Skip to main content

Advertisement

SpringerLink
Log in

Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

The lymphatic system provides important functions for tissue fluid homeostasis and immune response. Lymphangiogenesis, the formation of new lymphatics, comprises a series of complex cellular events in vitro or in vivo, e.g., proliferation, differentiation, and sprouting. Recent evidence has implied that macrophages act as a direct structural contributor to lymphatic endothelial walls or secret VEGF-C/-D and VEGF-A to initiate lymphangiogenesis in inflamed or tumor tissues. Bone marrow-derived macrophages are versatile cells that express different functional programs in response to exposure to microenvironmental signals, and can be identified by specific expression of a number of proteins, F4/80, CD11b, and CD68. Several causative factors, e.g., NF-κB, IL-1β, TNF-α, SDF-1, M-CSF, especially TonEBP/VEGF-C signaling, may be actively involved in macrophage-induced lymphangiogenesis. Alteration of macrophage phenotype and function has a profound effect on the development and progression of inflammation and malignancy, and macrophage depletion for controlling lymphangiogenesis may provide a novel approach for prevention and treatment of lymphatic-associated diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

BMDCs:

Bone marrow-derived cells

CEACAM-1:

Carcinoembryonic antigen-related cell adhesion molecule-1

CLEVER-1:

Common lymphatic endothelial and vascular endothelial receptor-1

CXCR-4:

CXC chemokine receptor-4

ECM:

Extracellular matrix

eNOS:

Endothelial nitric oxide synthase

HSD:

High-salt diet

HSV-1:

Herpes simplex virus-1

IFP:

Interstitial fluid pressure

IL-1β:

Interleukin-1β

LECs:

Lymphatic endothelial cells

LPS:

Lipopolysaccharide

LYVE-1:

Lymphatic vascular endothelial hyaluronan receptor-1

M-CSF:

Macrophage colony-stimulating factor

MMP:

Matrix metalloproteinase

MMR:

Macrophage mannose receptor

MPS:

Mononuclear phagocyte system

NF-κB:

Nuclear factor-κB

Prox-1 :

Prospero-related homeobox-1

VEGF-A/-C/-D:

Vascular endothelial growth factor-A/-C/-D

VEGFR-2/-3:

Vascular endothelial growth factor receptor-2/-3

SDF-1:

Stromal cell-derived factor-1

TAMs:

Tumor-associated macrophages

TGF-β:

Transforming growth factor-β

TLR-4:

Toll-like receptor-4

TNF-α:

Tumor necrosis factor-α

TonEBP:

Tonicity-responsive enhancer binding protein

References

  1. Muller WA, Randolph GJ (1999) Migration of leukocytes across endothelium and beyond: molecules involved in the transmigration and fate of monocytes. J Leukoc Biol 66:698–704

    PubMed  CAS  Google Scholar 

  2. Martinez FO, Helming L, Gordon S (2009) Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27:451–483

    Article  PubMed  CAS  Google Scholar 

  3. Kerjaschki D (2005) The crucial role of macrophages in lymphangiogenesis. J Clin Invest 115:2316–2319

    Article  PubMed  CAS  Google Scholar 

  4. Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita M, Van Rooijen N, Takenaka H, D’Amore PA, Stein-Streilein J, Losordo DW, Streilein JW (2005) Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 115:2363–2372

    Article  PubMed  CAS  Google Scholar 

  5. Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, Ellwanger U, Garbe C, Mihm MC, Detmar M (2003) Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 162:1951–1960

    Article  PubMed  Google Scholar 

  6. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, Christofori G, Pepper MS (2001) Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20:672–682

    Article  PubMed  CAS  Google Scholar 

  7. Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K, Detmar M (2001) Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol 159:893–903

    Article  PubMed  CAS  Google Scholar 

  8. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, Jackson DG, Nishikawa S, Kubo H, Achen MG (2001) VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 7:186–191

    Article  PubMed  CAS  Google Scholar 

  9. Alitalo K, Tammela T, Petrova TV (2005) Lymphangiogenesis in development and human disease. Nature 438:946–953

    Article  PubMed  CAS  Google Scholar 

  10. Baluk P, Tammela T, Ator E, Lyubynska N, Achen MG, Hicklin DJ, Jeltsch M, Petrova TV, Pytowski B, Stacker SA, Ylä-Herttuala S, Jackson DG, Alitalo K, McDonald DM (2005) Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J Clin Invest 115:247–257

    PubMed  CAS  Google Scholar 

  11. Ji RC (2006) Lymphatic endothelial cells, lymphangiogenesis, and extracellular matrix. Lymphat Res Biol 4:83–100

    Article  PubMed  CAS  Google Scholar 

  12. Lewis CE, Pollard JW (2006) Distinct role of macrophages in different tumor microenvironments. Cancer Res 66:605–612

    Article  PubMed  CAS  Google Scholar 

  13. Ji RC (2007) Lymphatic endothelial cells, inflammatory lymphangiogenesis, and prospective players. Curr Med Chem 14:2359–2368

    Article  PubMed  CAS  Google Scholar 

  14. Ji RC (2008) Lymphatic endothelial cells, lymphedematous lymphangiogenesis, and molecular control of edema formation. Lymphat Res Biol 6:123–137

    Article  PubMed  CAS  Google Scholar 

  15. Tabas I (2010) Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol 10:36–46

    Article  PubMed  CAS  Google Scholar 

  16. Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Müller DN, Derer W, Goss J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze J (2009) Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med 15:545–552

    Article  PubMed  CAS  Google Scholar 

  17. Wuest TR, Carr DJ (2010) VEGF-A expression by HSV-1-infected cells drives corneal lymphangiogenesis. J Exp Med 207:101–115, S1-2

    Google Scholar 

  18. Coffelt SB, Hughes R, Lewis CE (2009) Tumor-associated macrophages: effectors of angiogenesis and tumor progression. Biochim Biophys Acta 1796:11–18

    PubMed  CAS  Google Scholar 

  19. Mancino A, Lawrence T (2010) Nuclear factor-kappaB and tumor-associated macrophages. Clin Cancer Res 16:784–789

    Article  PubMed  CAS  Google Scholar 

  20. Stout RD, Suttles J (2004) Functional plasticity of macrophages: reversible adaptation to changing microenvironments. J Leukoc Biol 76:509–513

    Article  PubMed  CAS  Google Scholar 

  21. Cho CH, Koh YJ, Han J, Sung HK, Jong Lee H, Morisada T, Schwendener RA, Brekken RA, Kang G, Oike Y, Choi TS, Suda T, Yoo OJ, Koh GY (2007) Angiogenic role of LYVE-1-positive macrophages in adipose tissue. Circ Res 100:e47–e57

    Article  PubMed  CAS  Google Scholar 

  22. Edwards JP, Zhang X, Frauwirth KA, Mosser DM (2006) Biochemical and functional characterization of three activated macrophage populations. J Leukoc Biol 80:1298–1307

    Article  PubMed  CAS  Google Scholar 

  23. Gibbs DF, Shanley TP, Warner RL, Murphy HS, Varani J, Johnson KJ (1999) Role of matrix metalloproteinases in models of macrophage-dependent acute lung injury. Evidence for alveolar macrophage as source of proteinases. Am J Respir Cell Mol Biol 20:1145–1154

    PubMed  CAS  Google Scholar 

  24. Chizzolini C, Rezzonico R, De Luca C, Burger D, Dayer JM (2000) Th2 cell membrane factors in association with IL-4 enhance matrix metalloproteinase-1 (MMP-1) while decreasing MMP-9 production by granulocyte-macrophage colony-stimulating factor-differentiated human monocytes. J Immunol 164:5952–5960

    PubMed  CAS  Google Scholar 

  25. Sorimachi K, Akimoto K, Ikehara Y, Inafuku K, Okubo A, Yamazaki S (2001) Secretion of TNF-alpha, IL-8 and nitric oxide by macrophages activated with Agaricus blazei Murill fractions in vitro. Cell Struct Funct 26:103–108

    Article  PubMed  CAS  Google Scholar 

  26. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3:23–35

    Article  PubMed  CAS  Google Scholar 

  27. Gratchev A, Guillot P, Hakiy N, Politz O, Orfanos CE, Schledzewski K, Goerdt S (2001) Alternatively activated macrophages differentially express fibronectin and its splice variants and the extracellular matrix protein betaIG-H3. Scand J Immunol 53:386–392

    Article  PubMed  CAS  Google Scholar 

  28. Mantovani A, Sica A, Sozzani S, Allavena P, Vecchi A, Locati M (2004) The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol 25:677–686

    Article  PubMed  CAS  Google Scholar 

  29. Gordon S, Taylor PR (2005) Monocyte and macrophage heterogeneity. Nat Rev Immunol 5:953–964

    Article  PubMed  CAS  Google Scholar 

  30. Mosser DM (2003) The many faces of macrophage activation. J Leukoc Biol 73:209–212

    Article  PubMed  CAS  Google Scholar 

  31. Hagemann T, Biswas SK, Lawrence T, Sica A, Lewis CE (2009) Regulation of macrophage function in tumors: the multifaceted role of NF-kappaB. Blood 113:3139–3146

    Article  PubMed  CAS  Google Scholar 

  32. Chen L, Hamrah P, Cursiefen C, Zhang Q, Pytowski B, Streilein JW, Dana MR (2004) Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Nat Med 10:813–815

    Article  PubMed  CAS  Google Scholar 

  33. Chung ES, Chauhan SK, Jin Y, Nakao S, Hafezi-Moghadam A, van Rooijen N, Zhang Q, Chen L, Dana R (2009) Contribution of macrophages to angiogenesis induced by vascular endothelial growth factor receptor-3-specific ligands. Am J Pathol 175:1984–1992

    Article  PubMed  Google Scholar 

  34. Hamrah P, Chen L, Cursiefen C, Zhang Q, Joyce NC, Dana MR (2004) Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) on monocytic bone marrow-derived cells in the conjunctiva. Exp Eye Res 79:553–561

    Article  PubMed  CAS  Google Scholar 

  35. Gordon EJ, Rao S, Pollard JW, Nutt SL, Lang RA, Harvey NL (2010) Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation. Development 137:3899–3910

    Article  PubMed  CAS  Google Scholar 

  36. Böhmer R, Neuhaus B, Bühren S, Zhang D, Stehling M, Böck B, Kiefer F (2010) Regulation of developmental lymphangiogenesis by Syk(+) leukocytes. Dev Cell 18:437–449

    Article  PubMed  CAS  Google Scholar 

  37. Marttila-Ichihara F, Turja R, Miiluniemi M, Karikoski M, Maksimow M, Niemelä J, Martinez-Pomares L, Salmi M, Jalkanen S (2008) Macrophage mannose receptor on lymphatics controls cell trafficking. Blood 112:64–72

    Article  PubMed  CAS  Google Scholar 

  38. Linehan SA, Martínez-Pomares L, Stahl PD, Gordon S (1999) Mannose receptor and its putative ligands in normal murine lymphoid and nonlymphoid organs: in situ expression of mannose receptor by selected macrophages, endothelial cells, perivascular microglia, and mesangial cells, but not dendritic cells. J Exp Med 189:1961–1972

    Article  PubMed  CAS  Google Scholar 

  39. Martens JH, Kzhyshkowska J, Falkowski-Hansen M, Schledzewski K, Gratchev A, Mansmann U, Schmuttermaier C, Dippel E, Koenen W, Riedel F, Sankala M, Tryggvason K, Kobzik L, Moldenhauer G, Arnold B, Goerdt S (2006) Differential expression of a gene signature for scavenger/lectin receptors by endothelial cells and macrophages in human lymph node sinuses, the primary sites of regional metastasis. J Pathol 208:574–589

    Article  PubMed  CAS  Google Scholar 

  40. Irjala H, Alanen K, Grénman R, Heikkilä P, Joensuu H, Jalkanen S (2003) Mannose receptor (MR) and common lymphatic endothelial and vascular endothelial receptor (CLEVER)-1 direct the binding of cancer cells to the lymph vessel endothelium. Cancer Res 63:4671–4676

    PubMed  CAS  Google Scholar 

  41. Harel-Adar T, Mordechai TB, Amsalem Y, Feinberg MS, Leor J, Cohen S (2011) Modulation of cardiac macrophages by phosphatidylserine-presenting liposomes improves infarct repair. Proc Natl Acad Sci USA 108:1827–1832

    Article  PubMed  CAS  Google Scholar 

  42. Karikoski M, Irjala H, Maksimow M, Miiluniemi M, Granfors K, Hernesniemi S, Elima K, Moldenhauer G, Schledzewski K, Kzhyshkowska J, Goerdt S, Salmi M, Jalkanen S (2009) Clever-1/Stabilin-1 regulates lymphocyte migration within lymphatics and leukocyte entrance to sites of inflammation. Eur J Immunol 39:3477–3487

    Article  PubMed  CAS  Google Scholar 

  43. Salmi M, Koskinen K, Henttinen T, Elima K, Jalkanen S (2004) CLEVER-1 mediates lymphocyte transmigration through vascular and lymphatic endothelium. Blood 104:3849–3857

    Article  PubMed  CAS  Google Scholar 

  44. Angeli V, Ginhoux F, Llodrà J, Quemeneur L, Frenette PS, Skobe M, Jessberger R, Merad M, Randolph GJ (2006) B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 24:203–215

    Article  PubMed  CAS  Google Scholar 

  45. Ji RC, Eshita Y, Xing L, Miura M (2010) Multiple expressions of lymphatic markers and morphological evolution of newly formed lymphatics in lymphangioma and lymph node lymphangiogenesis. Microvasc Res 80:195–201

    Article  PubMed  CAS  Google Scholar 

  46. Ji RC (2006) Lymphatic endothelial cells, tumor lymphangiogenesis and metastasis: new insights into intratumoral and peritumoral lymphatics. Cancer Metastasis Rev 25:677–694

    Article  PubMed  Google Scholar 

  47. Ji RC (2009) Lymph node lymphangiogenesis: a new concept for modulating tumor metastasis and inflammatory process. Histol Histopathol 24:377–384

    PubMed  CAS  Google Scholar 

  48. Horst AK, Bickert T, Brewig N, Ludewig P, van Rooijen N, Schumacher U, Beauchemin N, Ito WD, Fleischer B, Wagener C, Ritter U (2009) CEACAM1+ myeloid cells control angiogenesis in inflammation. Blood 113:6726–6736

    Article  PubMed  CAS  Google Scholar 

  49. Kang J, Yoo J, Lee S, Tang W, Aguilar B, Ramu S, Choi I, Otu HH, Shin JW, Dotto GP, Koh CJ, Detmar M, Hong YK (2010) An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells. Blood 116:140–150

    Article  PubMed  CAS  Google Scholar 

  50. 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 116:829–840

    Article  PubMed  CAS  Google Scholar 

  51. Schmidt T, Carmeliet P (2010) Blood-vessel formation: Bridges that guide and unite. Nature 465:697–699

    Article  PubMed  CAS  Google Scholar 

  52. Tammela T, Zarkada G, Wallgard E, Murtomäki A, Suchting S, Wirzenius M, Waltari M, Hellström M, Schomber T, Peltonen R, Freitas C, Duarte A, Isoniemi H, Laakkonen P, Christofori G, Ylä-Herttuala S, Shibuya M, Pytowski B, Eichmann A, Betsholtz C, Alitalo K (2008) Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454:656–660

    Article  PubMed  CAS  Google Scholar 

  53. Kerjaschki D, Huttary N, Raab I, Regele H, Bojarski-Nagy K, Bartel G, Kröber SM, Greinix H, Rosenmaier A, Karlhofer F, Wick N, Mazal PR (2006) Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat Med 12:230–234

    Article  PubMed  CAS  Google Scholar 

  54. El-Chemaly S, Malide D, Zudaire E, Ikeda Y, Weinberg BA, Pacheco-Rodriguez G, Rosas IO, Aparicio M, Ren P, MacDonald SD, Wu HP, Nathan SD, Cuttitta F, McCoy JP, Gochuico BR, Moss J (2009) Abnormal lymphangiogenesis in idiopathic pulmonary fibrosis with insights into cellular and molecular mechanisms. Proc Natl Acad Sci USA 106:3958–3963

    Article  PubMed  CAS  Google Scholar 

  55. Zumsteg A, Baeriswyl V, Imaizumi N, Schwendener R, Rüegg C, Christofori G (2009) Myeloid cells contribute to tumor lymphangiogenesis. PLoS One 4:e7067

    Article  PubMed  CAS  Google Scholar 

  56. Bellingan GJ, Caldwell H, Howie SE, Dransfield I, Haslett C (1996) In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally, but emigrate to the draining lymph nodes. J Immunol 157:2577–2585

    PubMed  CAS  Google Scholar 

  57. Zeisberger SM, Odermatt B, Marty C, Zehnder-Fjällman AH, Ballmer-Hofer K, Schwendener RA (2006) Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach. Br J Cancer 95:272–281

    Article  PubMed  CAS  Google Scholar 

  58. Ahn GO, Tseng D, Liao CH, Dorie MJ, Czechowicz A, Brown JM (2010) Inhibition of Mac-1 (CD11b/CD18) enhances tumor response to radiation by reducing myeloid cell recruitment. Proc Natl Acad Sci USA 107:8363–8368

    Article  PubMed  CAS  Google Scholar 

  59. Holness CL, Simmons DL (1993) Molecular cloning of CD68, a human macrophage marker related to lysosomal glycoproteins. Blood 81:1607–1613

    PubMed  CAS  Google Scholar 

  60. Fogg DK, Sibon C, Miled C, Jung S, Aucouturier P, Littman DR, Cumano A, Geissmann F (2006) A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311:83–87

    Article  PubMed  CAS  Google Scholar 

  61. Kermani P, Rafii D, Jin DK, Whitlock P, Schaffer W, Chiang A, Vincent L, Friedrich M, Shido K, Hackett NR, Crystal RG, Rafii S, Hempstead BL (2005) Neurotrophins promote revascularization by local recruitment of TrkB+ endothelial cells and systemic mobilization of hematopoietic progenitors. J Clin Invest 115:653–663

    PubMed  CAS  Google Scholar 

  62. Ji RC, Kurihara K, Kato S (2006) Lymphatic vascular endothelial hyaluronan receptor (LYVE)-1- and CCL21-positive lymphatic compartments in the diabetic thymus. Anat Sci Int 81:201–209

    Article  PubMed  Google Scholar 

  63. Brown S, Heinisch I, Ross E, Shaw K, Buckley CD, Savill J (2002) Apoptosis disables CD31-mediated cell detachment from phagocytes promoting binding and engulfment. Nature 418:200–203

    Article  PubMed  CAS  Google Scholar 

  64. Schledzewski K, Falkowski M, Moldenhauer G, Metharom P, Kzhyshkowska J, Ganss R, Demory A, Falkowska-Hansen B, Kurzen H, Ugurel S, Geginat G, Arnold B, Goerdt S (2006) Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+, F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis. J Pathol 209:67–77

    Article  PubMed  CAS  Google Scholar 

  65. Ji RC, Eshita Y, Kato S (2007) Investigation of intratumoural and peritumoural lymphatics expressed by podoplanin and LYVE-1 in the hybridoma-induced tumours. Int J Exp Pathol 88:257–270

    Article  PubMed  CAS  Google Scholar 

  66. Guo R, Zhou Q, Proulx ST, Wood R, Ji RC, Ritchlin CT, Pytowski B, Zhu Z, Wang YJ, Schwarz EM, Xing L (2009) Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthritis Rheum 60:2666–2676

    Article  PubMed  CAS  Google Scholar 

  67. Coussens LM, Werb Z (2002) Inflammation and cancer. Nature 420:860–867

    Article  PubMed  CAS  Google Scholar 

  68. Schoppmann SF, Birner P, Stöckl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D (2002) Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 161:947–956

    Article  PubMed  CAS  Google Scholar 

  69. Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78

    Article  PubMed  CAS  Google Scholar 

  70. Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444

    Article  PubMed  CAS  Google Scholar 

  71. Moussai D, Mitsui H, Pettersen JS, Pierson KC, Shah KR, Suárez-Fariñas M, Cardinale IR, Bluth MJ, Krueger JG, Carucci JA (2011) The human cutaneous squamous cell carcinoma microenvironment is characterized by increased lymphatic density and enhanced expression of macrophage-derived VEGF-C. J Invest Dermatol 131:229–236

    Article  PubMed  CAS  Google Scholar 

  72. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV, Jeltsch M, Jackson DG, Talikka M, Rauvala H, Betsholtz C, Alitalo K (2004) Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5:74–80

    Article  PubMed  CAS  Google Scholar 

  73. Björndahl MA, Cao R, Burton JB, Brakenhielm E, Religa P, Galter D, Wu L, Cao Y (2005) Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res 65:9261–9268

    Article  PubMed  Google Scholar 

  74. Karpanen T, Alitalo K (2008) Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 3:367–397

    Article  PubMed  CAS  Google Scholar 

  75. Achen MG, Jeltsch M, Kukk E, Mäkinen T, Vitali A, Wilks AF, Alitalo K, Stacker SA (1998) Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci USA 95:548–553

    Article  PubMed  CAS  Google Scholar 

  76. Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D’Amore PA, Dana MR, Wiegand SJ, Streilein JW (2004) VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113:1040–1050

    PubMed  CAS  Google Scholar 

  77. Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF, Bohlen P, Senger DR, Detmar M (2004) VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J 18:1111–1113

    PubMed  CAS  Google Scholar 

  78. Barbera-Guillem E, Nyhus JK, Wolford CC, Friece CR, Sampsel JW (2002) Vascular endothelial growth factor secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process. Cancer Res 62:7042–7049

    PubMed  CAS  Google Scholar 

  79. Sica A, Rubino L, Mancino A, Larghi P, Porta C, Rimoldi M, Solinas G, Locati M, Allavena P, Mantovani A (2007) Targeting tumour-associated macrophages. Expert Opin Ther Targets 11:1219–1229

    Article  PubMed  CAS  Google Scholar 

  80. Attout T, Hoerauf A, Dénécé G, Debrah AY, Marfo-Debrekyei Y, Boussinesq M, Wanji S, Martinez V, Mand S, Adjei O, Bain O, Specht S, Martin C (2009) Lymphatic vascularisation and involvement of Lyve-1+ macrophages in the human onchocerca nodule. PLoS One 4:e8234

    Article  PubMed  CAS  Google Scholar 

  81. Yamashita M, Iwama N, Date F, Shibata N, Miki H, Yamauchi K, Sawai T, Sato S, Takahashi T, Ono M (2009) Macrophages participate in lymphangiogenesis in idiopathic diffuse alveolar damage through CCL19-CCR7 signal. Hum Pathol 40:1553–1563

    Article  PubMed  CAS  Google Scholar 

  82. Kim KE, Koh YJ, Jeon BH, Jang C, Han J, Kataru RP, Schwendener RA, Kim JM, Koh GY (2009) Role of CD11b+ macrophages in intraperitoneal lipopolysaccharide-induced aberrant lymphangiogenesis and lymphatic function in the diaphragm. Am J Pathol 175:1733–1745

    Article  PubMed  CAS  Google Scholar 

  83. Xing L, Ji RC (2008) Lymphangiogenesis, myeloid cells and inflammation. Expert Rev Clin Immunol 4:599–613

    Article  PubMed  Google Scholar 

  84. Watari K, Nakao S, Fotovati A, Basaki Y, Hosoi F, Bereczky B, Higuchi R, Miyamoto T, Kuwano M, Ono M (2008) Role of macrophages in inflammatory lymphangiogenesis: enhanced production of vascular endothelial growth factor C and D through NF-kappaB activation. Biochem Biophys Res Commun 377:826–831

    Article  PubMed  CAS  Google Scholar 

  85. Handa O, Naito Y, Takagi T, Shimozawa M, Kokura S, Yoshida N, Matsui H, Cepinskas G, Kvietys PR, Yoshikawa T (2004) Tumor necrosis factor-alpha-induced cytokine-induced neutrophil chemoattractant-1 (CINC-1) production by rat gastric epithelial cells: role of reactive oxygen species and nuclear factor-kappaB. J Pharmacol Exp Ther 309:670–676

    Article  PubMed  CAS  Google Scholar 

  86. Drayton DL, Liao S, Mounzer RH, Ruddle NH (2006) Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol 7:344–353

    Article  PubMed  CAS  Google Scholar 

  87. Halin C, Tobler NE, Vigl B, Brown LF, Detmar M (2007) VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. Blood 110:3158–3167

    Article  PubMed  CAS  Google Scholar 

  88. Harrell MI, Iritani BM, Ruddell A (2007) Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am J Pathol 170:774–786

    Article  PubMed  Google Scholar 

  89. Kalluri R, Zeisberg M (2006) Fibroblasts in cancer. Nat Rev Cancer 6:392–401

    Article  PubMed  CAS  Google Scholar 

  90. Liao D, Luo Y, Markowitz D, Xiang R, Reisfeld RA (2009) Cancer associated fibroblasts promote tumor growth and metastasis by modulating the tumor immune microenvironment in a 4T1 murine breast cancer model. PLoS One 4:e7965

    Article  PubMed  CAS  Google Scholar 

  91. Koyama H, Kobayashi N, Harada M, Takeoka M, Kawai Y, Sano K, Fujimori M, Amano J, Ohhashi T, Kannagi R, Kimata K, Taniguchi S, Itano N (2008) Significance of tumor-associated stroma in promotion of intratumoral lymphangiogenesis: pivotal role of a hyaluronan-rich tumor microenvironment. Am J Pathol 172:179–193

    Article  PubMed  CAS  Google Scholar 

  92. Kubota Y, Takubo K, Shimizu T, Ohno H, Kishi K, Shibuya M, Saya H, Suda T (2009) M-CSF inhibition selectively targets pathological angiogenesis and lymphangiogenesis. J Exp Med 206:1089–1102

    Article  PubMed  CAS  Google Scholar 

  93. Clavin NW, Avraham T, Fernandez J, Daluvoy SV, Soares MA, Chaudhry A, Mehrara BJ (2008) TGF-beta1 is a negative regulator of lymphatic regeneration during wound repair. Am J Physiol Heart Circ Physiol 295:H2113–H2127

    Article  PubMed  CAS  Google Scholar 

  94. Liao S, Liu J, Lin P, Shi T, Jain RK, Xu L (2011) TGF-{beta} blockade controls ascites by preventing abnormalization of lymphatic vessels in orthotopic human ovarian carcinoma models. Clin Cancer Res 17:1415–1424

    Article  PubMed  CAS  Google Scholar 

  95. Oka M, Iwata C, Suzuki HI, Kiyono K, Morishita Y, Watabe T, Komuro A, Kano MR, Miyazono K (2008) Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood 111:4571–4579

    Article  PubMed  CAS  Google Scholar 

  96. Kataru RP, Kim H, Jang C, Choi DK, Koh BI, Kim M, Gollamudi S, Kim YK, Lee SH, Koh GY (2011) T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 34:96–107

    Article  PubMed  CAS  Google Scholar 

  97. Johnson LA, Prevo R, Clasper S, Jackson DG (2007) Inflammation-induced uptake and degradation of the lymphatic endothelial hyaluronan receptor LYVE-1. J Biol Chem 282:33671–33680

    Article  PubMed  CAS  Google Scholar 

  98. Religa P, Cao R, Bjorndahl M, Zhou Z, Zhu Z, Cao Y (2005) Presence of bone marrow-derived circulating progenitor endothelial cells in the newly formed lymphatic vessels. Blood 106:4184–4190

    Article  PubMed  CAS  Google Scholar 

  99. Kusmartsev S, Gabrilovich DI (2005) STAT1 signaling regulates tumor-associated macrophage-mediated T cell deletion. J Immunol 174:4880–4891

    PubMed  CAS  Google Scholar 

  100. Nagaraj S, Gabrilovich DI (2008) Tumor escape mechanism governed by myeloid-derived suppressor cells. Cancer Res 68:2561–2563

    Article  PubMed  CAS  Google Scholar 

  101. Boardman KC, Swartz MA (2003) Interstitial flow as a guide for lymphangiogenesis. Circ Res 92:801–808

    Article  PubMed  CAS  Google Scholar 

  102. Miyakawa H, Woo SK, Dahl SC, Handler JS, Kwon HM (1999) Tonicity-responsive enhancer binding protein, a rel-like protein that stimulates transcription in response to hypertonicity. Proc Natl Acad Sci USA 96:2538–2542

    Article  PubMed  CAS  Google Scholar 

  103. Machnik A, Dahlmann A, Kopp C, Goss J, Wagner H, van Rooijen N, Eckardt KU, Müller DN, Park JK, Luft FC, Kerjaschki D, Titze J (2010) Mononuclear phagocyte system depletion blocks interstitial tonicity-responsive enhancer binding protein/vascular endothelial growth factor C expression and induces salt-sensitive hypertension in rats. Hypertension 55:755–761

    Article  PubMed  CAS  Google Scholar 

  104. Heldin CH, Rubin K, Pietras K, Ostman A (2004) High interstitial fluid pressure—an obstacle in cancer therapy. Nat Rev Cancer 4:806–813

    Article  PubMed  CAS  Google Scholar 

  105. Larrieu-Lahargue F, Welm AL, Thomas KR, Li DY (2010) Netrin-4 induces lymphangiogenesis in vivo. Blood 115:5418–5426

    Article  PubMed  CAS  Google Scholar 

  106. Wiig H, Keskin D, Kalluri R (2010) Interaction between the extracellular matrix and lymphatics: consequences for lymphangiogenesis and lymphatic function. Matrix Biol 29:645–656

    Article  PubMed  CAS  Google Scholar 

  107. Marvar PJ, Gordon FJ, Harrison DG (2009) Blood pressure control: salt gets under your skin. Nat Med 15:487–488

    Article  PubMed  CAS  Google Scholar 

  108. Lee S, Zheng M, Kim B, Rouse BT (2002) Role of matrix metalloproteinase-9 in angiogenesis caused by ocular infection with herpes simplex virus. J Clin Invest 110:1105–1111

    PubMed  CAS  Google Scholar 

  109. Hayashi K, Hooper LC, Chin MS, Nagineni CN, Detrick B, Hooks JJ (2006) Herpes simplex virus 1 (HSV-1) DNA and immune complex (HSV-1-human IgG) elicit vigorous interleukin 6 release from infected corneal cells via Toll-like receptors. J Gen Virol 87:2161–2169

    Article  PubMed  CAS  Google Scholar 

  110. Kaye S, Choudhary A (2006) Herpes simplex keratitis. Prog Retin Eye Res 25:355–380

    Article  PubMed  Google Scholar 

  111. Sottile J (2004) Regulation of angiogenesis by extracellular matrix. Biochim Biophys Acta 1654:13–22

    PubMed  CAS  Google Scholar 

  112. Jain RK (2003) Molecular regulation of vessel maturation. Nat Med 9:685–693

    Article  PubMed  CAS  Google Scholar 

  113. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196:1497–1506

    Article  PubMed  CAS  Google Scholar 

  114. Kajiya K, Hirakawa S, Detmar M (2006) Vascular endothelial growth factor-A mediates ultraviolet B-induced impairment of lymphatic vessel function. Am J Pathol 169:1496–1503

    Article  PubMed  CAS  Google Scholar 

  115. Lin EY, Nguyen AV, Russell RG, Pollard JW (2001) Colony-stimulating factor 1 promotes progression of mammary tumors to malignancy. J Exp Med 193:727–740

    Article  PubMed  CAS  Google Scholar 

  116. Hamilton JA (2008) Colony-stimulating factors in inflammation and autoimmunity. Nat Rev Immunol 8:533–544

    Article  PubMed  CAS  Google Scholar 

  117. Priceman SJ, Sung JL, Shaposhnik Z, Burton JB, Torres-Collado AX, Moughon DL, Johnson M, Lusis AJ, Cohen DA, Iruela-Arispe ML, Wu L (2010) Targeting distinct tumor-infiltrating myeloid cells by inhibiting CSF-1 receptor: combating tumor evasion of antiangiogenic therapy. Blood 115:1461–1471

    Article  PubMed  CAS  Google Scholar 

  118. Eubank TD, Galloway M, Montague CM, Waldman WJ, Marsh CB (2003) M-CSF induces vascular endothelial growth factor production and angiogenic activity from human monocytes. J Immunol 171:2637–2643

    PubMed  CAS  Google Scholar 

  119. Niida S, Kaku M, Amano H, Yoshida H, Kataoka H, Nishikawa S, Tanne K, Maeda N, Nishikawa S, Kodama H (1999) Vascular endothelial growth factor can substitute for macrophage colony-stimulating factor in the support of osteoclastic bone resorption. J Exp Med 190:293–298

    Article  PubMed  CAS  Google Scholar 

  120. Zhang Q, Lu Y, Proulx ST, Guo R, Yao Z, Schwarz EM, Boyce BF, Xing L (2007) Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthritis Res Ther 9:R118

    Article  PubMed  CAS  Google Scholar 

  121. Gray-Owen SD, Blumberg RS (2006) CEACAM1: contact-dependent control of immunity. Nat Rev Immunol 6:433–446

    Article  PubMed  CAS  Google Scholar 

  122. Ergün S, Kilik N, Ziegeler G, Hansen A, Nollau P, Götze J, Wurmbach JH, Horst A, Weil J, Fernando M, Wagener C (2000) CEA-related cell adhesion molecule 1: a potent angiogenic factor and a major effector of vascular endothelial growth factor. Mol Cell 5:311–320

    Article  PubMed  Google Scholar 

  123. Kilic N, Oliveira-Ferrer L, Neshat-Vahid S, Irmak S, Obst-Pernberg K, Wurmbach JH, Loges S, Kilic E, Weil J, Lauke H, Tilki D, Singer BB, Ergün S (2007) Lymphatic reprogramming of microvascular endothelial cells by CEA-related cell adhesion molecule-1 via interaction with VEGFR-3 and Prox1. Blood 110:4223–4233

    Article  PubMed  CAS  Google Scholar 

  124. Murdoch C (2000) CXCR4: chemokine receptor extraordinaire. Immunol Rev 177:175–184

    Article  PubMed  CAS  Google Scholar 

  125. Zou YR, Kottmann AH, Kuroda M, Taniuchi I, Littman DR (1998) Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393:595–599

    Article  PubMed  CAS  Google Scholar 

  126. Lapidot T, Petit I (2002) Current understanding of stem cell mobilization: the roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol 30:973–981

    Article  PubMed  CAS  Google Scholar 

  127. Kijowski J, Baj-Krzyworzeka M, Majka M, Reca R, Marquez LA, Christofidou-Solomidou M, Janowska-Wieczorek A, Ratajczak MZ (2001) The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells 19:453–466

    Article  PubMed  CAS  Google Scholar 

  128. Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC (1997) The chemokine SDF-1 is a chemoattractant for human CD34+ hematopoietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med 185:111–120

    Article  PubMed  CAS  Google Scholar 

  129. Ceradini DJ, Kulkarni AR, Callaghan MJ, Tepper OM, Bastidas N, Kleinman ME, Capla JM, Galiano RD, Levine JP, Gurtner GC (2004) Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med 10:858–864

    Article  PubMed  CAS  Google Scholar 

  130. Royston D, Jackson DG (2009) Mechanisms of lymphatic metastasis in human colorectal adenocarcinoma. J Pathol 217:608–619

    Article  PubMed  CAS  Google Scholar 

  131. Hirakawa S, Detmar M, Kerjaschki D, Nagamatsu S, Matsuo K, Tanemura A, Kamata N, Higashikawa K, Okazaki H, Kameda K, Nishida-Fukuda H, Mori H, Hanakawa Y, Sayama K, Shirakata Y, Tohyama M, Tokumaru S, Katayama I, Hashimoto K (2009) Nodal lymphangiogenesis and metastasis: role of tumor-induced lymphatic vessel activation in extramammary Paget’s disease. Am J Pathol 175:2235–2248

    Article  PubMed  Google Scholar 

  132. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL, Weinberg RA (2005) Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121:335–348

    Article  PubMed  CAS  Google Scholar 

  133. Müller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verástegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56

    Article  PubMed  Google Scholar 

  134. Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, Tesio M, Samstein RM, Goichberg P, Spiegel A, Elson A, Lapidot T (2006) Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med 12:657–664

    Article  PubMed  CAS  Google Scholar 

  135. Opal SM, Cohen J (1999) Clinical gram-positive sepsis: does it fundamentally differ from gram-negative bacterial sepsis? Crit Care Med 27:1608–1616

    Article  PubMed  CAS  Google Scholar 

  136. Bannerman DD, Sathyamoorthy M, Goldblum SE (1998) Bacterial lipopolysaccharide disrupts endothelial monolayer integrity and survival signaling events through caspase cleavage of adherens junction proteins. J Biol Chem 273:35371–35380

    Article  PubMed  CAS  Google Scholar 

  137. Kang S, Lee SP, Kim KE, Kim HZ, Mémet S, Koh GY (2009) Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages. Blood 113:2605–2613

    Article  PubMed  CAS  Google Scholar 

  138. Kataru RP, Jung K, Jang C, Yang H, Schwendener RA, Baik JE, Han SH, Alitalo K, Koh GY (2009) Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 113:5650–5659

    Article  PubMed  CAS  Google Scholar 

  139. Faure E, Equils O, Sieling PA, Thomas L, Zhang FX, Kirschning CJ, Polentarutti N, Muzio M, Arditi M (2000) Bacterial lipopolysaccharide activates NF-kappaB through toll-like receptor 4 (TLR-4) in cultured human dermal endothelial cells. Differential expression of TLR-4 and TLR-2 in endothelial cells. J Biol Chem 275:11058–11063

    Article  PubMed  CAS  Google Scholar 

  140. Flister MJ, Wilber A, Hall KL, Iwata C, Miyazono K, Nisato RE, Pepper MS, Zawieja DC, Ran S (2010) Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. Blood 115:418–429

    Article  PubMed  CAS  Google Scholar 

  141. Hagendoorn J, Padera TP, Kashiwagi S, Isaka N, Noda F, Lin MI, Huang PL, Sessa WC, Fukumura D, Jain RK (2004) Endothelial nitric oxide synthase regulates microlymphatic flow via collecting lymphatics. Circ Res 95:204–209

    Article  PubMed  CAS  Google Scholar 

  142. Lahdenranta J, Hagendoorn J, Padera TP, Hoshida T, Nelson G, Kashiwagi S, Jain RK, Fukumura D (2009) Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis. Cancer Res 69:2801–2808

    Article  PubMed  CAS  Google Scholar 

  143. Mogensen TH, Paludan SR (2001) Molecular pathways in virus-induced cytokine production. Microbiol Mol Biol Rev 65:131–150

    Article  PubMed  CAS  Google Scholar 

  144. Fiorentini S, Luganini A, Dell’oste V, Lorusso B, Cervi E, Caccuri F, Bonardelli S, Landolfo S, Caruso A, Gribaudo G (2011) Human cytomegalovirus productively infects lymphatic endothelial cells and induces a secretome that promotes angiogenesis and lymphangiogenesis through interleukin-6 and granulocyte-macrophage colony-stimulating factor. J Gen Virol 92:650–660

    Article  PubMed  CAS  Google Scholar 

  145. Jeon BH, Jang C, Han J, Kataru RP, Piao L, Jung K, Cha HJ, Schwendener RA, Jang KY, Kim KS, Alitalo K, Koh GY (2008) Profound but dysfunctional lymphangiogenesis via vascular endothelial growth factor ligands from CD11b+ macrophages in advanced ovarian cancer. Cancer Res 68:1100–1109

    Article  PubMed  CAS  Google Scholar 

  146. Dietrich T, Bock F, Yuen D, Hos D, Bachmann BO, Zahn G, Wiegand S, Chen L, Cursiefen C (2010) Cutting edge: lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. J Immunol 184:535–539

    Article  PubMed  CAS  Google Scholar 

  147. Maruyama K, Asai J, Ii M, Thorne T, Losordo DW, D’Amore PA (2007) Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol 170:1178–1191

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Human Anatomy, Oita University Faculty of Medicine, Oita, 879-5593, Japan

    Rui-Cheng Ji

Authors
  1. Rui-Cheng Ji
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rui-Cheng Ji.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ji, RC. Macrophages are important mediators of either tumor- or inflammation-induced lymphangiogenesis. Cell. Mol. Life Sci. 69, 897–914 (2012). https://doi.org/10.1007/s00018-011-0848-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00018-011-0848-6

Keywords

Search

Navigation