Zacchigna S (2012) Enhanced athletic performance on multisite AAV-IGF1 gene transfer coincides with massive modification of the muscle proteome. Hum Gene Ther 23(2):146–157. doi:10.1089/hum.2011.157

    Article  CAS  PubMed  Google Scholar 

  16. Pepe M, Mamdani M, Zentilin L, Csiszar A, Qanud K, Zacchigna S, Ungvari Z, Puligadda U, Moimas S, Xu X, Edwards JG, Hintze TH, Giacca M, Recchia FA (2010) Intramyocardial VEGF-B167 gene delivery delays the progression towards congestive failure in dogs with pacing-induced dilated cardiomyopathy. Circ Res 106(12):1893–1903. doi:10.1161/CIRCRESAHA.110.220855 CIRCRESAHA.110.220855 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Zhong X, Huang H, Shen J, Zacchigna S, Zentilin L, Giacca M, Vinores SA (2011) Vascular endothelial growth factor-B gene transfer exacerbates retinal and choroidal neovascularization and vasopermeability without promoting inflammation. Mol Vis 17:492–507

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161(6):1163–1177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Autiero M, De Smet F, Claes F, Carmeliet P (2005) Role of neural guidance signals in blood vessel navigation. Cardiovasc Res 65(3):629–638. doi:10.1016/j.cardiores.2004.09.013

    Article  CAS  PubMed  Google Scholar 

  20. Ferrara N, Gerber HP, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676

    Article  CAS  PubMed  Google Scholar 

  21. Zacchigna S, Ruiz de Almodovar C, Carmeliet P (2008) Similarities between angiogenesis and neural development: what small animal models can tell us. Curr Top Dev Biol 80:1–55. doi:10.1016/S0070-2153(07)80001-9

    Article  PubMed  Google Scholar 

  22. Weinstein BM (2005) Vessels and nerves: marching to the same tune. Cell 120(3):299–302. doi:10.1016/j.cell.2005.01.010

    Article  CAS  PubMed  Google Scholar 

  23. Sakurai A, Doci CL, Gutkind JS (2012) Semaphorin signaling in angiogenesis, lymphangiogenesis and cancer. Cell Res 22(1):23–32. doi:10.1038/cr.2011.198

    Article  CAS  PubMed  Google Scholar 

  24. 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(36):26294–26305. doi:10.1074/jbc.M609711200 M609711200 [pii]

    Article  CAS  PubMed  Google Scholar 

  25. Miao HQ, Soker S, Feiner L, Alonso JL, Raper JA, Klagsbrun M (1999) Neuropilin-1 mediates collapsin-1/semaphorin III inhibition of endothelial cell motility: functional competition of collapsin-1 and vascular endothelial growth factor-165. J Cell Biol 146(1):233–242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. 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 (11):3356-3372. doi: 10.1172/JCI36308. 36308 [pii]

  27. Serini G, Valdembri D, Zanivan S, Morterra G, Burkhardt C, Caccavari F, Zammataro L, Primo L, Tamagnone L, Logan M, Tessier-Lavigne M, Taniguchi M, Puschel AW, Bussolino F (2003) Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function. Nature 424(6947):391–397

    Article  CAS  PubMed  Google Scholar 

  28. Ruiz de Almodovar C, Coulon C, Salin PA, Knevels E, Chounlamountri N, Poesen K, Hermans K, Lambrechts D, Van Geyte K, Dhondt J, Dresselaers T, Renaud J, Aragones J, Zacchigna S, Geudens I, Gall D, Stroobants S, Mutin M, Dassonville K, Storkebaum E, Jordan BF, Eriksson U, Moons L, D'Hooge R, Haigh JJ, Belin MF, Schiffmann S, Van Hecke P, Gallez B, Vinckier S, Chedotal A, Honnorat J, Thomasset N, Carmeliet P, Meissirel C (2010) Matrix-binding vascular endothelial growth factor (VEGF) isoforms guide granule cell migration in the cerebellum via VEGF receptor Flk1. J Neurosci 30(45):15052–15066. doi:10.1523/JNEUROSCI.0477-10.2010

    Article  CAS  PubMed  Google Scholar 

  29. Schwarz Q, Gu C, Fujisawa H, Sabelko K, Gertsenstein M, Nagy A, Taniguchi M, Kolodkin AL, Ginty DD, Shima DT, Ruhrberg C (2004) Vascular endothelial growth factor controls neuronal migration and cooperates with Sema3A to pattern distinct compartments of the facial nerve. Genes Dev 18(22):2822–2834. doi:10.1101/gad.322904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kolodkin AL, Levengood DV, Rowe EG, Tai YT, Giger RJ, Ginty DD (1997) Neuropilin is a semaphorin III receptor. Cell 90(4):753–762

    Article  CAS  PubMed  Google Scholar 

  31. Zacchigna S, Pattarini L, Zentilin L, Moimas S, Carrer A, Sinigaglia M, Arsic N, Tafuro S, Sinagra G, Giacca M (2008) Bone marrow cells recruited through the Neuropilin-1 receptor promote arterial formation at the sites of adult neoangiogenesis. J Clin Invest 118:2062–2075

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Dor Y, Djonov V, Abramovitch R, Itin A, Fishman GI, Carmeliet P, Goelman G, Keshet E (2002) Conditional switching of VEGF provides new insights into adult neovascularization and pro-angiogenic therapy. EMBO J 21(8):1939–1947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Yung S, Chimenti S, Landsman L, Abramovitch R, Keshet E (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124(1):175–189

    Article  CAS  PubMed  Google Scholar 

  34. Springer ML, Ozawa CR, Banfi A, Kraft PE, Ip TK, Brazelton TR, Blau HM (2003) Localized arteriole formation directly adjacent to the site of VEGF-induced angiogenesis in muscle. Mol Ther 7(4):441–449

    Article  CAS  PubMed  Google Scholar 

  35. Zentilin L, Tafuro S, Zacchigna S, Arsic N, Pattarini L, Sinigaglia M, Giacca M (2006) Bone marrow mononuclear cells are recruited to the sites of VEGF-induced neovascularization but are not incorporated into the newly formed vessels. Blood 107(9):3546–3554

    Article  CAS  PubMed  Google Scholar 

  36. Carrer A, Moimas S, Zacchigna S, Pattarini L, Zentilin L, Ruozi G, Mano M, Sinigaglia M, Maione F, Serini G, Giraudo E, Bussolino F, Giacca M (2012) Neuropilin-1 identifies a subset of bone marrow Gr1- monocytes that can induce tumor vessel normalization and inhibit tumor growth. Cancer Res 72(24):6371–6381. doi:10.1158/0008-5472.CAN-12-0762 0008-5472.CAN-12-0762 [pii]

    Article  CAS  PubMed  Google Scholar 

  37. Carmeliet P, Ng YS, Nuyens D, Theilmeier G, Brusselmans K, Cornelissen I, Ehler E, Kakkar VV, Stalmans I, Mattot V, Perriard JC, Dewerchin M, Flameng W, Nagy A, Lupu F, Moons L, Collen D, D'Amore PA, Shima DT (1999) Impaired myocardial angiogenesis and ischemic cardiomyopathy in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Nat Med 5(5):495–502

    Article  CAS  PubMed  Google Scholar 

  38. Stalmans I, Ng YS, Rohan R, Fruttiger M, Bouche A, Yuce A, Fujisawa H, Hermans B, Shani M, Jansen S, Hicklin D, Anderson DJ, Gardiner T, Hammes HP, Moons L, Dewerchin M, Collen D, Carmeliet P, D'Amore PA (2002) Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 109(3):327–336

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Heil M, Schaper W (2004) Influence of mechanical, cellular, and molecular factors on collateral artery growth (arteriogenesis). Circ Res 95(5):449–458

    Article  CAS  PubMed  Google Scholar 

  40. Qin SL, He CY, Xu JS, Lai XY, Liu SS, He WP (2015) Meta-analysis of coronary artery bypass graft surgery combined with stem cell transplantation in the treatment of ischemic heart diseases. Coron Artery Dis 26(2):170–175. doi:10.1097/MCA.0000000000000193

    Article  PubMed  Google Scholar 

  41. Sun X, Ying J, Wang Y, Li W, Wu Y, Yao B, Liu Y, Gao H, Zhang X (2015) Meta-analysis on autologous stem cell transplantation in the treatment of limb ischemic. Int J Clin Exp Med 8(6):8740–8748

    PubMed  PubMed Central  Google Scholar 

  42. Geissmann F, Manz MG, Jung S, Sieweke MH, Merad M, Ley K (2010) Development of monocytes, macrophages, and dendritic cells. Science 327(5966):656–661. doi:10.1126/science.1178331 327/5966/656 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S, Peri F, Wilson SW, Ruhrberg C (2010) Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 116(5):829–840. doi:10.1182/blood-2009-12-257832 blood-2009-12-257832 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Pucci F, Venneri MA, Biziato D, Nonis A, Moi D, Sica A, Di Serio C, Naldini L, De Palma M (2009) A distinguishing gene signature shared by tumor-infiltrating Tie2-expressing monocytes, blood “resident” monocytes, and embryonic macrophages suggests common functions and developmental relationships. Blood 114(4):901–914. doi:10.1182/blood-2009-01-200931 blood-2009-01-200931 [pii]

    Article  CAS  PubMed  Google Scholar 

  45. Sica A, Larghi P, Mancino A, Rubino L, Porta C, Totaro MG, Rimoldi M, Biswas SK, Allavena P, Mantovani A (2008) Macrophage polarization in tumour progression. Semin Cancer Biol 18(5):349–355. doi:10.1016/j.semcancer.2008.03.004 S1044-579X(08)00023-0 [pii]

    Article  CAS  PubMed  Google Scholar 

  46. De Palma M, Venneri MA, Galli R, Sergi Sergi L, Politi LS, Sampaolesi M, Naldini L (2005) Tie2 identifies a hematopoietic lineage of proangiogenic monocytes required for tumor vessel formation and a mesenchymal population of pericyte progenitors. Cancer Cell 8(3):211–226. doi:10.1016/j.ccr.2005.08.002 S1535-6108(05)00260-6 [pii]

    Article  CAS  PubMed  Google Scholar 

  47. Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11(6):393–410. doi:10.1038/nrc3064 nrc3064 [pii]

    Article  CAS  PubMed  Google Scholar 

  48. Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62. doi:10.1126/science.1104819 307/5706/58 [pii]

    Article  CAS  PubMed  Google Scholar 

  49. Jain RK (2009) A new target for tumor therapy. N Engl J Med 360(25):2669–2671. doi:10.1056/NEJMcibr0902054 360/25/2669 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. 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(5):1832–1848. doi:10.1172/JCI5897658976 [pii]

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhao YJ, Han HZ, Liang Y, Shi CZ, Zhu QC, Yang J (2015) Alternative splicing of VEGFA, APP and NUMB genes in colorectal cancer. World J Gastroenterol 21(21):6550–6560. doi:10.3748/wjg.v21.i21.6550

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Woolard J, Wang WY, Bevan HS, Qiu Y, Morbidelli L, Pritchard-Jones RO, Cui TG, Sugiono M, Waine E, Perrin R, Foster R, Digby-Bell J, Shields JD, Whittles CE, Mushens RE, Gillatt DA, Ziche M, Harper SJ, Bates DO (2004) VEGF165b, an inhibitory vascular endothelial growth factor splice variant: mechanism of action, in vivo effect on angiogenesis and endogenous protein expression. Cancer Res 64(21):7822–7835. doi:10.1158/0008-5472.CAN-04-0934 64/21/7822 [pii]

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Cardiovascular Biology, International Center for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34149, Trieste, Italy

    Serena Zacchigna

  2. Department of Medical, Surgical and Health Sciences, University Hospital of Trieste, Strada di Fiume, 447, Trieste, Italy

    Serena Zacchigna & Mauro Giacca

  3. Molecular Medicine, International Center for Genetic Engineering and Biotechnology (ICGEB), Padriciano 99, 34149, Trieste, Italy

    Mauro Giacca

Authors
  1. Serena Zacchigna
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Correspondence to Serena Zacchigna .

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Editors and Affiliations

  1. Department Anatomy and Cell Biology, Israel Institute of Technology Technion, Haifa, Israel

    Gera Neufeld

  2. Department Anatomy and Cell Biology, Israel Institute of Technology Technion, Haifa, Israel

    Ofra Kessler

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Zacchigna, S., Giacca, M. (2017). Neuropilin-1-Expressing Monocytes: Implications for Therapeutic Angiogenesis and Cancer Therapy. In: Neufeld, G., Kessler, O. (eds) The Neuropilins: Role and Function in Health and Disease. Springer, Cham. https://doi.org/10.1007/978-3-319-48824-0_12

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