Embryonic Development of the Lymphovascular System and Tumor Lymphangiogenesis

  • Jörg Wilting
  • Maria Papoutsi
  • Kerstin Buttler
  • Jürgen Becker
Part of the Cancer Treatment and Research book series (CTAR, volume 135)

The embryonic development of the lymphatic vascular system starts considerably later than the blood vascular system. In chick embryos, the first blood vessels can be seen after 1 day of incubation, whereas morphological evidence for lymphatic endothelial cells (LECs) is present around day 5.However, with specific marker molecules, such as the transcription factor Prox1, LEC precursors can be identified in day-3.5 embryos. In the mouse, blood vessel development starts at embryonic day (ED) 7.5, whereas the anlagen of lymph vessels can be seen in the jugular region at ED 10. In human embryos there is a period of 3–4 weeks between the appearance of the first blood vascular endothelial cells (BECs) and LECs.


Lymphatic Endothelial Cell Lymphatic Vessel Density Cardinal Vein A375 Melanoma Cell Human A375 Melanoma Cell 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG (1999) LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 144: 789–801.PubMedCrossRefGoogle Scholar
  2. 2.
    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: 630–641.PubMedGoogle Scholar
  3. 3.
    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: 1554–1562.PubMedCrossRefGoogle Scholar
  4. 4.
    Cann SA, van Netten JP, Ashby TL, Ashwood-Smith MJ, van der Westhuizen NG (1995) Role of lymphangiogenesis in neovascularization. Lancet 346: 903.PubMedCrossRefGoogle Scholar
  5. 5.
    Clark ER, Clark EL (1920) On the origin and early development of the lymphatic system of the chick. Contr Embryol 9: 447–482.Google Scholar
  6. 6.
    Dumont DJ, Fong G, Puri PC, Gradwohl G, Alitalo K, Breitman ML (1995) Vascularisation of the mouse embryo: A study of flk-1, tek, tie and vascular endothelial growth factor expression during development. Dev Dyn 203: 80–92.PubMedGoogle Scholar
  7. 7.
    Folkman J (1974) Tumor angiogenesis factors. Cancer Res 34: 2109–2113.PubMedGoogle Scholar
  8. 8.
    Folkman J (1996) Angiogenesis and tumor growth. New England J Med 334: 921.Google Scholar
  9. 9.
    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: 351–357.PubMedCrossRefGoogle Scholar
  10. 10.
    Huntington GS, McClure CFW (1908) The anatomy and development of the jugular lymph sacs in the domestic cat (Felis domestica). Anat Rec 2: 1–18.CrossRefGoogle Scholar
  11. 11.
    Jan YN, Jan LY (1998) Asymmetric cell division. Nature 392: 775–778.PubMedCrossRefGoogle Scholar
  12. 12.
    Kaiserling E (2003) Metastasis of malignant tumors. In: Földi M, Földi E, Kubik S (eds) Textbook of lymphology. Urban and Fischer, München, Jena, Germany, pp. 455–465.Google Scholar
  13. 13.
    Kampmeier OF (1912) The value of the injection method in the study of the lymphatic development. Anat Rec 6: 223–233.CrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    Lauria R, Perrone F, Carlomagno C, De Laurentiis M, Pettinato G, Panico L, Petrelle G, Bianco R, De Placido S (1995) The prognostic value of lymphatic and blood vessel invasion in operable breast cancer. Cancer 15: 1772–1778.CrossRefGoogle Scholar
  16. 16.
    Lee AKC, DeLellis RA, Silverman ML, Heatley GJ, Wolfe HJ (1990) Prognostic significance of peritumoral lymphatic and blood vessel invasion in node-negative carcinoma of the breast. J Clin Oncol 8: 1457–1465.PubMedGoogle Scholar
  17. 17.
    Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK (2000) Absence of Functional Lymphatics within a Murine Sarcoma: A Molecular and Functional Evaluation. Cancer Res 60: 4324–4327.PubMedGoogle Scholar
  18. 18.
    Macchiarini P, Dulmet E, De Montpreville V (1995) Prognostic significance of peri-tumoural blood and lymphatic vessel invasion by tumour cells in T4 non-small cell lung cancer following induction therapy. Surg Oncol 4: 91–99.PubMedCrossRefGoogle Scholar
  19. 19.
    Maehara Y, Oshiro T, Baba H, Ohno S, Kohnoe S, Sugimachi K (1995) Lymphatic invasion and potential for tumor growth and metastasis in patients with gastric cancer. Surgery 117: 380–385.PubMedCrossRefGoogle Scholar
  20. 20.
    Ny A, Koch M, Schneider M, Neven E, Tong RT, Maity S, Fischer C, Plaisance S, Lambrechts D, Heligon C, Terclavers S, Ciesiolka M, Kalin R, Man WY, Senn I, Wyns S, Lupu F, Brandli A, Vleminckx K, Collen D, Dewerchin M, Conway EM, Moons L, Jain RK, Carmeliet, P (2005) A genetic Xenopus laevis tadpole model to study lymphangiogenesis. Nat Med 11: 998–1004.PubMedGoogle Scholar
  21. 21.
    Oh S-J, Jeltsch MM, Birkenhäger R, McCarthy JEG, Weich HA, Christ B, Alitalo K, Wilting J (1997) VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 188: 96–109.PubMedCrossRefGoogle Scholar
  22. 22.
    Oliver G, Harvey N (2002) A stepwise model of the development of lymphatic vasculature. Ann N Y Acad Sci 979: 159–165.PubMedCrossRefGoogle Scholar
  23. 23.
    Oliver G, Sosa-Pineda B, Geisendorf S, Spana EP, Doe CQ, Gruss P (1993) Prox 1, a prospero-related homeobox gene expressed during mouse development. Mech Dev 44: 3–16.PubMedCrossRefGoogle Scholar
  24. 24.
    Papoutsi M, Siemeister G, Weindel K, Tomarev S, Kurz H, Schächtele C, Martiny-Baron G, Christ B, Marmé D, Wilting J (2000) Active interaction of human A375 melanoma cells with the lymphatics in vivo. Histochem Cell Biol 114: 373–385.PubMedGoogle Scholar
  25. 25.
    Papoutsi M, Tomarev SI, Eichmann A, Pröls F, Christ B, Wilting J (2001) Endogenous origin of the lymphatics in the avian chorioallantoic membrane. Dev Dyn 222: 238–251.PubMedCrossRefGoogle Scholar
  26. 26.
    Pardanaud L, Altmann C, Kitos P, Dieterlen-Liévre F, Buck CA (1987) Vasculogenesis in the early quail blastodisc as studied with a monoclonal antibody recognizing endothelial cells. Development 100: 339–349.PubMedGoogle Scholar
  27. 27.
    Pepper MS, Tille JC, Nisato R, Skobe M (2003) Lymphangiogenesis and tumor metastasis. Cell Tissue Res 314: 167–177.PubMedCrossRefGoogle Scholar
  28. 28.
    Petrova TV, Makinen T, Makela TP, Saarela J, Virtanen I, Ferrell RE, Finegold DN, Kerjaschki D, Yla-Herttuala S, Alitalo K (2002) Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 21: 4593–4599.PubMedCrossRefGoogle Scholar
  29. 29.
    Sabin FR (1902) On the origin of the lymphatic system from the veins and the development of the lymph hearts and thoracic duct in the pig. Amer J Anat 1: 367–389.CrossRefGoogle Scholar
  30. 30.
    Sabin FR (1909) The lymphatic system in human embryos, with a consideration of the morphology of the system as a whole. Am J Anat 9: 43–91.CrossRefGoogle Scholar
  31. 31.
    Schneider M, Othman-Hassan K, Christ B, Wilting J (1999) Lymphangioblast in the developing avian wing bud. Dev Dyn 216: 311–319.PubMedCrossRefGoogle Scholar
  32. 32.
    Tanigawa N, Kanazawa T, Satomura K, Hikasa Y, Hashida M, Muranishi S, Sezaki H (1981) Experimental study on lymphatic vascular changes in the development of cancer. Lymphology 4: 149–154.Google Scholar
  33. 33.
    Weidner N (1995) Intratumoral microvessel density as a prognostic factor in cancer. Am J Pathol 147: 9–19.PubMedGoogle Scholar
  34. 34.
    Wigle JT, Oliver, G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98: 769–778.PubMedCrossRefGoogle Scholar
  35. 35.
    Wigle JT, Harvey N, Detmar M, Lagutina I, Grosveld G, Gunn MD, Jackson DG, Oliver G (2002) An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. Embo J 21: 1505–1513.PubMedCrossRefGoogle Scholar
  36. 36.
    Wilting J, Becker J (2006) Two endothelial cell lines derived from the somite. Anat Embryol 211 Suppl 7: 57–63.PubMedGoogle Scholar
  37. 37.
    Wilting J, Birkenhäger R, Eichmann A, Kurz H, Martiny-Baron G, Marmé D, McCarthy JE, Christ B, Weich HA (1996) VEGF121 induces proliferation of vascular endothelial cells and expression of flk-1 without affecting lymphatic vessels of the chorioallantoic membrane. Dev Biol 176: 76–85.PubMedCrossRefGoogle Scholar
  38. 38.
    Wilting J, Papoutsi M, Othman-Hassan K, Rodriguez-Niedenführ M, Pröls F, Tomarev SI, Eichmann A (2001) Development of the avian lymphatic system. Microsc Res Tech 55: 81–91.PubMedCrossRefGoogle Scholar
  39. 39.
    Wilting J, Hawighorst T, Hecht M, Christ B, Papoutsi M (2005) Development of lymphatic vessels: Tumour lymphangiogenesis and lymphatic invasion. Curr Med Chem 12: 3043–3053.PubMedCrossRefGoogle Scholar
  40. 40.
    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: 165–173.PubMedCrossRefGoogle Scholar
  41. 41.
    Yaniv K, Isogai S, Castranova D, Dye L, Hitomi J, Weinstein BM (2006) Live imaging of lymphatic development in the zebrafish. Nat Med 12: 711–716.PubMedCrossRefGoogle Scholar
  42. 42.
    Zeidman I, Copeland B, Waren S (1955) Experimental studies on the spread of cancer in the lymphatic system. II. Absence of the lymphatic supply in carcinoma. Cancer 8: 123–127.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Jörg Wilting
    • 1
  • Maria Papoutsi
    • 1
  • Kerstin Buttler
    • 1
  • Jürgen Becker
    • 1
  1. 1.Children's Hospital, Pediatrics IUniversity of GoettingenGermany

Personalised recommendations