Skip to main content
SpringerLink
Log in

Landmarks and Advances in Translational Lymphology

  • Chapter
Cancer Metastasis And The Lymphovascular System: Basis For Rational Therapy

Part of the book series: Cancer Treatment and Research ((CTAR,volume 135))

  • 1001 Accesses

The lymph vascular system parallels the blood vasculature and as one of its key functions, returns liquid and solute to the bloodstream, including macromolecules that have escaped from blood capillaries and entered the interstitium. In conjunction with interspersed lymph nodes and lymphoid organs, the lymphatic vasculature also acts as a conduit for trafficking immune cell populations. Lymphatics are involved in diverse developmental, growth, repair, and pathologic processes similar to but distinct from those affecting the blood vasculature. Interference with the blood–lymph circulatory loop produces edema, scarring, nutritional, and immunodysregulatory disorders as well as disturbances in lymph(hem)angiogenesis (lymphedema–angiodysplasia syndromes). The lymphatic system – encompassing lymphatics, lymph, lymph nodes, and lymphocytes – is also the stage on which key events in tumor biology and cancer progression are played out, and historically, also has formed the basis for evaluation, prognostication, and both operative and nonoperative treatment of most cancers. Interpreted in the light of landmark discoveries about the structure and function of the lymphatic system during the last century, recent advances in molecular lymphology combined with fresh insights and refined tools in clinical lymphology, including noninvasive lymphatic imaging, are fueling translation to the clinical arena, i.e., translational lymphology.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  1. Achen MG, McColl BK, Stacker SA (2005) Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 7: 121–127.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Aselli G (1627) De Lactibus sive Lacteis Venis, Quarto Vasorum Mesarai corum Genere novo invento. J.B. Biddellium, Mediolani, Milano.

    Google Scholar 

  4. Azzali G (2003) Transendothelial transport and migration in vessels of the apparatus lymphaticus periphericus absorbens (ALPA). Int Rev of Cytology 230: 41–87.

    Article  CAS  Google Scholar 

  5. Banerji S, Ni J, Wang S-X, 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 Biology 144: 789–801.

    Article  CAS  Google Scholar 

  6. Bowman C, Witte MH, Witte CL, Way D, Nagle R, Copeland J, Daschbach C (1984) Cystic hygroma reconsidered: hamartoma or neoplasm? Primary culture of an endothelial cell line from a massive cervicomediastinal cystic hygroma with bony lymphangiomatosis. Lymphology 17: 15–22.

    PubMed  CAS  Google Scholar 

  7. Breiteneder-Geleff, S, Soleiman A, Kowalski H, Horvat R, Amann G, Kreihuber 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 Path 154: 385–394.

    PubMed  CAS  Google Scholar 

  8. Casley-Smith JR, Florey HL (1961) The structure of normal small lymphatics. Quart J Exp Physiol 46: 101–106.

    PubMed  CAS  Google Scholar 

  9. Clark ER, Clark EL (1932) Observations on the new growth of lymphatic vessels as seen in transparent chambers introduced into the rabbit’s ear. Am J Anat 51: 49–87.

    Article  Google Scholar 

  10. Drinker CK, Yoffey JM (1941) Lymph flow and lymph pressure. In: Lymphatics, lymph and lymphoid Tissue. Harvard University Press, Cambridge, pp. 112–145.

    Google Scholar 

  11. Dumont AE, Witte MH (1969) Clinical usefulness of thoracic duct cannulation. In: Stollerman GH (ed), Advances in internal medicine, vol. XV, Year Book Medical Publ., Inc., pp. 51–72.

    Google Scholar 

  12. Evans AL, Brice G, Sotirova V, Mortimer P, Beninson J, Burnand K, Rosbotham J, Child A, Sarfarazi M (1999) Mapping of primary congenital lymphedema to the 5q35.3 region. Am J Hum Genet 64: 547–555.

    Article  PubMed  CAS  Google Scholar 

  13. Fang JM, 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: 1382–1388.

    Article  PubMed  CAS  Google Scholar 

  14. Ferrell RE, Levinson KL, Esman JH, Kimak MA, Lawrence EC, Barmada MM, Finegold DN (1998) Hereditary lymphedema: evidence for linkage and genetic heterogeneity. Hum Mol Genet 7: 2073–2078.

    Article  PubMed  CAS  Google Scholar 

  15. Florey H (1927) Observations on the contractility of lacteals. Part II. J Physiol 63: 1–18.

    PubMed  CAS  Google Scholar 

  16. Földi M, Földi E, (eds) (2006) Földi’s textbook of lymphology. Urban & Fischer Verlag, München, Germany, 2nd ed, pp. 735.

    Google Scholar 

  17. Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, 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. Developmental Cell 3: 411–423.

    Article  PubMed  CAS  Google Scholar 

  18. Galland F, Karamysheva A, Mattei MG, Rosnet O, Marchetto S, Birnbaum D (1992) Chromosomal localization of FLT4, a novel receptor-type tyrosine kinase gene. Genomics 13: 475–478.

    Article  PubMed  CAS  Google Scholar 

  19. Gnepp DR, Chandler W (1985) Tissue culture of human and canine thoracic duct endothelium. In Vitro 21: 200–206.

    CAS  Google Scholar 

  20. Hall JG, Morris B, Woolley G (1965) Intrinsic rhythmic propulsion of lymph in the unanaesthetised sheep. J Physiol (Lond) 180: 336–349.

    CAS  Google Scholar 

  21. Harvey W (1628) Exertatio anatomico de motu cordis et sanguinis in animalibus. Frankfurt, Guilielmi Fitzeri.

    Google Scholar 

  22. Hong YK, Shin JW, Detmar M (2004) Development of the lymphatic vascular system: a mystery unravels. Dev Dyn 231: 462–473.

    Article  PubMed  CAS  Google Scholar 

  23. Iida K, Koseki H, Kakinuma H, Kato N, Mizutani-Koseki Y, Ohuchi H, Yoshioka H, Noji S, Kawamura K, Kataoka Y, Ueno F, Taniguchi M, Yoshida N, Sugiyama T, Miura N (1997) Essential roles of the winged helix transcription factor MFH-1 in aortic arch patterning and skeletogenesis. Development 124: 4627–4638.

    PubMed  CAS  Google Scholar 

  24. Irrthum A, Devriend K, Chitayat D, Matthijs G, Glade C, Steijlen PM, Fryns J-P, Van Steensel AM, Vikkula M (2003) Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasis. Am J Hum Genet 72: 1470–1478.

    Article  PubMed  CAS  Google Scholar 

  25. Johnston MG, Walker MA (1984) Lymphatic endothelial and smooth-muscle cells in tissue culture. In Vitro 20: 566–572.

    Article  PubMed  CAS  Google Scholar 

  26. Joukov V, Pajusola K, Kaipainen A, Chilov D, Lahtinen I, Kukk E, Saksela O, Kalkkinen N, Alitalo K (1996) A novel vascular endothelial growth factor, VEGF-C, is a ligand for the Flt-4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO 15: 290–298.

    CAS  Google Scholar 

  27. Kampmeier OF (ed) (1969) Evolution and comparative morphology of the lymphatic system. Charles C. Thomas, Springfield, Illinois, 620 p.

    Google Scholar 

  28. Karkkainen MJ, Ferrell RE, Lawrence EC, Kimak MA, Levinson KL, McTigue MA, Alitalo K, Finegold DN (2000) Missense mutations interfere with vascular endothelial growth factor receptor-3 signaling in primary lymphedema. Nature Genet 25: 153–159.

    Article  PubMed  CAS  Google Scholar 

  29. Kinmonth JB (ed) (1972) The lymphatics: diseases, lymphography and surgery. Edward Arnold, London, 420 p.

    Google Scholar 

  30. Kriederman BM, Myloyde TL, Witte MH, Dagenais SL, Witte CL, Rennels M, Bernas MJ, Lynch MT, Erickson RP, Caulder MS, Miura N, Jackson D, Brooks BP, Glover TW (2003) Foxc2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome. Hum Molec Genet 12: 1179–1185.

    Article  PubMed  CAS  Google Scholar 

  31. Leak LV, Burke JF (1966) Fine structure of the lymphatic capillary and the adjoining connective tissue area. Am J Anat 118: 785–809.

    Article  PubMed  CAS  Google Scholar 

  32. Leak LV, Jones M (1994) Lymphangiogenesis in vitro: formation of lymphatic capillary-like channels from confluent monolayers of lymphatic endothelial cells. In Vitro Cell Dev Biol 30A: 512–518.

    Article  CAS  Google Scholar 

  33. Lymphology 1–40, 1967–2007.

    Google Scholar 

  34. Mansel RE, Khonji NI, Clarke D (2000) History, present status and future of sentinel node biopsy in breast cancer. Acta Oncologica 39: 265–268.

    Article  PubMed  CAS  Google Scholar 

  35. Mawhinney HJ, Roddie IC (1973) Spontaneous activity in isolated bovine mesenteric lymphatics. J Physiol 229: 339–348.

    PubMed  CAS  Google Scholar 

  36. Mayerson HS, Wolfram CG, Shirley HH, Wasserman K (1960) Regional differences in capillary permeability. Am J Physiol 198: 155–160.

    Google Scholar 

  37. McHale NG, Thornbury KD (1986) A method for studying lymphatic pumping activity in conscious and anaesthetised sheep. J Physiol 378: 109–118.

    PubMed  CAS  Google Scholar 

  38. McMaster PD (1937) The lymphatics and lymph flow in the edematous skin of human beings with cardiac and renal disease. J Exp Med 65: 373–397.

    Article  Google Scholar 

  39. Morton DL, Wien DR, Wong JH, Economou JS, Cagle LA, Storm FK, Foshag LJ, Cochran AJ (1992) Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surgery 127: 392–399.

    CAS  Google Scholar 

  40. Noon A, Hunter RJ, Witte MH, Kriederman B, Bernas M, Rennels M, Percy D, Enerback S, Erickson RP (2006) Comparative lymphatic ocular and metabolic phenotypes of Foxc2 haploinsufficient and aP2-FOXC2 transgenic mice. Lymphology 39: 84–94.

    PubMed  CAS  Google Scholar 

  41. Northup KA, Witte MH, Witte CL (2003) Syndromic classification of hereditary lymphedema. Lymphology 36: 162–189.

    PubMed  CAS  Google Scholar 

  42. Oliver G (2004) Lymphatic vascular development. Nat Rev Immunol 4: 35–45.

    Article  PubMed  CAS  Google Scholar 

  43. Olszewski WL (1991) Lymph pressure and flow in limbs. In: Lymph stasis: pathophysiology, diagnosis and treatment. Boca Raton, FL, CRC Press, pp. 109–156.

    Google Scholar 

  44. Petrova TV, Karpanen T, Norrmén C, Mellor R, Tamakoshi T, Finegold D, Ferrell R, Kerjaschki D, Mortimer P, Ylä-Herttuala S, Miura N, Alitalo K (2004) Defective valves and abnormal mural cell recruitment underlie lymphatic vascular failure in lymphedema distichiasis. Nature Med 10: 974–981.

    Article  PubMed  CAS  Google Scholar 

  45. Pippard C, Roddie IC (1987) Comparison of fluid transport systems in lymphatics and veins. Lymphology 20: 224–229.

    PubMed  CAS  Google Scholar 

  46. Progress in Lymphology I-XX (1967–2007) Proceedings of the International Congresses of Lymphology.

    Google Scholar 

  47. Pullinger DB, Florey HW (1937) Proliferation of lymphatics in inflammation. J Path Bacter 45: 157–170.

    Article  Google Scholar 

  48. Rusznyák I, Földi M, Szabo G (1960) Lymphatics and lymph circulation. Pergamon Press, New York:Oxford, 853 p.

    Google Scholar 

  49. Sabin FR (1902) On the origin and development of the lymphatic system from the veins and the development of the lymph hearts and the thoracic duct in the pig. Am J Anat 1: 367–389.

    Article  Google Scholar 

  50. Sage HH, Kizilay D, Miyazaki M, Shapiro G, Sinha B (1960) Lymph node scintigrams. Am J Roentgenol Radium Ther Nucl Med: 84: 606–672.

    Google Scholar 

  51. Starling EH (1896) Physiologic factors involved in the causation of dropsy. Lancet 1: 1267–1270.

    Google Scholar 

  52. Starling EH (1909) The fluids of the body. The Herter Lectures. Chicago, WT Keener, p 81.

    Google Scholar 

  53. Tilney ML, Murray JE (1968): Chronic thoracic duct fistula: operative technic and physiologic effects in man. Ann Surg 167:1–8.

    Article  PubMed  CAS  Google Scholar 

  54. Triola VA (1965) Nineteenth century foundations of cancer research. Advances in tumor pathology, nomenclature, and theories of oncogenesis. Cancer Res 25: 75–106.

    Google Scholar 

  55. Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98: 769–778.

    Article  PubMed  CAS  Google Scholar 

  56. Witte CL, Witte MH (1985) Lymphatics in pathophysiology of edema. In: Johnston MG (ed) Experimental biology of the lymph circulation. New York, pp. 165–188.

    Google Scholar 

  57. Witte CL, Witte MH (2005) Lymph circulatory dynamics, lymphangiogenesis, and pathophysiology of the lymphvascular system. In: Rutherford RB (ed) Vascular surgery. 6th ed, W.B. Saunders Company, Philadelphia, Pennsylvania, Chapter 166, pp. 2379–2396.

    Google Scholar 

  58. Witte CL, Myers J, Witte MH, Katz M (1983) Transcapillary water and protein flux in the canine intestine with chronic extrahepatic portal hypertension. Circulation Res 53: 622–629.

    PubMed  CAS  Google Scholar 

  59. Witte CL, Witte MH, Dumont AE (1980) Lymph imbalance in the genesis and perpetuation of the ascites syndrome in hepatic cirrhosis. Gastroenterology 78: 1059–1068.

    PubMed  CAS  Google Scholar 

  60. Witte CL, Witte MH, Unger EC, Williams WH, Bernas MJ, McNeill GC, Stazzone A (2000) Advances in imaging of lymph flow disorders. RadioGraphics 20:1697–1719.

    PubMed  CAS  Google Scholar 

  61. Witte MH (2007) Translational lymphology and the Földiklinik. Eur J Lymphology (in press).

    Google Scholar 

  62. Witte MH, Witte CL (1999) What we don’t know about cancer. Epilogue. In: Otter W, Root-Bernstein R, Koten J-W (eds) What is cancer? Theories on carcinogenesis. Anticancer Research 19: 4919–4934.

    Google Scholar 

  63. Witte MH, Witte CL (1986) Lymphangiogenesis and lymphologic syndromes. Lymphology 19:21–28.

    PubMed  CAS  Google Scholar 

  64. Witte MH, Bernas M, Martin C, Witte CL (2001) Lymphangiogenesis and lymphangiodysplasias: from molecular to clinical lymphology. In: Wilting J (guest ed) The biology of lymphangiogenesis. Microscopy Research and Techniques 55: 122–145.

    Google Scholar 

  65. Witte MH, Dellinger M, Northup K, Bernas M, Witte CL (2006a) Molecular lymphology and genetics of lymphedema-angiodysplasia syndromes. In: Földi M, Földi E (eds) Földi’s textbook of lymphology, 2th ed, Chapter 16. Urban & Fischer Verlag, München, Germany, pp. 498–523.

    Google Scholar 

  66. Witte MH, Dumont AE, Clauss RH, Rader B, Levine N, Breed ES (1969a) Lymph circulation in congestive heart failure: effect of external thoracic duct drainage. Circulation 39: 723–733.

    PubMed  CAS  Google Scholar 

  67. Witte MH, Dumont AE, Cole WR, Witte CL, Kintner K (1969b) Lymph circulation in hepatic cirrhosis: effect of portacaval shunt. Ann Intern Med 70: 303–310.

    PubMed  CAS  Google Scholar 

  68. Witte MH, Erickson R, Bernas M, Andrade M, Reiser F, Conlon W, Hoyme HE, Witte CL (1998) Phenotypic and genotypic heterogeneity in familial Milroy lymphedema. Lymphology 31: 145–155.

    PubMed  CAS  Google Scholar 

  69. Witte MH, Jones K, Wilting J, Dictor M, Selg M, McHale N, Gershenwald JE, Jackson DG (2006b) Structure function relationships in the lymphatic system and implications for cancer biology. Cancer Metastasis Rev 25: 159–184.

    Article  PubMed  Google Scholar 

  70. Witte MH, Way DL, Witte CL, Bernas M (1997) Lymphangiogenesis: mechanisms, significance and clinical implications. In: Goldberg ID, Rosen EM (eds) Regulation of angiogenesis, Birkhäuser Verlag Basel/Switzerland, pp. 65–112.

    Google Scholar 

  71. Witte MH, Witte CL, Way DL (1990) Medical ignorance, AIDS-Kaposi sarcoma complex, and the lymphatic system. Western J Med 153: 17–23.

    Google Scholar 

  72. Yoffey JM, Courtice, FC (eds) (1970) Lymphatics, lymph and the lymphomyeloid complex. Academic Press, London, 942 p.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgery, University of Arizona College of Medicine, Tucson, Arizona, USA

    Marlys H. Witte MD, Michael Bernas MS & Charles L. Witte MD

  2. Department of Medicine (Oncology), University of Utah, Salt Lake, Utah, USA

    Kimberly Jones MD

Authors
  1. Marlys H. Witte MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kimberly Jones MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael Bernas MS
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Charles L. Witte MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. University of California San Francisco and UCSF Comprehensive Cancer Center at Mount Zion, 1600 Divisadero Street, 94143, San Francisco, CA, USA

    Stanley P. L. Leong MD, FACS

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Witte, M.H., Jones, K., Bernas, M., Witte, C.L. (2007). Landmarks and Advances in Translational Lymphology. In: Leong, S.P.L. (eds) Cancer Metastasis And The Lymphovascular System: Basis For Rational Therapy. Cancer Treatment and Research, vol 135. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-69219-7_1

Download citation

  • DOI: https://doi.org/10.1007/978-0-387-69219-7_1

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-0-387-69218-0

  • Online ISBN: 978-0-387-69219-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation