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Developmental and Pathological Lymphangiogenesis

  • Angelika Chachaj
  • Andrzej SzubaEmail author
Chapter

Abstract

The past two decades have significantly improved our understanding of the mechanisms of lymphangiogenesis. Identification of lymphatic endothelial specific immunohistochemical markers and development of new experimental animal models have been instrumental in the identification of a number of molecular players regulating growth and remodeling of the lymphatic vasculature during embryonic development. Studies with different models of genetically deficient mice identified also a spectrum of primary lymphedema phenotypes. Recent findings have highlighted the role of lymphangiogenesis in various pathological conditions. It was clearly demonstrated that lymph vessels are active participants in acute and chronic inflammation, organ transplant rejection, metastatic tumor dissemination, and hypertension. Therefore, the specific targeting of the lymphatic vasculature could be a promising approach for pro- or anti-lymphangiogenic treatment in inflammatory disorders, graft rejection, lymphedema, and cancer.

Keywords

Lymphatic endothelial cells VEGF-A VEGF-C VEGF-D VEGFR-3 Inflammation Tumor Metastasis 

References

  1. 1.
    Alitalo K, Tammela T, Petrova TV (2005) Lymphangiogenesis in development and human disease. Nature 438:946–953PubMedGoogle Scholar
  2. 2.
    Xu F, Stouffer RL (2009) Existence of the lymphatic system in the primate corpus luteum. Lymphat Res Biol 7:159–168PubMedGoogle Scholar
  3. 3.
    Achen MG, McColl BK, Stacker SA (2005) Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 7:121–127PubMedGoogle Scholar
  4. 4.
    Karpanen T, Alitalo K (2008) Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 3:367–397PubMedGoogle Scholar
  5. 5.
    Breier G, Breviario F, Caveda L, Berthier R, Schnurch H, Gotsch U, Vestweber D, Risau W, Dejana E (1996) Molecular cloning and expression of murine vascular endothelial-cadherin in early stage development of cardiovascular system. Blood 87:630–641PubMedGoogle Scholar
  6. 6.
    Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–778PubMedGoogle Scholar
  7. 7.
    van der Putte SC (1975) The development of the lymphatic system in man. Adv Anat Embryol Cell Biol 51:3–60PubMedGoogle Scholar
  8. 8.
    Lewis FT (1909) On the cervical veins and lymphatics in four human embryos. With an interpretation of anomalies of the subclavian and jugular veins in the adult. Am J Anat 9:33–43Google Scholar
  9. 9.
    Sabin FR (1909) The lymphatic system in human embryos, with consideration of the system as a whole. Am J Anat 9:43–91Google Scholar
  10. 10.
    Faul JL, Berry GJ, Colby TV, Ruoss SJ, Walter MB, Rosen GD, Raffin TA (2000) Thoracic lymphangiomas, lymphangiectasis, lymphangiomatosis, and lymphatic dysplasia syndrome. Am J Respir Crit Care Med 161:1037–1046PubMedGoogle Scholar
  11. 11.
    Wiegand S, Eivazi B, Barth PJ, von Rautenfeld DB, Folz BJ, Mandic R, Werner JA (2008) Pathogenesis of lymphangiomas. Virchows Arch 453:1–8PubMedGoogle Scholar
  12. 12.
    Sabin F (1902) On the origin of the lymphatics system from the veins and the development of the lymph hearts and thorarcic duct in the pig. Am J Anat 1:367–391Google Scholar
  13. 13.
    Sabin F (1904) On the development of the superficial lymphatics in the skin of the pig. Am J Anat 3:183–195Google Scholar
  14. 14.
    Srinivasan RS, Dillard ME, Lagutin OV, Lin FJ, Tsai S, Tsai MJ, Samokhvalov IM, Oliver G (2007) Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev 21:2422–2432PubMedGoogle Scholar
  15. 15.
    Yaniv K, Isogai S, Castranova D, Dye L, Hitomi J, Weinstein BM (2006) Live imaging of lymphatic development in the zebrafish. Nat Med 12:711–716PubMedGoogle Scholar
  16. 16.
    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 5:74–80PubMedGoogle Scholar
  17. 17.
    Oliver G (2004) Lymphatic vasculature development. Nat Rev Immunol 4:35–45PubMedGoogle Scholar
  18. 18.
    Huntington GC, Mc Clure CFW (1910) The anatomy and development of the jugular lymph sacs in the domestic cat (Felis domestica). Am J Anat 10:177–311Google Scholar
  19. 19.
    Wilting J, Aref Y, Huang R, Tomarev SI, Schweigerer L, Christ B, Valasek P, Papoutsi M (2006) Dual origin of avian lymphatics. Dev Biol 292:165–173PubMedGoogle Scholar
  20. 20.
    Buttler K, Kreysing A, von Kaisenberg CS, Schweigerer L, Gale N, Papoutsi M, Wilting J (2006) Mesenchymal cells with leukocyte and lymphendothelial characteristics in murine embryos. Dev Dyn 235:1554–1562PubMedGoogle Scholar
  21. 21.
    Buttler K, Ezaki T, Wilting J (2008) Proliferating mesodermal cells in murine embryos exhibiting macrophage and lymphendothelial characteristics. BMC Dev Biol 8:43PubMedCentralPubMedGoogle Scholar
  22. 22.
    Ran S, Montgomery KE (2012) Macrophage-mediated lymphangiogenesis: the emerging role of macrophages as lymphatic endothelial progenitors. Cancers (Basel) 4:618–657Google Scholar
  23. 23.
    Asahara T, Kawamoto A (2004) Endothelial progenitor cells for postnatal vasculogenesis. Am J Physiol Cell Physiol 287:C572–579PubMedGoogle Scholar
  24. 24.
    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 106:4184–4190PubMedGoogle Scholar
  25. 25.
    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 115:2363–2372PubMedCentralPubMedGoogle Scholar
  26. 26.
    Zumsteg A, Baeriswyl V, Imaizumi N, Schwendener R, Ruegg C, Christofori G (2009) Myeloid cells contribute to tumor lymphangiogenesis. PLoS One 4:e7067PubMedCentralPubMedGoogle Scholar
  27. 27.
    Grunewald M, Avraham I, Dor Y, Bachar-Lustig E, Itin A, Jung S, Chimenti S, Landsman L, Abramovitch R, Keshet E (2006) VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 124:175–189PubMedGoogle Scholar
  28. 28.
    Mounzer RH, Svendsen OS, Baluk P, Bergman CM, Padera TP, Wiig H, Jain RK, McDonald DM, Ruddle NH (2010) Lymphotoxin-alpha contributes to lymphangiogenesis. Blood 116:2173–2182PubMedGoogle Scholar
  29. 29.
    Fraser JR, Kimpton WG, Laurent TC, Cahill RN, Vakakis N (1988) Uptake and degradation of hyaluronan in lymphatic tissue. Biochem J 256:153–158PubMedGoogle Scholar
  30. 30.
    Gale NW, Prevo R, Espinosa J, Ferguson DJ, Dominguez MG, Yancopoulos GD, Thurston G, Jackson DG (2007) Normal lymphatic development and function in mice deficient for the lymphatic hyaluronan receptor LYVE-1. Mol Cell Biol 27:595–604PubMedCentralPubMedGoogle Scholar
  31. 31.
    Hong YK, Harvey N, Noh YH, Schacht V, Hirakawa S, Detmar M, Oliver G (2002) Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn 225:351–357PubMedGoogle Scholar
  32. 32.
    Francois M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, Browne C, Paavonen K, Karnezis T, Shayan R, Downes M, Davidson T, Tutt D, Cheah KS, Stacker SA, Muscat GE, Achen MG, Dejana E, Koopman P (2008) Sox18 induces development of the lymphatic vasculature in mice. Nature 456:643–647PubMedGoogle Scholar
  33. 33.
    Srinivasan RS, Geng X, Yang Y, Wang Y, Mukatira S, Studer M, Porto MP, Lagutin O, Oliver G (2010) The nuclear hormone receptor Coup-TFII is required for the initiation and early maintenance of Prox1 expression in lymphatic endothelial cells. Genes Dev 24:696–707PubMedGoogle Scholar
  34. 34.
    Irrthum A, Devriendt K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns JP, Van Steensel MA, Vikkula M (2003) Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am J Hum Genet 72:1470–1478PubMedCentralPubMedGoogle Scholar
  35. 35.
    Lin FJ, Chen X, Qin J, Hong YK, Tsai MJ, Tsai SY (2010) Direct transcriptional regulation of neuropilin-2 by COUP-TFII modulates multiple steps in murine lymphatic vessel development. J Clin Invest 120:1694–1707PubMedCentralPubMedGoogle Scholar
  36. 36.
    Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D, Breitman M, Alitalo K (1995) Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 92:3566–3570PubMedGoogle Scholar
  37. 37.
    Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K, Breitman M, Alitalo K (1998) Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282:946–949PubMedGoogle Scholar
  38. 38.
    Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K, Bueler H, Eichmann A, Kauppinen R, Kettunen MI, Yla-Herttuala S, Finegold DN, Ferrell RE, Alitalo K (2001) A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci USA 98:12677–12682PubMedGoogle Scholar
  39. 39.
    Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, Alitalo K, Finegold DN (2000) Missense mutations interfere with VEGFR-3 signalling in primary lymphoedema. Nat Genet 25:153–159PubMedGoogle Scholar
  40. 40.
    Achen MG, Jeltsch M, Kukk E, Makinen 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 95:548–553PubMedGoogle Scholar
  41. 41.
    Baldwin ME, Catimel B, Nice EC, Roufail S, Hall NE, Stenvers KL, Karkkainen MJ, Alitalo K, Stacker SA, Achen MG (2001) The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man. J Biol Chem 276:19166–19171PubMedGoogle Scholar
  42. 42.
    Millauer B, Wizigmann-Voos S, Schnurch H, Martinez R, Moller NP, Risau W, Ullrich A (1993) High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell 72:835–846PubMedGoogle Scholar
  43. 43.
    Cao R, Eriksson A, Kubo H, Alitalo K, Cao Y, Thyberg J (2004) Comparative evaluation of FGF-2-, VEGF-A-, and VEGF-C-induced angiogenesis, lymphangiogenesis, vascular fenestrations, and permeability. Circ Res 94:664–670PubMedGoogle Scholar
  44. 44.
    Kubo H, Cao R, Brakenhielm E, Makinen T, Cao Y, Alitalo K (2002) Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci USA 99:8868–8873PubMedGoogle Scholar
  45. 45.
    Saaristo A, Veikkola T, Enholm B, Hytonen M, Arola J, Pajusola K, Turunen P, Jeltsch M, Karkkainen MJ, Kerjaschki D, Bueler H, Yla-Herttuala S, Alitalo K (2002) Adenoviral VEGF-C overexpression induces blood vessel enlargement, tortuosity, and leakiness but no sprouting angiogenesis in the skin or mucous membranes. FASEB J 16:1041–1049PubMedGoogle Scholar
  46. 46.
    Kukk E, Lymboussaki A, Taira S, Kaipainen A, Jeltsch M, Joukov V, Alitalo K (1996) VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development 122:3829–3837PubMedGoogle Scholar
  47. 47.
    Byzova TV, Goldman CK, Jankau J, Chen J, Cabrera G, Achen MG, Stacker SA, Carnevale KA, Siemionow M, Deitcher SR, DiCorleto PE (2002) Adenovirus encoding vascular endothelial growth factor-D induces tissue-specific vascular patterns in vivo. Blood 99:4434–4442PubMedGoogle Scholar
  48. 48.
    Baldwin ME, Halford MM, Roufail S, Williams RA, Hibbs ML, Grail D, Kubo H, Stacker SA, Achen MG (2005) Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol 25:2441–2449PubMedCentralPubMedGoogle Scholar
  49. 49.
    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 20:1462–1472PubMedGoogle Scholar
  50. 50.
    Yuan L, Moyon D, Pardanaud L, Breant C, Karkkainen MJ, Alitalo K, Eichmann A (2002) Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129:4797–4806PubMedGoogle Scholar
  51. 51.
    Xu Y, Yuan L, Mak J, Pardanaud L, Caunt M, Kasman I, Larrivee B, Del Toro R, Suchting S, Medvinsky A, Silva J, Yang J, Thomas JL, Koch AW, Alitalo K, Eichmann A, Bagri A (2010) Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J Cell Biol 188:115–130PubMedGoogle Scholar
  52. 52.
    Takashima S, Kitakaze M, Asakura M, Asanuma H, Sanada S, Tashiro F, Niwa H, Miyazaki Ji J, Hirota S, Kitamura Y, Kitsukawa T, Fujisawa H, Klagsbrun M, Hori M (2002) Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci USA 99:3657–3662PubMedGoogle Scholar
  53. 53.
    Oliver G, Srinivasan RS (2008) Lymphatic vasculature development: current concepts. Ann N Y Acad Sci 1131:75–81PubMedGoogle Scholar
  54. 54.
    Taniguchi K, Kohno R, Ayada T, Kato R, Ichiyama K, Morisada T, Oike Y, Yonemitsu Y, Maehara Y, Yoshimura A (2007) Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. Mol Cell Biol 27:4541–4550PubMedCentralPubMedGoogle Scholar
  55. 55.
    Abtahian F, Guerriero A, Sebzda E, Lu MM, Zhou R, Mocsai A, Myers EE, Huang B, Jackson DG, Ferrari VA, Tybulewicz V, Lowell CA, Lepore JJ, Koretzky GA, Kahn ML (2003) Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299:247–251PubMedCentralPubMedGoogle Scholar
  56. 56.
    Fritz-Six KL, Dunworth WP, Li M, Caron KM (2008) Adrenomedullin signaling is necessary for murine lymphatic vascular development. J Clin Invest 118:40–50PubMedCentralPubMedGoogle Scholar
  57. 57.
    Hirashima M, Sano K, Morisada T, Murakami K, Rossant J, Suda T (2008) Lymphatic vessel assembly is impaired in Aspp1-deficient mouse embryos. Dev Biol 316:149–159PubMedGoogle Scholar
  58. 58.
    Langton PF, Colombani J, Aerne BL, Tapon N (2007) Drosophila ASPP regulates C-terminal Src kinase activity. Dev Cell 13:773–782PubMedGoogle Scholar
  59. 59.
    Yoon CM, Hong BS, Moon HG, Lim S, Suh PG, Kim YK, Chae CB, Gho YS (2008) Sphingosine-1-phosphate promotes lymphangiogenesis by stimulating S1P1/Gi/PLC/Ca2+ signaling pathways. Blood 112:1129–1138PubMedGoogle Scholar
  60. 60.
    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:H2113–2127PubMedGoogle Scholar
  61. 61.
    Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, Meister B, Ikomi F, Tritsaris K, Dissing S, Ohhashi T, Jackson DG, Cao Y (2004) PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6:333–345PubMedGoogle Scholar
  62. 62.
    Chang LK, Garcia-Cardena G, Farnebo F, Fannon M, Chen EJ, Butterfield C, Moses MA, Mulligan RC, Folkman J, Kaipainen A (2004) Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA 101:11658–11663PubMedGoogle Scholar
  63. 63.
    Bjorndahl M, Cao R, Nissen LJ, Clasper S, Johnson LA, Xue Y, Zhou Z, Jackson D, Hansen AJ, Cao Y (2005) Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc Natl Acad Sci USA 102:15593–15598PubMedGoogle Scholar
  64. 64.
    Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M (2005) Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J 24:2885–2895PubMedGoogle Scholar
  65. 65.
    Banziger-Tobler NE, Halin C, Kajiya K, Detmar M (2008) Growth hormone promotes lymphangiogenesis. Am J Pathol 173:586–597PubMedGoogle Scholar
  66. 66.
    Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D (1999) Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 154:385–394PubMedGoogle Scholar
  67. 67.
    Schacht V, Ramirez MI, Hong YK, Hirakawa S, Feng D, Harvey N, Williams M, Dvorak AM, Dvorak HF, Oliver G, Detmar M (2003) T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J 22:3546–3556PubMedGoogle Scholar
  68. 68.
    Suzuki-Inoue K, Kato Y, Inoue O, Kaneko MK, Mishima K, Yatomi Y, Yamazaki Y, Narimatsu H, Ozaki Y (2007) Involvement of the snake toxin receptor CLEC-2, in podoplanin-mediated platelet activation, by cancer cells. J Biol Chem 282:25993–26001PubMedGoogle Scholar
  69. 69.
    Sebzda E, Hibbard C, Sweeney S, Abtahian F, Bezman N, Clemens G, Maltzman JS, Cheng L, Liu F, Turner M, Tybulewicz V, Koretzky GA, Kahn ML (2006) Syk and Slp-76 mutant mice reveal a cell-autonomous hematopoietic cell contribution to vascular development. Dev Cell 11:349–361PubMedGoogle Scholar
  70. 70.
    Backhed F, Crawford PA, O'Donnell D, Gordon JI (2007) Postnatal lymphatic partitioning from the blood vasculature in the small intestine requires fasting-induced adipose factor. Proc Natl Acad Sci USA 104:606–611PubMedGoogle Scholar
  71. 71.
    Maby-El Hajjami H, Petrova TV (2008) Developmental and pathological lymphangiogenesis: from models to human disease. Histochem Cell Biol 130:1063–1078PubMedGoogle Scholar
  72. 72.
    Albrecht I, Christofori G (2011) Molecular mechanisms of lymphangiogenesis in development and cancer. Int J Dev Biol 55:483–494PubMedGoogle Scholar
  73. 73.
    Petrova TV, Karpanen T, Norrmen C, Mellor R, Tamakoshi T, Finegold D, Ferrell R, Kerjaschki D, Mortimer P, Yla-Herttuala S, Miura N, Alitalo K (2004) Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nat Med 10:974–981PubMedGoogle Scholar
  74. 74.
    Dagenais SL, Hartsough RL, Erickson RP, Witte MH, Butler MG, Glover TW (2004) Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome. Gene Expr Patterns 4:611–619PubMedGoogle Scholar
  75. 75.
    Norrmen C, Ivanov KI, Cheng J, Zangger N, Delorenzi M, Jaquet M, Miura N, Puolakkainen P, Horsley V, Hu J, Augustin HG, Yla-Herttuala S, Alitalo K, Petrova TV (2009) FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J Cell Biol 185:439–457PubMedGoogle Scholar
  76. 76.
    Fang J, Dagenais SL, Erickson RP, Arlt MF, Glynn MW, Gorski JL, Seaver LH, Glover TW (2000) Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. Am J Hum Genet 67:1382–1388PubMedCentralPubMedGoogle Scholar
  77. 77.
    Augustin HG, Koh GY, Thurston G, Alitalo K (2009) Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol 10:165–177PubMedGoogle Scholar
  78. 78.
    Saharinen P, Kerkela K, Ekman N, Marron M, Brindle N, Lee GM, Augustin H, Koh GY, Alitalo K (2005) Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J Cell Biol 169:239–243PubMedGoogle Scholar
  79. 79.
    Davis S, Aldrich TH, Jones PF, Acheson A, Compton DL, Jain V, Ryan TE, Bruno J, Radziejewski C, Maisonpierre PC, Yancopoulos GD (1996) Isolation of angiopoietin-1, a ligand for the TIE2 receptor, by secretion-trap expression cloning. Cell 87:1161–1169PubMedGoogle Scholar
  80. 80.
    Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, Jackson D, Suri C, Campochiaro PA, Wiegand SJ, Yancopoulos GD (2002) Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell 3:411–423PubMedGoogle Scholar
  81. 81.
    Lee HJ, Cho CH, Hwang SJ, Choi HH, Kim KT, Ahn SY, Kim JH, Oh JL, Lee GM, Koh GY (2004) Biological characterization of angiopoietin-3 and angiopoietin-4. FASEB J 18:1200–1208PubMedGoogle Scholar
  82. 82.
    Vikkula M, Boon LM, Carraway KL 3rd, Calvert JT, Diamonti AJ, Goumnerov B, Pasyk KA, Marchuk DA, Warman ML, Cantley LC, Mulliken JB, Olsen BR (1996) Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87:1181–1190PubMedGoogle Scholar
  83. 83.
    Makinen T, Adams RH, Bailey J, Lu Q, Ziemiecki A, Alitalo K, Klein R, Wilkinson GA (2005) PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev 19:397–410PubMedGoogle Scholar
  84. 84.
    Zhou F, Chang Z, Zhang L, Hong YK, Shen B, Wang B, Zhang F, Lu G, Tvorogov D, Alitalo K, Hemmings BA, Yang Z, He Y (2010) Akt/Protein kinase B is required for lymphatic network formation, remodeling, and valve development. Am J Pathol 177:2124–2133PubMedGoogle Scholar
  85. 85.
    Chen J, Alexander JS, Orr AW (2012) Integrins and their extracellular matrix ligands in lymphangiogenesis and lymph node metastasis. Int J Cell Biol 2012:853703PubMedCentralPubMedGoogle Scholar
  86. 86.
    Gerli R, Solito R, Weber E, Agliano M (2000) Specific adhesion molecules bind anchoring filaments and endothelial cells in human skin initial lymphatics. Lymphology 33:148–157PubMedGoogle Scholar
  87. 87.
    Vlahakis NE, Young BA, Atakilit A, Sheppard D (2005) The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1. J Biol Chem 280:4544–4552PubMedCentralPubMedGoogle Scholar
  88. 88.
    Bazigou E, Xie S, Chen C, Weston A, Miura N, Sorokin L, Adams R, Muro AF, Sheppard D, Makinen T (2009) Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell 17:175–186PubMedCentralPubMedGoogle Scholar
  89. 89.
    Ma GC, Liu CS, Chang SP, Yeh KT, Ke YY, Chen TH, Wang BB, Kuo SJ, Shih JC, Chen M (2008) A recurrent ITGA9 missense mutation in human fetuses with severe chylothorax: possible correlation with poor response to fetal therapy. Prenat Diagn 28:1057–1063PubMedGoogle Scholar
  90. 90.
    Danussi C, Spessotto P, Petrucco A, Wassermann B, Sabatelli P, Montesi M, Doliana R, Bressan GM, Colombatti A (2008) Emilin1 deficiency causes structural and functional defects of lymphatic vasculature. Mol Cell Biol 28:4026–4039PubMedCentralPubMedGoogle Scholar
  91. 91.
    Podgrabinska S, Braun P, Velasco P, Kloos B, Pepper MS, Skobe M (2002) Molecular characterization of lymphatic endothelial cells. Proc Natl Acad Sci USA 99:16069–16074PubMedGoogle Scholar
  92. 92.
    Hogan BM, Bos FL, Bussmann J, Witte M, Chi NC, Duckers HJ, Schulte-Merker S (2009) Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nat Genet 41:396–398PubMedGoogle Scholar
  93. 93.
    Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, Hennekam EA, Holmberg EE, Mannens MM, Mulder MF, Offerhaus GJ, Prescott TE, Schroor EJ, Verheij JB, Witte M, Zwijnenburg PJ, Vikkula M, Schulte-Merker S, Hennekam RC (2009) Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet 41:1272–1274PubMedGoogle Scholar
  94. 94.
    Hahn C, Schwartz MA (2009) Mechanotransduction in vascular physiology and atherogenesis. Nat Rev Mol Cell Biol 10:53–62PubMedCentralPubMedGoogle Scholar
  95. 95.
    Chiquet M, Gelman L, Lutz R, Maier S (2009) From mechanotransduction to extracellular matrix gene expression in fibroblasts. Biochim Biophys Acta 1793:911–920PubMedGoogle Scholar
  96. 96.
    Rutkowski JM, Swartz MA (2007) A driving force for change: interstitial flow as a morphoregulator. Trends Cell Biol 17:44–50PubMedGoogle Scholar
  97. 97.
    Goldman J, Conley KA, Raehl A, Bondy DM, Pytowski B, Swartz MA, Rutkowski JM, Jaroch DB, Ongstad EL (2007) Regulation of lymphatic capillary regeneration by interstitial flow in skin. Am J Physiol Heart Circ Physiol 292:H2176–2183PubMedGoogle Scholar
  98. 98.
    Ng CP, Helm CL, Swartz MA (2004) Interstitial flow differentially stimulates blood and lymphatic endothelial cell morphogenesis in vitro. Microvasc Res 68:258–264PubMedGoogle Scholar
  99. 99.
    Karpanen T, Wirzenius M, Makinen T, Veikkola T, Haisma HJ, Achen MG, Stacker SA, Pytowski B, Yla-Herttuala S, Alitalo K (2006) Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation. Am J Pathol 169:708–718PubMedGoogle Scholar
  100. 100.
    Enholm B, Karpanen T, Jeltsch M, Kubo H, Stenback F, Prevo R, Jackson DG, Yla-Herttuala S, Alitalo K (2001) Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin. Circ Res 88:623–629PubMedGoogle Scholar
  101. 101.
    Baluk P, Tammela T, Ator E, Lyubynska N, Achen MG, Hicklin DJ, Jeltsch M, Petrova TV, Pytowski B, Stacker SA, Yla-Herttuala S, Jackson DG, Alitalo K, McDonald DM (2005) Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J Clin Invest 115:247–257PubMedCentralPubMedGoogle Scholar
  102. 102.
    Kaiserling E, Krober S, Geleff S (2003) Lymphatic vessels in the colonic mucosa in ulcerative colitis. Lymphology 36:52–61PubMedGoogle Scholar
  103. 103.
    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:R118PubMedCentralPubMedGoogle Scholar
  104. 104.
    Kunstfeld R, Hirakawa S, Hong YK, Schacht V, Lange-Asschenfeldt B, Velasco P, Lin C, Fiebiger E, Wei X, Wu Y, Hicklin D, Bohlen P, Detmar M (2004) Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia. Blood 104:1048–1057PubMedGoogle Scholar
  105. 105.
    Henno A, Blacher S, Lambert C, Colige A, Seidel L, Noel A, Lapiere C, de la Brassinne M, Nusgens BV (2009) Altered expression of angiogenesis and lymphangiogenesis markers in the uninvolved skin of plaque-type psoriasis. Br J Dermatol 160:581–590PubMedGoogle Scholar
  106. 106.
    Kajiya K, Sawane M, Huggenberger R, Detmar M (2009) Activation of the VEGFR-3 pathway by VEGF-C attenuates UVB-induced edema formation and skin inflammation by promoting lymphangiogenesis. J Invest Dermatol 129:1292–1298PubMedGoogle Scholar
  107. 107.
    Jackowski S, Janusch M, Fiedler E, Marsch WC, Ulbrich EJ, Gaisbauer G, Dunst J, Kerjaschki D, Helmbold P (2007) Radiogenic lymphangiogenesis in the skin. Am J Pathol 171:338–348PubMedGoogle Scholar
  108. 108.
    Kerjaschki D, Regele HM, Moosberger I, Nagy-Bojarski K, Watschinger B, Soleiman A, Birner P, Krieger S, Hovorka A, Silberhumer G, Laakkonen P, Petrova T, Langer B, Raab I (2004) Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 15:603–612PubMedGoogle Scholar
  109. 109.
    Huggenberger R, Siddiqui SS, Brander D, Ullmann S, Zimmermann K, Antsiferova M, Werner S, Alitalo K, Detmar M (2011) An important role of lymphatic vessel activation in limiting acute inflammation. Blood 117:4667–4678PubMedGoogle Scholar
  110. 110.
    Paavonen K, Puolakkainen P, Jussila L, Jahkola T, Alitalo K (2000) Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol 156:1499–1504PubMedGoogle Scholar
  111. 111.
    Yao LC, Baluk P, Feng J, McDonald DM (2010) Steroid-resistant lymphatic remodeling in chronically inflamed mouse airways. Am J Pathol 176:1525–1541PubMedGoogle Scholar
  112. 112.
    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 113:5650–5659PubMedGoogle Scholar
  113. 113.
    Kajiya K, Hirakawa S, Detmar M (2006) Vascular endothelial growth factor-A mediates ultraviolet B-induced impairment of lymphatic vessel function. Am J Pathol 169:1496–1503PubMedGoogle Scholar
  114. 114.
    Forster R, Davalos-Misslitz AC, Rot A (2008) CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol 8:362–371PubMedGoogle Scholar
  115. 115.
    Issa A, Le TX, Shoushtari AN, Shields JD, Swartz MA (2009) Vascular endothelial growth factor-C and C-C chemokine receptor 7 in tumor cell-lymphatic cross-talk promote invasive phenotype. Cancer Res 69:349–357PubMedGoogle Scholar
  116. 116.
    Kabashima K, Shiraishi N, Sugita K, Mori T, Onoue A, Kobayashi M, Sakabe J, Yoshiki R, Tamamura H, Fujii N, Inaba K, Tokura Y (2007) CXCL12-CXCR4 engagement is required for migration of cutaneous dendritic cells. Am J Pathol 171:1249–1257PubMedGoogle Scholar
  117. 117.
    Wick N, Haluza D, Gurnhofer E, Raab I, Kasimir MT, Prinz M, Steiner CW, Reinisch C, Howorka A, Giovanoli P, Buchsbaum S, Krieger S, Tschachler E, Petzelbauer P, Kerjaschki D (2008) Lymphatic precollectors contain a novel, specialized subpopulation of podoplanin low, CCL27-expressing lymphatic endothelial cells. Am J Pathol 173:1202–1209PubMedGoogle Scholar
  118. 118.
    Ledgerwood LG, Lal G, Zhang N, Garin A, Esses SJ, Ginhoux F, Merad M, Peche H, Lira SA, Ding Y, Yang Y, He X, Schuchman EH, Allende ML, Ochando JC, Bromberg JS (2008) The sphingosine 1-phosphate receptor 1 causes tissue retention by inhibiting the entry of peripheral tissue T lymphocytes into afferent lymphatics. Nat Immunol 9:42–53PubMedGoogle Scholar
  119. 119.
    Johnson LA, Clasper S, Holt AP, Lalor PF, Baban D, Jackson DG (2006) An inflammation-induced mechanism for leukocyte transmigration across lymphatic vessel endothelium. J Exp Med 203:2763–2777PubMedCentralPubMedGoogle Scholar
  120. 120.
    Wyble CW, Hynes KL, Kuchibhotla J, Marcus BC, Hallahan D, Gewertz BL (1997) TNF-alpha and IL-1 upregulate membrane-bound and soluble E-selectin through a common pathway. J Surg Res 73:107–112PubMedGoogle Scholar
  121. 121.
    Salmi M, Koskinen K, Henttinen T, Elima K, Jalkanen S (2004) CLEVER-1 mediates lymphocyte transmigration through vascular and lymphatic endothelium. Blood 104:3849–3857PubMedGoogle Scholar
  122. 122.
    Irjala H, Johansson EL, Grenman R, Alanen K, Salmi M, Jalkanen S (2001) Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte binding to lymphatic endothelium. J Exp Med 194:1033–1042PubMedCentralPubMedGoogle Scholar
  123. 123.
    Baluk P, Fuxe J, Hashizume H, Romano T, Lashnits E, Butz S, Vestweber D, Corada M, Molendini C, Dejana E, McDonald DM (2007) Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med 204:2349–2362PubMedCentralPubMedGoogle Scholar
  124. 124.
    Kiriakidis S, Andreakos E, Monaco C, Foxwell B, Feldmann M, Paleolog E (2003) VEGF expression in human macrophages is NF-kappaB-dependent: studies using adenoviruses expressing the endogenous NF-kappaB inhibitor IkappaBalpha and a kinase-defective form of the IkappaB kinase 2. J Cell Sci 116:665–674PubMedGoogle Scholar
  125. 125.
    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 18:1111–1113PubMedGoogle Scholar
  126. 126.
    Angeli V, Ginhoux F, Llodra 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 24:203–215PubMedGoogle Scholar
  127. 127.
    Sawano A, Iwai S, Sakurai Y, Ito M, Shitara K, Nakahata T, Shibuya M (2001) Flt-1, vascular endothelial growth factor receptor 1, is a novel cell surface marker for the lineage of monocyte-macrophages in humans. Blood 97:785–791PubMedGoogle Scholar
  128. 128.
    Mallory BP, Mead TJ, Wiginton DA, Kulkarni RM, Greenberg JM, Akeson AL (2006) Lymphangiogenesis in the developing lung promoted by VEGF-A. Microvasc Res 72:62–73PubMedGoogle Scholar
  129. 129.
    Kang S, Lee SP, Kim KE, Kim HZ, Memet S, Koh GY (2009) Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages. Blood 113:2605–2613PubMedGoogle Scholar
  130. 130.
    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 115:418–429PubMedGoogle Scholar
  131. 131.
    Al-Rawi MA, Watkins G, Mansel RE, Jiang WG (2005) The effects of interleukin-7 on the lymphangiogenic properties of human endothelial cells. Int J Oncol 27:721–730PubMedGoogle Scholar
  132. 132.
    Cao R, Bjorndahl MA, Gallego MI, Chen S, Religa P, Hansen AJ, Cao Y (2006) Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action. Blood 107:3531–3536PubMedGoogle Scholar
  133. 133.
    Armengol MP, Juan M, Lucas-Martin A, Fernandez-Figueras MT, Jaraquemada D, Gallart T, Pujol-Borrell R (2001) Thyroid autoimmune disease: demonstration of thyroid antigen-specific B cells and recombination-activating gene expression in chemokine-containing active intrathyroidal germinal centers. Am J Pathol 159:861–873PubMedGoogle Scholar
  134. 134.
    Shrestha B, Hashiguchi T, Ito T, Miura N, Takenouchi K, Oyama Y, Kawahara K, Tancharoen S, Ki IY, Arimura N, Yoshinaga N, Noma S, Shrestha C, Nitanda T, Kitajima S, Arimura K, Sato M, Sakamoto T, Maruyama I (2010) B cell-derived vascular endothelial growth factor A promotes lymphangiogenesis and high endothelial venule expansion in lymph nodes. J Immunol 184:4819–4826PubMedGoogle Scholar
  135. 135.
    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 175:1733–1745PubMedGoogle Scholar
  136. 136.
    Chyou S, Ekland EH, Carpenter AC, Tzeng TC, Tian S, Michaud M, Madri JA, Lu TT (2008) Fibroblast-type reticular stromal cells regulate the lymph node vasculature. J Immunol 181:3887–3896PubMedCentralPubMedGoogle Scholar
  137. 137.
    Zhu M, Fu YX (2011) The role of core TNF/LIGHT family members in lymph node homeostasis and remodeling. Immunol Rev 244:75–84PubMedGoogle Scholar
  138. 138.
    Zhu M, Yang Y, Wang Y, Wang Z, Fu YX (2011) LIGHT regulates inflamed draining lymph node hypertrophy. J Immunol 186:7156–7163PubMedCentralPubMedGoogle Scholar
  139. 139.
    Tammela T, Alitalo K (2010) Lymphangiogenesis: molecular mechanisms and future promise. Cell 140:460–476PubMedGoogle Scholar
  140. 140.
    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 111:4571–4579PubMedGoogle Scholar
  141. 141.
    Shull MM, Ormsby I, Kier AB, Pawlowski S, Diebold RJ, Yin M, Allen R, Sidman C, Proetzel G, Calvin D et al (1992) Targeted disruption of the mouse transforming growth factor-beta 1 gene results in multifocal inflammatory disease. Nature 359:693–699PubMedCentralPubMedGoogle Scholar
  142. 142.
    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 34:96–107PubMedGoogle Scholar
  143. 143.
    Kim H, Kataru RP, Koh GY (2012) Regulation and implications of inflammatory lymphangiogenesis. Trends Immunol 33:350–356PubMedGoogle Scholar
  144. 144.
    Mumprecht V, Roudnicky F, Detmar M (2012) Inflammation-induced lymph node lymphangiogenesis is reversible. Am J Pathol 180:874–879PubMedGoogle Scholar
  145. 145.
    Fisher B, Fisher ER (1966) The interrelationship of hematogenous and lymphatic tumor cell dissemination. Surg Gynecol Obstet 122:791–798PubMedGoogle Scholar
  146. 146.
    Li T, Yang J, Zhou Q, He Y (2012) Molecular regulation of lymphangiogenesis in development and tumor microenvironment. Cancer Microenviron 5:249–260PubMedCentralPubMedGoogle Scholar
  147. 147.
    Van der Auwera I, Cao Y, Tille JC, Pepper MS, Jackson DG, Fox SB, Harris AL, Dirix LY, Vermeulen PB (2006) First international consensus on the methodology of lymphangiogenesis quantification in solid human tumours. Br J Cancer 95:1611–1625PubMedCentralPubMedGoogle Scholar
  148. 148.
    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 7:186–191PubMedGoogle Scholar
  149. 149.
    Schoppmann SF, Fenzl A, Nagy K, Unger S, Bayer G, Geleff S, Gnant M, Horvat R, Jakesz R, Birner P (2006) VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival. Surgery 139:839–846PubMedGoogle Scholar
  150. 150.
    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 20:672–682PubMedGoogle Scholar
  151. 151.
    He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S, Harding T, Jooss K, Takahashi T, Alitalo K (2005) Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res 65:4739–4746PubMedGoogle Scholar
  152. 152.
    Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y, Choi NC, Mathisen D, Wain J, Mark EJ, Munn LL, Jain RK (2002) Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296:1883–1886PubMedGoogle Scholar
  153. 153.
    McAllaster JD, Cohen MS (2011) Role of the lymphatics in cancer metastasis and chemotherapy applications. Adv Drug Deliv Rev 63:867–875PubMedGoogle Scholar
  154. 154.
    Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M (2005) VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201:1089–1099PubMedCentralPubMedGoogle Scholar
  155. 155.
    Alitalo K (2011) The lymphatic vasculature in disease. Nat Med 17:1371–1380PubMedGoogle Scholar
  156. 156.
    He Y, Rajantie I, Ilmonen M, Makinen T, Karkkainen MJ, Haiko P, Salven P, Alitalo K (2004) Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res 64:3737–3740PubMedGoogle Scholar
  157. 157.
    Condeelis J, Pollard JW (2006) Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124:263–266PubMedGoogle Scholar
  158. 158.
    Pollard JW (2004) Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4:71–78PubMedGoogle Scholar
  159. 159.
    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 172:179–193PubMedGoogle Scholar
  160. 160.
    Shields JD, Kourtis IC, Tomei AA, Roberts JM, Swartz MA (2010) Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science 328:749–752PubMedGoogle Scholar
  161. 161.
    Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, McClanahan T, Murphy E, Yuan W, Wagner SN, Barrera JL, Mohar A, Verastegui E, Zlotnik A (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50–56PubMedGoogle Scholar
  162. 162.
    Irjala H, Alanen K, Grenman R, Heikkila 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 63:4671–4676PubMedGoogle Scholar
  163. 163.
    Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M, Alitalo K (2001) Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61:1786–1790PubMedGoogle Scholar
  164. 164.
    Kozaki K, Miyaishi O, Tsukamoto T, Tatematsu Y, Hida T, Takahashi T (2000) Establishment and characterization of a human lung cancer cell line NCI-H460-LNM35 with consistent lymphogenous metastasis via both subcutaneous and orthotopic propagation. Cancer Res 60:2535–2540PubMedGoogle Scholar
  165. 165.
    Kraizer Y, Mawasi N, Seagal J, Paizi M, Assy N, Spira G (2001) Vascular endothelial growth factor and angiopoietin in liver regeneration. Biochem Biophys Res Commun 287:209–215PubMedGoogle Scholar
  166. 166.
    Qian CN, Berghuis B, Tsarfaty G, Bruch M, Kort EJ, Ditlev J, Tsarfaty I, Hudson E, Jackson DG, Petillo D, Chen J, Resau JH, Teh BT (2006) Preparing the “soil”: the primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. Cancer Res 66:10365–10376PubMedGoogle Scholar
  167. 167.
    Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M (2007) VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 109:1010–1017PubMedGoogle Scholar
  168. 168.
    Witte MH, Dellinger MT, McDonald DM, Nathanson SD, Boccardo FM, Campisi CC, Sleeman JP, Gershenwald JE (2011) Lymphangiogenesis and hemangiogenesis: potential targets for therapy. J Surg Oncol 103:489–500PubMedGoogle Scholar
  169. 169.
    Spring H, Schuler T, Arnold B, Hammerling GJ, Ganss R (2005) Chemokines direct endothelial progenitors into tumor neovessels. Proc Natl Acad Sci USA 102:18111–18116PubMedGoogle Scholar
  170. 170.
    Titze J, Machnik A (2010) Sodium sensing in the interstitium and relationship to hypertension. Curr Opin Nephrol Hypertens 19:385–392PubMedGoogle Scholar
  171. 171.
    Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Muller 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 15:545–552PubMedGoogle Scholar
  172. 172.
    Machnik A, Dahlmann A, Kopp C, Goss J, Wagner H, van Rooijen N, Eckardt KU, Muller 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 55:755–761PubMedGoogle Scholar
  173. 173.
    Halin C, Fahrngruber H, Meingassner JG, Bold G, Littlewood-Evans A, Stuetz A, Detmar M (2008) Inhibition of chronic and acute skin inflammation by treatment with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Am J Pathol 173:265–277PubMedGoogle Scholar
  174. 174.
    Schonthaler HB, Huggenberger R, Wculek SK, Detmar M, Wagner EF (2009) Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis. Proc Natl Acad Sci USA 106:21264–21269PubMedGoogle Scholar
  175. 175.
    Huggenberger R, Ullmann S, Proulx ST, Pytowski B, Alitalo K, Detmar M (2010) Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. J Exp Med 207:2255–2269PubMedCentralPubMedGoogle Scholar
  176. 176.
    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 60:2666–2676PubMedCentralPubMedGoogle Scholar
  177. 177.
    Yin N, Zhang N, Xu J, Shi Q, Ding Y, Bromberg JS (2011) Targeting lymphangiogenesis after islet transplantation prolongs islet allograft survival. Transplantation 92:25–30PubMedCentralPubMedGoogle Scholar
  178. 178.
    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 184:535–539PubMedGoogle Scholar
  179. 179.
    Albuquerque RJ, Hayashi T, Cho WG, Kleinman ME, Dridi S, Takeda A, Baffi JZ, Yamada K, Kaneko H, Green MG, Chappell J, Wilting J, Weich HA, Yamagami S, Amano S, Mizuki N, Alexander JS, Peterson ML, Brekken RA, Hirashima M, Capoor S, Usui T, Ambati BK, Ambati J (2009) Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat Med 15:1023–1030PubMedCentralPubMedGoogle Scholar
  180. 180.
    Yan ZX, Jiang ZH, Liu NF (2012) Angiopoietin-2 promotes inflammatory lymphangiogenesis and its effect can be blocked by the specific inhibitor L1-10. Am J Physiol Heart Circ Physiol 302:H215–223PubMedGoogle Scholar
  181. 181.
    Szuba A, Skobe M, Karkkainen MJ, Shin WS, Beynet DP, Rockson NB, Dakhil N, Spilman S, Goris ML, Strauss HW, Quertermous T, Alitalo K, Rockson SG (2002) Therapeutic lymphangiogenesis with human recombinant VEGF-C. FASEB J 16:1985–1987PubMedGoogle Scholar
  182. 182.
    Tammela T, Saaristo A, Holopainen T, Lyytikka J, Kotronen A, Pitkonen M, Abo-Ramadan U, Yla-Herttuala S, Petrova TV, Alitalo K (2007) Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat Med 13:1458–1466PubMedGoogle Scholar
  183. 183.
    Duong T, Koopman P, Francois M (2012) Tumor lymphangiogenesis as a potential therapeutic target. J Oncol 2012:204946PubMedCentralPubMedGoogle Scholar
  184. 184.
    Roberts N, Kloos B, Cassella M, Podgrabinska S, Persaud K, Wu Y, Pytowski B, Skobe M (2006) Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res 66:2650–2657PubMedGoogle Scholar
  185. 185.
    Wong SY, Haack H, Crowley D, Barry M, Bronson RT, Hynes RO (2005) Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Res 65:9789–9798PubMedGoogle Scholar
  186. 186.
    Pytowski B, Goldman J, Persaud K, Wu Y, Witte L, Hicklin DJ, Skobe M, Boardman KC, Swartz MA (2005) Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst 97:14–21PubMedGoogle Scholar
  187. 187.
    Lin J, Lalani AS, Harding TC, Gonzalez M, Wu WW, Luan B, Tu GH, Koprivnikar K, VanRoey MJ, He Y, Alitalo K, Jooss K (2005) Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res 65:6901–6909PubMedGoogle Scholar
  188. 188.
    Caunt M, Mak J, Liang WC, Stawicki S, Pan Q, Tong RK, Kowalski J, Ho C, Reslan HB, Ross J, Berry L, Kasman I, Zlot C, Cheng Z, Le Couter J, Filvaroff EH, Plowman G, Peale F, French D, Carano R, Koch AW, Wu Y, Watts RJ, Tessier-Lavigne M, Bagri A (2008) Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13:331–342PubMedGoogle Scholar
  189. 189.
    Basak A, Khatib AM, Mohottalage D, Basak S, Kolajova M, Bag SS (2009) A novel enediynyl peptide inhibitor of furin that blocks processing of proPDGF-A, B and proVEGF-C. PLoS One 4:e7700PubMedCentralPubMedGoogle Scholar
  190. 190.
    Kirkin V, Mazitschek R, Krishnan J, Steffen A, Waltenberger J, Pepper MS, Giannis A, Sleeman JP (2001) Characterization of indolinones which preferentially inhibit VEGF-C- and VEGF-D-induced activation of VEGFR-3 rather than VEGFR-2. Eur J Biochem 268:5530–5540PubMedGoogle Scholar
  191. 191.
    Kirkin V, Thiele W, Baumann P, Mazitschek R, Rohde K, Fellbrich G, Weich H, Waltenberger J, Giannis A, Sleeman JP (2004) MAZ51, an indolinone that inhibits endothelial cell and tumor cell growth in vitro, suppresses tumor growth in vivo. Int J Cancer 112:986–993PubMedGoogle Scholar
  192. 192.
    Liu H, Yang Y, Xiao J, Lv Y, Liu Y, Yang H, Zhao L (2009) Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via VEGF-C. Anat Rec (Hoboken) 292:1577–1583Google Scholar
  193. 193.
    Rothley M, Schmid A, Thiele W, Schacht V, Plaumann D, Gartner M, Yektaoglu A, Bruyere F, Noel A, Giannis A, Sleeman JP (2009) Hyperforin and aristoforin inhibit lymphatic endothelial cell proliferation in vitro and suppress tumor-induced lymphangiogenesis in vivo. Int J Cancer 125:34–42PubMedGoogle Scholar
  194. 194.
    Garmy-Susini B, Avraamides CJ, Schmid MC, Foubert P, Ellies LG, Barnes L, Feral C, Papayannopoulou T, Lowy A, Blair SL, Cheresh D, Ginsberg M, Varner JA (2010) Integrin alpha4beta1 signaling is required for lymphangiogenesis and tumor metastasis. Cancer Res 70:3042–3051PubMedCentralPubMedGoogle Scholar
  195. 195.
    Thiele W, Sleeman JP (2006) Tumor-induced lymphangiogenesis: a target for cancer therapy? J Biotechnol 124:224–241PubMedGoogle Scholar
  196. 196.
    Schomber T, Zumsteg A, Strittmatter K, Crnic I, Antoniadis H, Littlewood-Evans A, Wood J, Christofori G (2009) Differential effects of the vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 on tumor angiogenesis and tumor lymphangiogenesis. Mol Cancer Ther 8:55–63PubMedGoogle Scholar

Copyright information

© Springer-Verlag Wien 2013

Authors and Affiliations

  1. 1.Department of Internal MedicineWrocław Medical UniversityWrocławPoland
  2. 2.Department of Internal Medicine4th Military Hospital in WrocławWrocławPoland
  3. 3.Wrocław Medical UniversityWrocławPoland

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