European Archives of Oto-Rhino-Laryngology

, Volume 269, Issue 3, pp 731–737 | Cite as

Molecular pathways of lymphangiogenesis and lymph node metastasis in head and neck cancer

  • A. D. Karatzanis
  • E. Koudounarakis
  • I. Papadakis
  • G. Velegrakis
Review Article

Abstract

Metastasis to regional lymph nodes constitutes the main route toward progression and dissemination of head and neck carcinoma; at the same time it is the most significant adverse prognostic indicator for this disease. In recent years, significant focus has been given on the molecular mechanisms behind lymph node metastasis of head and neck cancer. The aim of this study is to assess the role of growth factor expression and function in association with lymph node metastasis and overall prognosis of head and neck cancer. Current literature, searching for experimental data regarding the molecular pathways of lymph node dissemination of head and neck cancer, is reviewed giving special emphasis on the expression and prognostic significance of specific growth factors. Members of the vascular endothelial growth factor (VEGF), mostly VEGF-C and VEGF-D, with their action through the receptors VEGFR-3 and VEGFR-2, constitute the most extensively studied growth factors associated with lymphangiogenesis so far. High expression of these as well as other molecules, including angiopoietins, insulin-like growth factor, and fibroblast growth factor, has been associated with lymph node metastasis and poor prognosis in head and neck squamous cell carcinoma. Numerous growth factors seem to play an important role regarding the lymph node metastatic potential of head and neck cancer. Further research is necessary in order to further clarify the molecular pathways and introduce novel therapeutic options.

Keywords

Head and neck cancer Squamous cell carcinoma Growth factors Lymphangiogenesis VEGF Metastasis Lymph nodes Angiopoietins 

References

  1. 1.
    Karatzanis AD, Waldfahrer F, Psychogios G, Hornung J, Zenk J, Velegrakis GA, Iro H (2010) Effect of repeated laser microsurgical operations on laryngeal cancer prognosis. Head Neck 32(7):921–928PubMedGoogle Scholar
  2. 2.
    Karatzanis AD, Waldfahrer F, Psychogios G, Hornung J, Zenk J, Velegrakis GA, Iro H (2010) Resection margins and other prognostic factors regarding surgically treated glottic carcinomas. J Surg Oncol 101(2):131–136PubMedGoogle Scholar
  3. 3.
    Takes RP (2010) Staging of the neck in patients with head and neck squamous cell cancer: imaging techniques and biomarkers. Oral Oncol 40(7):656–667CrossRefGoogle Scholar
  4. 4.
    Wissmann C, Detmar M (2006) Pathways targeting tumor lymphangiogenesis. Clin Cancer Res 12(23):6865–6868PubMedCrossRefGoogle Scholar
  5. 5.
    Zhang Z, Helman JI, Li LJ (2010) Lymphangiogenesis, lymphatic endothelial cells and lymphatic metastasis in head and neck cancer—a review of mechanisms. Int J Oral Sci 2(1):5–14PubMedCrossRefGoogle Scholar
  6. 6.
    Franchi A, Gallo O, Massi D, Baroni G, Santucci M (2004) Tumor lymphangiogenesis in head and neck squamous cell carcinoma: a morphometric study with clinical correlations. Cancer 101(5):973–978PubMedCrossRefGoogle Scholar
  7. 7.
    Leak LV, Burke JF (1966) Fine structure of the lymphatic capillary and the adjoining connective tissue area. Am J Anat 118(3):785–809PubMedCrossRefGoogle Scholar
  8. 8.
    Kato S, Shimoda H, Ji RC, Miura M (2006) Lymphangiogenesis and expression of specific molecules as lymphatic endothelial cell markers. Anat Sci Int 81(2):71–83PubMedCrossRefGoogle Scholar
  9. 9.
    Adams RH, Alitalo K (2007) Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol 8(6):464–478PubMedCrossRefGoogle Scholar
  10. 10.
    Pan WR, le Roux CM, Levy SM, Briggs CA (2010) The morphology of the human lymphatic vessels in the head and neck. Clin Anat 23(6):654–661PubMedCrossRefGoogle Scholar
  11. 11.
    Witte MH, Bernas MJ, Martin CP, Witte CL (2001) Lymphangiogenesis and lymphangiodysplasia: from molecular to clinical lymphology. Microsc Res Tech 55(2):122–145PubMedCrossRefGoogle Scholar
  12. 12.
    Alitalo K, Carmeliet P (2002) Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell 1(3):219–227PubMedCrossRefGoogle Scholar
  13. 13.
    Swartz MA, Skobe M (2001) Lymphatic function, lymphangiogenesis and cancer metastasis. Microsc Res Tech 55(2):92–99PubMedCrossRefGoogle Scholar
  14. 14.
    Garcia-Carracedo D, Rodrigo JP, Astudillo A, Nieto CS, Gonzalez MV (2010) Prognostic significance of lymphangiogenesis in pharyngolaryngeal carcinoma patients. BMC Cancer 10:416. doi:10.1186/1471-2407-10-416 PubMedCrossRefGoogle Scholar
  15. 15.
    Jackson DG (2004) Biology of the lymphatic marker LYVE-1 and applications in research into lymphatic trafficking and lymphangiogenesis. APMIS 112(7–8):526–538PubMedCrossRefGoogle Scholar
  16. 16.
    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(7):1505–1513PubMedCrossRefGoogle Scholar
  17. 17.
    Fiedler U, Christian S, Koidl S, Kerjaschki D, Emmett MS, Bates DO, Christofori G, Augustin HG (2006) The sialomucin CD34 is a marker of lymphatic endothelial cells in human tumors. Am J Pathol 168(3):1045–1053PubMedCrossRefGoogle Scholar
  18. 18.
    Lee SK, Cho EY, Kim WW, Kim SH, Hur SM, Kim S, Choe JH, Kim JH, Kim JS, Lee JE, Nam SJ, Yang JH (2010) The prediction of lymph node metastasis in ductal carcinoma in situ with microinvasion by assessing lymphangiogenesis. J Surg Oncol 102(3):225–229PubMedCrossRefGoogle Scholar
  19. 19.
    Coşkun U, Akyürek N, Dursun A, Yamaç D (2010) Peritumoral lymphatic microvessel density associated with tumor progression and poor prognosis in gastric carcinoma. J Surg Res 164(1):110–115PubMedCrossRefGoogle Scholar
  20. 20.
    Audet N, Beasley NJ, MacMillan C, Jackson DG, Gullane PJ, Kamel-Reid S (2005) Lymphatic vessel density, nodal metastases and prognosis in patients with head and neck cancer. Arch Otolaryngol Head Neck Surg 131(12):1065–1070PubMedCrossRefGoogle Scholar
  21. 21.
    Miyahara M, Tanuma J, Sugihara K, Semba I (2007) Tumor lymphangiogenesis correlates with lymph node metastasis and clinicopathologic parameters in oral squamous cell carcinoma. Cancer 110(6):1287–1294PubMedCrossRefGoogle Scholar
  22. 22.
    Beasley NJ, Prevo R, Banerji S, Leek RD, Moore J, van Trappen P, Cox G, Harris AL, Jackson DG (2002) Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res 62(5):1315–1320PubMedGoogle Scholar
  23. 23.
    Maula SM, Luukkaa M, Grénman R, Jackson D, Jalkanen S, Ristamäki R (2003) Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region. Cancer Res 63(8):1920–1926PubMedGoogle Scholar
  24. 24.
    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(21):9789–9798PubMedCrossRefGoogle Scholar
  25. 25.
    Tobler NE, Detmar M (2006) Tumor and lymph node lymphangiogenesis—impact on cancer metastasis. J Leukoc Biol 80(4):691–696PubMedCrossRefGoogle Scholar
  26. 26.
    Roy H, Bhardwaj S, Ylä-Herttuala S (2006) Biology of vascular endothelial growth factors. FEBS Lett 580(12):2879–2887PubMedCrossRefGoogle Scholar
  27. 27.
    Petrova TV, Makinen T, Alitalo K (1999) Signaling via vascular endothelial growth factor receptors. Exp Cell Res 253(1):117–130PubMedCrossRefGoogle Scholar
  28. 28.
    Ferrara N, Alitalo K (1999) Clinical applications of angiogenic growth factors and their inhibitors. Nat Med 5(12):1359–1364PubMedCrossRefGoogle Scholar
  29. 29.
    Ferrara N (2004) Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25(4):581–611PubMedCrossRefGoogle Scholar
  30. 30.
    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 Flt4 (VEGFR-3) and KDR (VEGFR-2) receptor tyrosine kinases. EMBO J 159(2):290–298Google Scholar
  31. 31.
    Marconcini L, Marchio S, Morbidelli L, Cartocci E, Albini A, Ziche M, Bussolino F, Oliviero S (1999) C-fos-induced growth factor/vascular endothelial growth factor D induces angiogenesis in vivo and in vitro. Proc Natl Acad Sci USA 96(17):9671–9676PubMedCrossRefGoogle Scholar
  32. 32.
    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 FLT4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 92(8):3566–3570PubMedCrossRefGoogle Scholar
  33. 33.
    Kubo H, Fujiwara T, Jussila L, Hashi H, Ogawa M, Shimizu K, Awane M, Sakai Y, Takabayashi A, Alitalo K, Yamaoka Y, Nishikawa SI (2000) Involvement of vascular endothelial growth factor receptor-3 in maintenance of integrity of endothelial cell lining during tumor angiogenesis. Blood 96(2):546–553PubMedGoogle Scholar
  34. 34.
    Hughes DC (2001) Alternative splicing of the human VEGFGR-3/FLT4 gene as a consequence of an integrated human endogenous retrovirus. J Mol Evol 53(2):77–79PubMedGoogle Scholar
  35. 35.
    Makinen T, Veikkola T, Mustioki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K (2001) Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20(17):4762–4773PubMedCrossRefGoogle Scholar
  36. 36.
    McColl BK, Baldwin ME, Roufail S, Freeman C, Moritz RL, Simpson RJ, Alitalo K, Stacker SA, Achen MG (2003) Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. J Exp Med 198(6):863–868PubMedCrossRefGoogle Scholar
  37. 37.
    Siegfried G, Basak A, Cromlish JA, Benjannet S, Marcinkiewicz J, Chrétien M, Seidah NG, Khatib AM (2003) The secretory proprotein convertases furin, PC5 and PC7 activate VEGF-C to induce tumorigenesis. J Clin Invest 111(11):1723–1732PubMedCrossRefGoogle Scholar
  38. 38.
    Saaristo A, Veikkola T, Enholm B, Hytönen M, Arola J, Pajusola K, Turunen P, Jeltsch M, Karkkainen MJ, Kerjaschki D, Bueler H, Ylä-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(9):1041–1049PubMedCrossRefGoogle Scholar
  39. 39.
    Lahdenranta J, Hagendoorn J, Padera T, Hoshida T, Nelson G, Kashiwagi S, Jain RK, Fukumura D (2009) Endothelial nitric oxide synthase mediates lymphangiogenesis and lymphatic metastasis. Cancer Res 69(7):2801–2808PubMedCrossRefGoogle Scholar
  40. 40.
    Björndahl MA, Cao R, Burton JB, Brakenhielm E, Religa P, Galter D, Wu L, Cao Y (2005) Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res 65(20):9261–9268PubMedCrossRefGoogle Scholar
  41. 41.
    Gannon G, Mandriota SJ, Cui L, Baetens D, Pepper MS, Christofori G (2002) Overexpression of vascular endothelial growth factor-A165 enhances tumor angiogenesis but not metastasis during beta-cell carcinogenesis. Cancer Res 62(2):603–608PubMedGoogle Scholar
  42. 42.
    Akagi K, Ikeda Y, Miyazaki M, Abe T, Kinoshita J, Maehara Y, Sugimachi K (2000) Vascular endothelial growth factor-C (VEGF-C) expression in human colorectal cancer tissues. Br J Cancer 83(7):887–891PubMedCrossRefGoogle Scholar
  43. 43.
    Kajita T, Ohta Y, Kimura K, Tamura M, Tanaka Y, Tsunezuka Y, Oda M, Sasaki T, Watanabe G (2001) The expression of vascular endothelial growth factor C and its receptors in non-small cell lung cancer. Br J Cancer 85(2):255–260PubMedCrossRefGoogle Scholar
  44. 44.
    Salven P, Lymboussaki A, Heikkilä P, Jääskela-Saari H, Enholm B, Aase K, von Euler G, Eriksson U, Alitalo K, Joensuu H (1998) Vascular endothelial growth factors VEGF-B and VEGF-C are expressed in human tumors. Am J Pathol 153(1):103–108PubMedCrossRefGoogle Scholar
  45. 45.
    Shintani S, Li C, Ishikawa T, Mihara M, Nakashiro K, Hamakawa H (2004) Expression of vascular endothelial growth factor A, B, C, and D in oral squamous cell carcinoma. Oral Oncol 40(1):13–20PubMedCrossRefGoogle Scholar
  46. 46.
    Sugiura T, Inoue Y, Matsuki R, Ishii K, Takahashi M, Abe M, Shirasuna K (2009) VEGF-C and VEGF-D expression is correlated with lymphatic vessel density and lymph node metastasis in oral squamous cell carcinoma: Implications for use as a prognostic marker. Int J Oncol 34(3):673–680PubMedCrossRefGoogle Scholar
  47. 47.
    Deryugina EI, Quigley JP (2006) Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev 25(1):9–34PubMedCrossRefGoogle Scholar
  48. 48.
    Bock J, Sinclair L, Bedford N, Jackson RE, Lee JH, Trask DK (2008) Modulation of cellular invasion by VEGF-C expression in squamous cell carcinoma of the head and neck. Arch Otolaryngol Head Neck Surg 134(4):355–362PubMedCrossRefGoogle Scholar
  49. 49.
    Parikh RR, Yang Q, Haffty BG (2007) Prognostic significance of vascular endothelial growth factor protein levels in T1-2 N0 laryngeal cancer treated with primary radiation therapy. Cancer 109(3):566–573PubMedCrossRefGoogle Scholar
  50. 50.
    Boonkitticharoen V, Kulapaditharom B, Leopairut J, Kraiphibul P, Larbcharoensub N, Cheewaruangroj W, Chintrakarn C, Pochanukul L (2008) Vascular endothelial growth factor A and proliferation marker in prediction of lymph node metastasis in oral and pharyngeal squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 134(12):1305–1311PubMedCrossRefGoogle Scholar
  51. 51.
    Mohammed RA, Green A, El-Shikh S, Paish EC, Ellis IO, Martin SG (2007) Prognostic significance of vascular endothelial growth factor-A, -C and -D in breast cancer and their relationships with angio- and lymphangiogenesis. Br J Cancer 96(7):1092–1100PubMedCrossRefGoogle Scholar
  52. 52.
    Kondo K, Kaneko T, Baba M, Konno H (2007) VEGF-C and VEGF-A synergistically enhance lymph node metastasis of gastric cancer. Biol Pharm Bull 30(4):633–637PubMedCrossRefGoogle Scholar
  53. 53.
    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(7):1161–1169PubMedCrossRefGoogle Scholar
  54. 54.
    Suri C, Jones PF, Patan S, Bartunkova S, Maisonpierre PC, Davis S, Sato TN, Yancopoulos GD (1996) Requisite role of angiopoietin-1, a ligand for the TIE2 receptor, during embryonic angiogenesis. Cell 87(7):1171–1180PubMedCrossRefGoogle Scholar
  55. 55.
    Morisada T, Oike Y, Yamada Y, Urano T, Akao M, Kubota Y, Maekawa H, Kimura Y, Ohmura M, Miyamoto T, Nozawa S, Koh GY, Alitalo K, Suda T (2005) Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 105(12):4649–4656PubMedCrossRefGoogle Scholar
  56. 56.
    Tammela T, Saaristo A, Lohela M, Morisada T, Tornberg J, Norrmén C, Oike Y, Pajusola K, Thurston G, Suda T, Yla-Herttuala S, Alitalo K (2005) Angiopoietin-1 promotes lymphatic sprouting and hyperplasia. Blood 105(12):4642–4648PubMedCrossRefGoogle Scholar
  57. 57.
    Wang J, Wu K, Zhang D, Tang H, Xie H, Hong L, Pan Y, Lan M, Hu S, Ning X, Fan D (2005) Expressions and clinical significances of angiopoietin-1, -2 and Tie2 in human gastric cancer. Biochem Biophys Res Commun 337(1):386–393PubMedCrossRefGoogle Scholar
  58. 58.
    Chung YC, Hou YC, Chang CN, Hseu TH (2006) Expression and prognostic significance of angiopoietin in colorectal carcinoma. J Surg Oncol 94(7):631–638PubMedCrossRefGoogle Scholar
  59. 59.
    Chien CY, Su CY, Chuang HC, Fang FM, Huang HY, Chen CM, Chen CH, Huang CC (2008) Angiopoietin-1 and -2 expression in recurrent squamous cell carcinoma of the oral cavity. J Surg Oncol 97(3):273–277PubMedCrossRefGoogle Scholar
  60. 60.
    Samani AA, Yakar S, LeRoith D, Brodt P (2007) The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 28(1):20–47PubMedCrossRefGoogle Scholar
  61. 61.
    Clemmons DR (1997) Insulin-like growth factor binding proteins and their role in controlling IGF actions. Cytokine Growth Factor Rev 8(1):45–62PubMedCrossRefGoogle Scholar
  62. 62.
    Lee OH, Bae SK, Bae MH, Lee YM, Moon EJ, Cha HJ, Kwon YG, Kim KW (2000) Identification of angiogenic properties of insulin-like growth factor II in in vitro angiogenesis models. Br J Cancer 82(2):385–391PubMedCrossRefGoogle Scholar
  63. 63.
    Rabinovsky ED, Draghia-Akli R (2004) Insulin-like growth factor I plasmid therapy promotes in vivo angiogenesis. Mol Ther 9(1):46–55PubMedCrossRefGoogle Scholar
  64. 64.
    Reinmuth N, Fan F, Liu W, Parikh AA, Stoeltzing O, Jung YD, Bucana CD, Radinsky R, Gallick GE, Ellis LM (2002) Impact of insulin-like growth factor receptor-I function on angiogenesis, growth and metastasis of colon cancer. Lab Invest 82(10):1377–1389PubMedGoogle Scholar
  65. 65.
    Mohanraj L, Oh Y (2011) Targeting IGF-I, IGFBPs and IGF-I receptor system in cancer: the current and future in breast cancer therapy. Recent Pat Anticancer Drug Discov 6(2):166–177PubMedCrossRefGoogle Scholar
  66. 66.
    Chang MH, Lee J, Han J, Park YH, Ahn JS, Park K, Ahn MJ (2009) Prognostic role of insulin-like growth factor receptor-1 expression in small cell lung cancer. APMIS 117(12):861–869PubMedCrossRefGoogle Scholar
  67. 67.
    Björndahl 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(43):15593–15598PubMedCrossRefGoogle Scholar
  68. 68.
    Friedrich RE, Hagel C, Bartel-Friedrich S (2010) Insulin-like growth factor-1 receptor (IGF-1R) in primary and metastatic undifferentiated carcinoma of the head and neck: a possible target of immunotherapy. Anticancer Res 30(5):1641–1643PubMedGoogle Scholar
  69. 69.
    Yuan Y, Zhou X, Song J, Qiu X, Li J, Ye L, Meng X, Xia D (2008) Expression and clinical significance of epidermal growth factor receptor and type 1 insulin-like growth factor receptor in nasopharyngeal carcinoma. Ann Otol Rhinol Laryngol 117(3):192–200PubMedGoogle Scholar
  70. 70.
    Papadimitrakopoulou VA, Brown EN, Liu DD, El-Naggar AK, Jack Lee J, Hong WK, Lee HY (2006) The prognostic role of loss of insulin-like growth factor-binding protein-3 expression in head and neck carcinogenesis. Cancer Lett 239(1):136–143PubMedCrossRefGoogle Scholar
  71. 71.
    Brady G, O’Regan E, Miller I, Ogungbowale A, Kapas S, Crean SJ (2007) Serum levels of insulin-like growth factors (IGFs) and their binding proteins (IGFBPs), -1, -2, -3, in oral cancer. Int J Oral Maxillofac Surg 36(3):259–262PubMedCrossRefGoogle Scholar
  72. 72.
    Ornitz DM, Itoh N (2001) Fibroblast growth factors. Genome Biol 2(3):reviews3005–reviews3005.12. doi:10.1186/gb-2001-2-3-reviews3005 Google Scholar
  73. 73.
    Shing Y, Folkman J, Sullivan R, Butterfield C, Murray J, Klagsbrun M (1984) Heparin affinity: purification of a tumor-derived capillary endothelial cell growth factor. Science 223(4642):1296–1299PubMedCrossRefGoogle Scholar
  74. 74.
    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(32):11658–11663PubMedCrossRefGoogle Scholar
  75. 75.
    Kubo H, Cao R, Brakenhielm E, Mäkinen 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(13):8868–8873PubMedCrossRefGoogle Scholar
  76. 76.
    Donnem T, Al-Shibli K, Al-Saad S, Busund LT, Bremnes RM (2009) Prognostic impact of fibroblast growth factor 2 in non-small cell lung cancer: coexpression with VEGFR-3 and PDGF-B predicts poor survival. J Thorac Oncol 4(5):578–585PubMedCrossRefGoogle Scholar
  77. 77.
    Wang J, Yu W, Cai Y, Ren C, Ittmann MM (2008) Altered fibroblast growth factor receptor 4 stability promotes prostate cancer progression. Neoplasia 10(8):847–856PubMedGoogle Scholar
  78. 78.
    de la Torre NG, Buley I, Wass JA, Turner HE (2006) Angiogenesis and lymphangiogenesis in thyroid proliferative lesions: relationship to type and tumour behaviour. Endocr Relat Cancer 13(3):931–944PubMedCrossRefGoogle Scholar
  79. 79.
    Drugan CS, Paterson IC, Prime SS (1998) Fibroblast growth factor receptor expression reflects cellular differentiation in human oral squamous carcinoma cell lines. Carcinogenesis 19(6):1153–1156PubMedCrossRefGoogle Scholar
  80. 80.
    Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M (2005) Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J 24(16):2885–2895PubMedCrossRefGoogle Scholar
  81. 81.
    Cao R, Björndahl 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(4):333–345PubMedCrossRefGoogle Scholar
  82. 82.
    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(15):6901–6909PubMedCrossRefGoogle Scholar
  83. 83.
    Achen MG, Roufail S, Domagala T, Catimel B, Nice EC, Geleick DM, Murphy R, Scott AM, Caesar C, Makinen T, Alitalo K, Stacker SA (2000) Monoclonal antibodies to vascular endothelial growth factor-D block interactions with both VEGF receptor-2 and VEGF receptor-3. Eur J Biochem 267(9):2505–2515PubMedCrossRefGoogle Scholar
  84. 84.
    Ferrara N, Hillan KJ, Gerber HP, Novotny W (2004) Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov 3(5):391–400PubMedCrossRefGoogle Scholar
  85. 85.
    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(1):14–21PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • A. D. Karatzanis
    • 1
  • E. Koudounarakis
    • 1
  • I. Papadakis
    • 1
  • G. Velegrakis
    • 1
  1. 1.Department of OtorhinolaryngologyUniversity of Crete Medical School, University Hospital of CreteHeraklionGreece

Personalised recommendations