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Lymphangiogenesis in development and human disease

Nature volume 438, pages 946–953 (2005)Cite this article

Abstract

The lymphatic vasculature forms a vessel network that drains interstitial fluid from tissues and returns it to the blood. Lymphatic vessels are also an essential part of the body's immune defence. They have an important role in the pathogenesis of several diseases, such as cancer, lymphoedema and various inflammatory conditions. Recent biological and technological developments in lymphatic vascular biology will lead to a better understanding and treatment of these diseases.

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Figure 1: Organization of lymphatic vasculature.
Figure 2: VEGF-C/D-VEGFR-3 pathway in the regulation of the lymphatic vessel growth.
Figure 3: Model for the development of mouse lymphatic vasculature
Figure 4: Role of VEGF-C/D in lymphatic metastasis in cancer.

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References

  1. Hirakawa, S. & Detmar, M. New insights into the biology and pathology of the cutaneous lymphatic system. J. Dermatol. Sci. 35, 1–8 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Oliver, G. Lymphatic vasculature development. Nature Rev. Immunol. 4, 35–45 (2004).

    Article  CAS  Google Scholar 

  3. Tammela, T., Petrova, T. V. & Alitalo, K. Molecular lymphangiogenesis: new players. Trends Cell Biol. 15, 434–441 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Kaipainen, A. et al. Expression of the fms-like tyrosine kinase FLT4 gene becomes restricted to lymphatic endothelium during development. Proc. Natl Acad. Sci. USA 92, 3566–3570 (1995).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  5. Achen, M. G. et al. 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 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  6. Joukov, V. et al. A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J. 15, 290–298 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Jeltsch, M. et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276, 1423–1425 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Mäkinen, T. et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 20, 4762–4773 (2001).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Karkkainen, M. J. et al. A model for gene therapy of human hereditary lymphedema. Proc. Natl Acad. Sci. USA 98, 12677–12682 (2001).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yuan, L. et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 129, 4797–4806 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Joukov, V. et al. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 16, 3898–3911 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cao, Y. et al. Vascular endothelial growth factor C induces angiogenesis in vivo. Proc. Natl Acad. Sci. USA 95, 14389–14392 (1998).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stacker, S. A. et al. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J. Biol. Chem. 274, 32127–32136 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Rissanen, T. T. et al. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ. Res. 92, 1098–1106 (2003).

    Article  CAS  PubMed  Google Scholar 

  15. Nagy, J. A. et al. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J. Exp. Med. 196, 1497–1506 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Karkkainen, M. J. et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nature Immunol. 5, 74–80 (2004).

    Article  CAS  Google Scholar 

  17. Gannon, G. et al. Overexpression of vascular endothelial growth factor-A165 enhances tumor angiogenesis but not metastasis during beta-cell carcinogenesis. Cancer Res. 62, 603–608 (2002).

    CAS  PubMed  Google Scholar 

  18. Oh, S. J. et al. VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev. Biol. 188, 96–109 (1997).

    Article  CAS  PubMed  Google Scholar 

  19. Cursiefen, C. et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J. Clin. Invest. 113, 1040–1050 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Baluk, P. et al. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J. Clin. Invest. 115, 247–257 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Wang, J. F., Zhang, X. F. & Groopman, J. E. Stimulation of beta 1 integrin induces tyrosine phosphorylation of vascular endothelial growth factor receptor-3 and modulates cell migration. J. Biol. Chem. 276, 41950–41957 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Vlahakis, N. E., Young, B. A., Atakilit, A. & Sheppard, D. The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1. J. Biol. Chem. 280, 4544–4552 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Huang, X. Z. et al. Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1. Mol. Cell Biol. 20, 5208–5215 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang, X. et al. KSHV activation of VEGFR-3 alters endothelial function and enhances infection. J. Biol. Chem. 280, 26216–26224 (2005).

    Article  CAS  PubMed  Google Scholar 

  25. Kubo, H. et al. 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, 8868–8873 (2002).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cao, R. et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes tumour metastasis. Cancer Cell 6, 333–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  27. Kajiya, K., Hirakawa, S., Ma, B., Drinnenberg, I. & Detmar, M. Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J. 24, 2885–2895 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sabin, F. R. The lymphatic system in human embryos, with a consideration of the morphology of the system as a whole. Am. J. Anat. 9, 43–91 (1909).

    Article  Google Scholar 

  29. Wigle, J. T. & Oliver, G. Prox1 function is required for the development of the murine lymphatic system. Cell 98, 769–778 (1999).

    Article  CAS  PubMed  Google Scholar 

  30. Wigle, J. T. et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J. 21, 1505–1513 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Hong, Y. K. et al. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev. Dyn. 225, 351–357 (2002).

    Article  CAS  PubMed  Google Scholar 

  32. Petrova, T. V. et al. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J. 21, 4593–4599. (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Harvey, N. L. et al. Lymphatic vascular defects promoted by Prox1 haploinsufficiency cause adult-onset obesity. Nature Genet. 37, 1072–1081 (2005).

    Article  CAS  PubMed  Google Scholar 

  34. Baldwin, M. E. et al. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol. Cell Biol. 25, 2441–2449 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Dumont, D. J. et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282, 946–949 (1998).

    Article  ADS  CAS  PubMed  Google Scholar 

  36. Karkkainen, M. J. et al. Missense mutations interfere with VEGFR-3 signaling in primary lymphoedema. Nature Genet. 25, 153–159 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Jackson, D. G. Biology of the lymphatic marker LYVE-1 and applications in research into lymphatic trafficking and lymphangiogenesis. APMIS 112, 526–538 (2004).

    Article  CAS  PubMed  Google Scholar 

  38. Makinen, T. et al. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev. 19, 397–410 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Jeltsch, M., Tammela, T., Alitalo, K. & Wilting, J. Genesis and pathogenesis of lymphatic vessels. Cell Tissue Res. 314, 69–84 (2003).

    Article  CAS  PubMed  Google Scholar 

  40. Aalami, O. O., Allen, D. B. & Organ, C. H. Jr. Chylous ascites: a collective review. Surgery 128, 761–778 (2000).

    Article  CAS  PubMed  Google Scholar 

  41. Abtahian, F. et al. Regulation of blood and lymphatic vascular separation by signaling proteins SLP-76 and Syk. Science 299, 247–251 (2003).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  42. Saharinen, P. et al. Multiple angiopoietin recombinant proteins activate the Tie1 receptor tyrosine kinase and promote its interaction with Tie2. J. Cell Biol. 169, 239–243 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gale, N. W. et al. Angiopoietin-2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev. Cell 3, 411–423 (2002).

    Article  CAS  PubMed  Google Scholar 

  44. Morisada, T. et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 105, 4649–4656 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Tammela, T. et al. Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood 105, 4642–4648 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Adams, R. H. & Klein, R. Eph receptors and ephrin ligands. essential mediators of vascular development. Trends Cardiovasc. Med. 10, 183–188 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Petrova, T. V. et al. Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nature Med. 10, 974–981 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Dagenais, S. L. et al. Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome. Gene Expr. Patterns 4, 611–619 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Ferrell, R. E. Research perspectives in inherited lymphatic disease. Ann. N Y Acad. Sci. 979, 39–51 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  50. Brice, G. et al. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. J. Med. Genet. 39, 478–483 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schacht, V. et al. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J. 22, 3546–3556 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kriehuber, E. et al. Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J. Exp. Med. 194, 797–808 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Makinen, T. et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 20, 4762–4773. (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Podgrabinska, S. et al. Molecular characterization of lymphatic endothelial cells. Proc. Natl Acad. Sci. USA 99, 16069–16074 (2002).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  55. Hirakawa, S. et al. Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am. J. Pathol. 162, 575–586 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rockson, S. G. Lymphedema. Am. J. Med. 110, 288–295 (2001).

    Article  CAS  PubMed  Google Scholar 

  57. Yla-Herttuala, S. & Alitalo, K. Gene transfer as a tool to induce therapeutic vascular growth. Nature Med. 9, 694–701 (2003).

    Article  PubMed  CAS  Google Scholar 

  58. Saaristo, A. et al. Lymphangiogenic gene therapy with minimal blood vascular side effects. J. Exp. Med. 196, 719–730 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Thurston, G. et al. Angiopoietin-1 protects the adult vasculature against plasma leakage. Nature Med. 6, 460–463 (2000).

    Article  CAS  PubMed  Google Scholar 

  60. Weis, S. & Cheresh, D. A. Pathophysiological consequences of VEGF-induced vascular permeability. Nature 65, 9789–9798 (2005).

    Google Scholar 

  61. Pepper, M. S. Lymphangiogenesis and tumor metastasis: myth or reality? Clin. Cancer Res. 7, 462–468 (2001).

    CAS  PubMed  Google Scholar 

  62. Stacker, S. A., Achen, M. G., Jussila, L., Baldwin, M. E. & Alitalo, K. Lymphangiogenesis and cancer metastasis. Nature Rev. Cancer 2, 573–583 (2002).

    Article  CAS  Google Scholar 

  63. He, Y. et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J. Natl Cancer Inst. 94, 819–825 (2002).

    Article  CAS  PubMed  Google Scholar 

  64. Skobe, M. et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Med. 7, 192–198 (2001).

    Article  CAS  PubMed  Google Scholar 

  65. Mandriota, S. J. et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 20, 672–682 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Stacker, S. A. et al. Vascular endothelial growth factor-D promotes the metastatic spread of cancer via the lymphatics. Nature Med. 7, 186–191 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Karpanen, T. et al. Vacular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res. 61, 1786–1790 (2001).

    CAS  PubMed  Google Scholar 

  68. Valtola, R. et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am. J. Pathol. 154, 1381–1390 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Krishnan, J. et al. Differential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in tumors and its relationship to lymphatic metastasis in immunocompetent rats. Cancer Res. 63, 713–722 (2003).

    CAS  PubMed  Google Scholar 

  70. Dadras, S. S. et al. Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am. J. Pathol. 162, 1951–1960 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  71. Maula, S. M. et al. Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region. Cancer Res. 63, 1920–1926 (2003).

    CAS  PubMed  Google Scholar 

  72. Padera, T. P. et al. Pathology: cancer cells compress intratumour vessels. Nature 427, 695 (2004).

    Article  ADS  CAS  PubMed  Google Scholar 

  73. Wong, S. Y. et al. Tumor-secreted VEGF-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Res. 65, 9789–9798.

  74. Padera, T. P. et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296, 1883–1886 (2002).

    Article  ADS  CAS  PubMed  Google Scholar 

  75. He, Y. et al. 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, 4739–4746 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Laakkonen, P., Porkka, K., Hoffman, J. A. & Ruoslahti, E. A tumor-homing peptide with a targeting specificity related to lymphatic vessels. Nature Med. 8, 751–755 (2002).

    Article  CAS  PubMed  Google Scholar 

  77. Zlotnik, A. Chemokines in neoplastic progression. Semin. Cancer Biol. 14, 181–185 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Hirakawa, S. et al. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J. Exp. Med. 201, 1089–1099 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Pullinger, B. D. & Florey, H. W. Proliferation of lymphatics in inflammation. J. Pathol. Bact. 45, 157–170 (1937).

    Article  Google Scholar 

  80. Ristimaki, A., Narko, K., Enholm, B., Joukov, V. & Alitalo, K. Proinflammatory cytokines regulate expression of the lymphatic endothelial mitogen vascular endothelial growth factor-C. J. Biol. Chem. 273, 8413–8418 (1998).

    Article  CAS  PubMed  Google Scholar 

  81. Saban, M. R. et al. Visualization of lymphatic vessels through NF-kappaB activity. Blood 104, 3228–3230 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Kerjaschki, D. et al. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J. Am. Soc. Nephrol. 15, 603–612 (2004).

    Article  CAS  PubMed  Google Scholar 

  83. Hamrah, P., Chen, L., Zhang, Q. & Dana, M. R. Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. Am. J. Pathol. 163, 57–68 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Chen, L. et al. Vascular endothelial growth factor receptor-3 mediates induction of corneal alloimmunity. Nature Med. 10, 813–815 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Ohl, L. et al. CCR7 governs skin dendritic cell migration under inflammatory and steady-state conditions. Immunity 21, 279–288 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Irjala, H. et al. Mannose receptor is a novel ligand for L-selectin and mediates lymphocyte binding to lymphatic endothelium. J. Exp. Med. 194, 1033–1041 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  88. Nibbs, R. J. et al. The beta-chemokine receptor D6 is expressed by lymphatic endothelium and a subset of vascular tumors. Am. J. Pathol. 158, 867–877 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kriederman, B. M. et al. FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome. Hum. Mol. Genet. 12, 1179–1185 (2003).

    Article  CAS  PubMed  Google Scholar 

  90. Ayadi, A. et al. Net-targeted mutant mice develop a vascular phenotype and up-regulate egr-1. EMBO J. 20, 5139–5152 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Fruman, D. A. et al. Hypoglycaemia, liver necrosis and perinatal death in mice lacking all isoforms of phosphoinositide 3-kinase p85 alpha. Nature Genet. 26, 379–382 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Pennisi, D. et al. Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice. Nature Genet. 24, 434–437 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Gittenberger-De Groot, A. C. et al. Abnormal lymphatic development in trisomy 16 mouse embryos precedes nuchal edema. Dev. Dyn. 230, 378–384 (2004).

    Article  PubMed  Google Scholar 

  94. Dixelius, J. et al. Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. J. Biol. Chem. 278, 40973–40979 (2003).

    Article  CAS  PubMed  Google Scholar 

  95. Salameh, A., Galvagni, F., Bardelli, M., Bussolino, F. & Oliviero, S. Direct recruitment of CRK and GRB2 to VEGFR-3 induce proliferation, migration and survival of endothelial cells through the activation of ERK, AKT and JNK pathways. Blood 15, 3423–3431 (2005).

    Article  CAS  Google Scholar 

  96. Ny, A. et al. A genetic Xenopus laevis tadpole model to study lymphangiogenesis. Nature Med. 11, 998–1004 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Schneider, M., Othman-Hassan, K., Christ, B. & Wilting, J. Lymphangioblasts in the avian wing bud. Dev. Dyn. 216, 311–319 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Rajantie, I. et al. Adult bone marrow-derived cells recruited during angiogenesis comprise precursors for periendothelial vascular mural cells. Blood 104, 2084–2086 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Wang, H. W. et al. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nature Genet. 36, 687–693 (2004).

    Article  CAS  PubMed  Google Scholar 

  100. Hong, Y. K. et al. Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nature Genet. 36, 683–685 (2004).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We extend our gratitude to the many colleagues who have contributed to the field, but whose work could not be cited here owing to space limitations. We thank C. Norrmén for providing confocal image of lymphatic vessels, A. Parsons for assistance in editing, and H. Schmidt for the drawing of figures. The work in the authors' laboratories is supported by the US National Institutes of Health, the European Union, the Finnish Academy, the Sigrid Juselius Foundation and the Finnish Cancer Organizations.

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Authors and Affiliations

  1. Molecular/Cancer Biology Laboratory, Ludwig Institute for Cancer, Research, 00014

    Kari Alitalo & Tuomas Tammela

  2. University of Helsinki, Finland

    Kari Alitalo & Tuomas Tammela

  3. Development and Differentiation Laboratory, Molecular/Cancer Biology Program, Biomedicum Helsinki, Haartman Institute and Helsinki University Central Hospital, 00014

    Tatiana V. Petrova

  4. University of Helsinki, Finland

    Tatiana V. Petrova

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  1. Kari Alitalo
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Correspondence to Kari Alitalo.

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The authors declare competing financial interests: Kari Alitalo is a board member and minority owner of Lymphatix Ltd. (Anti-VEGFR-3 monoclonal antibodies have been licenced to ImClone Systems Inc by the University of Helsinki.)

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Alitalo, K., Tammela, T. & Petrova, T. Lymphangiogenesis in development and human disease. Nature 438, 946–953 (2005). https://doi.org/10.1038/nature04480

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