Cell and Tissue Research

, Volume 314, Issue 1, pp 167–177 | Cite as

Lymphangiogenesis and tumor metastasis

  • Michael S. PepperEmail author
  • Jean-Christophe Tille
  • Riccardo Nisato
  • Mihaela Skobe


The lymphatic system transports interstitial fluid and macromolecules from tissues back to the blood circulation, and plays an important role in the immune response by directing the traffic of lymphocytes and antigen-presenting cells. The lymphatic system also constitutes one of the most important pathways of tumor dissemination. In many human cancers, increased expression of vascular endothelial growth factor-C (VEGF-C) is correlated with regional lymph node metastases. Experimental studies using transgenic mice overexpressing VEGF-C or xenotransplantation of VEGF-C-expressing tumor cells into immunodeficient mice have demonstrated a role for VEGF-C in tumor lymphangiogenesis and the subsequent formation of lymph node metastases. However, there is at present little evidence for lymphangiogenesis in human tumors and the relative importance of preexisting vs. newly formed lymphatics for metastasis in humans remains to be determined. Nonetheless, the striking correlation between the levels of VEGF-C in primary human tumors and lymph node metastases predicts its importance in cancer spread. Aside from promoting lymphangiogenesis, VEGF-C may also activate lymphatics to promote tumor cell chemotaxis, lymphatic intravasation and hence tumor cell dissemination.


Cancer Metastasis Lymphangiogenesis VEGF-C VEGFR-3 


  1. Achen MG, Williams RA, Minekus MP, Thornton GE, Stenvers K, Rogers PA, Lederman F, Roufail S, Stacker SA (2001) Localization of vascular endothelial growth factor-D in malignant melanoma suggests a role in tumour angiogenesis. J Pathol 193:147–154CrossRefPubMedGoogle Scholar
  2. 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 83:887–891CrossRefPubMedGoogle Scholar
  3. Amioka T, Kitadai Y, Tanaka S, Haruma K, Yoshihara M, Yasui W, Chayama K (2002) Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa. Eur J Cancer 38:1413–1419CrossRefPubMedGoogle Scholar
  4. Arinaga M, Noguchi T, Takeno S, Chujo M, Miura T, Uchida Y (2003) Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma. Cancer 97:457–464CrossRefPubMedGoogle Scholar
  5. 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 144:789–801Google Scholar
  6. 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 62:1315–1320PubMedGoogle Scholar
  7. Birner P, Obermair A, Schindl M, Kowalski H, Breitenecker G, Oberhuber G (2001) Selective immunohistochemical staining of blood and lymphatic vessels reveals independent prognostic influence of blood and lymphatic vessel invasion in early-stage cervical cancer. Clin Cancer Res 7:93–97PubMedGoogle Scholar
  8. 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
  9. Bunone G, Vigneri P, Mariani L, Buto S, Collini P, Pilotti S, Pierotti MA, Bongarzone I (1999) Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. Am J Pathol 155:1967–1976PubMedGoogle Scholar
  10. 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 99:4434–4442CrossRefPubMedGoogle Scholar
  11. Carmeliet P, Jain RK (2000) Angiogenesis in cancer and other diseases. Nature 407:249–257PubMedGoogle Scholar
  12. de Waal RM, van Altena MC, Erhard H, Weidle UH, Nooijen PT, Ruiter DJ (1997) Lack of lymphangiogenesis in human primary cutaneous melanoma. Consequences for the mechanism of lymphatic dissemination. Am J Pathol 150:1951–1957PubMedGoogle Scholar
  13. Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, jackson DG, Ellwanger U, Garbe C, Mihm MC, Detmar M (2003) Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 162:1951–1960Google Scholar
  14. 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 282:946–949CrossRefPubMedGoogle Scholar
  15. 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
  16. Fielder W, Graeven U, Ergun S, Verago S, Kilic N, Stockschlader M, Hossfeld DK (1997) Expression of FLT4 and its ligand VEGF-C in acute myeloid leukemia. Leukemia 11:1234–1237CrossRefPubMedGoogle Scholar
  17. Furudoi A, Tanaka S, Haruma K, Kitadai Y, Yoshihara M, Chayama K, Shimamoto F (2002) Clinical significance of vascular endothelial growth factor C expression and angiogenesis at the deepest invasive site of advanced colorectal carcinoma. Oncology 62:157–166CrossRefPubMedGoogle Scholar
  18. Gale N, Thurston G, Hackett S, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte M, Jackson D, Suri C, Campochiaro P, Wiegand S, Yancopoulos G (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
  19. 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 62:603–608PubMedGoogle Scholar
  20. George ML, Tutton MG, Janssen F, Arnaout A, Abulafi AM, Eccles SA, Swift RI (2001) VEGF-A, VEGF-C, and VEGF-D in colorectal cancer progression. Neoplasia 3:420–427CrossRefPubMedGoogle Scholar
  21. Gunningham SP, Currie MJ, Han C, Robinson BA, Scott PA, Harris AL, Fox SB (2000) The short form of the alternatively spliced flt-4 but not its ligand vascular endothelial growth factor C is related to lymph node metastasis in human breast cancers. Clin Cancer Res 6:4278–4286PubMedGoogle Scholar
  22. Hanahan D (1985) Heritable formation of pancreatic beta-cell tumours in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315:115–122PubMedGoogle Scholar
  23. Hartveit E (1990) Attenuated cells in breast stroma: the missing lymphatic system of the breast. Histopathology 16:533–543PubMedGoogle Scholar
  24. Hashimoto I, Kodama J, Seki N, Hongo A, Yoshinouchi M, Okuda H, Kudo T (2001) Vascular endothelial growth factor-C expression and its relationship to pelvic lymph node status in invasive cervical cancer. Br J Cancer 85:93–97CrossRefPubMedGoogle Scholar
  25. He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, Alitalo K (2002) Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 94:819–825CrossRefPubMedGoogle Scholar
  26. Hirai M, Nakagawara A, Oosaki T, Hayashi Y, Hirono M, Yoshihara T (2001) Expression of vascular endothelial growth factors (VEGF-A/VEGF-1 and VEGF-C/VEGF-2) in postmenopausal uterine endometrial carcinoma. Gynecol Oncol 80:181–188CrossRefPubMedGoogle Scholar
  27. Ichikura T, Tomimatsu S, Ohkura E, Mochizuki H (2001) Prognostic significance of the expression of vascular endothelial growth factor (VEGF) and VEGF-C in gastric carcinoma. J Surg Oncol 78:132–137CrossRefPubMedGoogle Scholar
  28. Ishikawa M, Kitayama J, Kazama S, Nagawa H (2003) Expression of vascular endothelial growth factor C and D (VEGF-C and -D) is an important risk factor for lymphatic metastasis in undifferentiated early gastric carcinoma. Jpn J Clin Oncol 33:21–27CrossRefPubMedGoogle Scholar
  29. Jain RK (1987) Transport of molecules in the tumor interstitium: a review. Cancer Res 47:3039–3051PubMedGoogle Scholar
  30. Jain RK (1990) Vascular and interstitial barriers to delivery of therapeutic agents in tumors. Cancer Metastasis Rev 9:253–266PubMedGoogle Scholar
  31. Jain RK, Padera TP (2002) Prevention and treatment of lymphatic metastasis by antilymphangiogenic therapy. J Natl Cancer Inst 94:785–787CrossRefPubMedGoogle Scholar
  32. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K (1997) Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276:1423–1425PubMedGoogle Scholar
  33. 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 15:290–298PubMedGoogle Scholar
  34. Joukov V, Sorsa T, Kumar V, Jeltsch M, Claesson-Welsh L, Cao Y, Saksela O, Kalkkinen N, Alitalo K (1997) Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 16:3898–3911CrossRefPubMedGoogle Scholar
  35. Kabashima A, Maehara Y, Kakeji Y, Sugimachi K (2001) Overexpression of vascular endothelial growth factor C is related to lymphogenous metastasis in early gastric carcinoma. Oncology 60:146–150CrossRefPubMedGoogle Scholar
  36. Kaio E, Tanaka S, Kitadai Y, Sumii M, Yoshihara M, Haruma K, Chayama K (2003) Clinical significance of angiogenic factor expression at the deepest invasive site of advanced colorectal carcinoma. Oncology 64:61–73CrossRefPubMedGoogle Scholar
  37. 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 85:255–260CrossRefPubMedGoogle Scholar
  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 U S A 98:12677–12682CrossRefPubMedGoogle Scholar
  39. 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
  40. Kinoshita J, Kitamura K, Kabashima A, Saeki H, Tanaka S, Sugimachi K (2001) Clinical significance of vascular endothelial growth factor-C (VEGF-C) in breast cancer. Breast Cancer Res Treat 66:159–164CrossRefPubMedGoogle Scholar
  41. 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 268:5530–5540CrossRefPubMedGoogle Scholar
  42. Kitadai Y, Amioka T, Haruma K, Tanaka S, Yoshihara M, Sumii K, Matsutani N, Yasui W, Chayama K (2001) Clinicopathological significance of vascular endothelial growth factor (VEGF)-C in human esophageal squamous cell carcinomas. Int J Cancer 93:662–666Google Scholar
  43. Komuro H, Kaneko S, Kaneko M, Nakanishi Y (2001) Expression of angiogenic factors and tumor progression in human neuroblastoma. J Cancer Res Clin Oncol 127:739–743PubMedGoogle Scholar
  44. Kriehuber E, Breiteneder-Geleff S, Groeger M, Soleiman A, Schoppmann SF, Stingl G, Kerjaschki D, Maurer D (2001) Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med 194:797–808PubMedGoogle Scholar
  45. Krishnan J, Kirkin V, Steffen A, Hegen M, Weih D, Tomarev S, Wilting J, Sleeman JP (2003) 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 63:713–722PubMedGoogle Scholar
  46. 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 U S A 99:8868–8873CrossRefPubMedGoogle Scholar
  47. Kurebayashi J, Otsuki T, Kunisue H, Mikami Y, Tanaka K, Yamamoto S, Sonoo H (1999) Expression of vascular endothelial growth factor (VEGF) family members in breast cancer. Jpn J Cancer Res 90:977–981PubMedGoogle Scholar
  48. 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 60:4324–4327PubMedGoogle Scholar
  49. Liotta LA, Steeg PS, Stetler-Stevenson WG (1991) Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 64:327–336PubMedGoogle Scholar
  50. Makinen T, Jussila L, Veikkola T, Karpanen T, Kettunen MI, Pulkkanen KJ, Kauppinen R, Jackson DG, Kubo H, Nishikawa S, Yla-Herttuala S, Alitalo K (2001a) Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7:199–205CrossRefPubMedGoogle Scholar
  51. Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, Alitalo K (2001b) Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20:4762–4773CrossRefPubMedGoogle Scholar
  52. 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
  53. Mattila MM, Ruohola JK, Karpanen T, Jackson DG, Alitalo K, Harkonen PL (2002) VEGF-C induced lymphangiogenesis is associated with lymph node metastasis in orthotopic MCF-7 tumors. Int J Cancer 98:946–951CrossRefPubMedGoogle Scholar
  54. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196:1497–1506CrossRefPubMedGoogle Scholar
  55. Nakamura Y, Yasuoka H, Tsujimoto M, Yang Q, Imabun S, Nakahara M, Nakao K, Nakamura M, Mori I, Kakudo K (2003) Prognostic significance of vascular endothelial growth factor d in breast carcinoma with long-term follow-up. Clin Cancer Res 9:716–721PubMedGoogle Scholar
  56. Nakashima T, Kondoh S, Kitoh H, Ozawa H, Okita S, Harada T, Shiraishi K, Ryozawa S, Okita K (2003) Vascular endothelial growth factor-C expression in human gallbladder cancer and its relationship to lymph node metastasis. Int J Mol Med 11:33–39PubMedGoogle Scholar
  57. Narko K, Enholm B, Makinen T, Ristimaki A (1999) Effect of inflammatory cytokines on the expression of the vascular endothelial growth factor-C. Int J Exp Pathol 80:109–112CrossRefPubMedGoogle Scholar
  58. Nathanson SD, Zarbo RJ, Wachna DL, Spence CA, Andrzejewski TA, Abrams J (2000) Microvessels that predict axillary lymph node metastases in patients with breast cancer. Arch Surg 135:586–593; discussion 593–594CrossRefPubMedGoogle Scholar
  59. Niki T, Iba S, Tokunou M, Yamada T, Matsuno Y, Hirohashi S (2000) Expression of vascular endothelial growth factors A, B, C, and D and their relationships to lymph node status in lung adenocarcinoma. Clin Cancer Res 6:2431–2439PubMedGoogle Scholar
  60. Niki T, Iba S, Yamada T, Matsuno Y, Enholm B, Hirohashi S (2001) Expression of vascular endothelial growth factor receptor 3 in blood and lymphatic vessels of lung adenocarcinoma. J Pathol 193:450–457CrossRefPubMedGoogle Scholar
  61. O-Charoenrat P, Rhys-Evans P, Eccles SA (2001) Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis. Cancer 92:556–568CrossRefPubMedGoogle Scholar
  62. Oh SJ, Jeltsch MM, Birkenhager R, McCarthy JE, 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 188:96–109CrossRefPubMedGoogle Scholar
  63. Ohta Y, Shridhar V, Bright RK, Kalemkerian GP, Du W, Carbone M, Watanabe Y, Pass HI (1999) VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer 81:54–61CrossRefPubMedGoogle Scholar
  64. Ohta Y, Nozawa H, Tanaka Y, Oda M, Watanabe Y (2000) Increased vascular endothelial growth factor and vascular endothelial growth factor-c and decreased nm23 expression associated with microdissemination in the lymph nodes in stage I non-small cell lung cancer. J Thorac Cardiovasc Surg 119:804–813PubMedGoogle Scholar
  65. Okamoto M, Nishimine M, Kishi M, Kirita T, Sugimura M, Nakamura M, Konishi N (2002) Prediction of delayed neck metastasis in patients with stage I/II squamous cell carcinoma of the tongue. J Oral Pathol Med 31:227–233CrossRefPubMedGoogle Scholar
  66. Orpana A, Salven P (2002) Angiogenic and lymphangiogenic molecules in hematological malignancies. Leuk Lymphoma 43:219–224CrossRefPubMedGoogle Scholar
  67. 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 296:1883–1886CrossRefPubMedGoogle Scholar
  68. Papoutsi M, Siemeister G, Weindel K, Tomarev SI, Kurz H, Schachtele C, Martiny-Baron G, Christ B, Marme D, Wilting J (2000) Active interaction of human A375 melanoma cells with the lymphatics in vivo. Histochem Cell Biol 114:373–385PubMedGoogle Scholar
  69. Papoutsi M, Sleeman JP, Wilting J (2001) Interaction of rat tumor cells with blood vessels and lymphatics of the avian chorioallantoic membrane. Microsc Res Tech 55:100–107PubMedGoogle Scholar
  70. Partanen TA, Arola J, Saaristo A, Jussila L, Ora A, Miettinen M, Stacker SA, Achen MG, Alitalo K (2000) VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. FASEB J 14:2087–2096Google Scholar
  71. Pepper MS (2001) Lymphangiogenesis and tumor metastasis: myth or reality? Clin Cancer Res 7:462–468Google Scholar
  72. 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 21:4593–4599CrossRefPubMedGoogle Scholar
  73. Podgrabinska S, Braun P, Velasco P, Kloos B, Janes L, Pepper MS, Jackson DG, Skobe M (2002) Molecular characterization of lymphatic endothelial cells. Proc Natl Acad Sci U S A (in press)Google Scholar
  74. Ryan TJ (1989) Structure and function of lymphatics. J Invest Dermatol 93:18S–24SPubMedGoogle Scholar
  75. Saaristo A, Veikkola T, Tammela T, Enholm B, Karkkainen MJ, Pajusola K, Bueler H, Yla-Herttuala S, Alitalo K (2002) Lymphangiogenic gene therapy with minimal blood vascular side effects. J Exp Med 196:719–730CrossRefPubMedGoogle Scholar
  76. Salven P, Lymboussaki A, Heikkila P, Jaaskela-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 153:103–108PubMedGoogle Scholar
  77. Schmid-Schonbein GW (1990) Microlymphatics and lymph flow. Physiol Rev 70:987–1028PubMedGoogle Scholar
  78. Schoppmann SF, Birner P, Studer P, Breiteneder-Geleff S (2001a) Lymphatic microvessel density and lymphovascular invasion assessed by anti-podoplanin immunostaining in human breast cancer. Anticancer Res 21:2351–2355PubMedGoogle Scholar
  79. Schoppmann SF, Schindl M, Breiteneder-Geleff S, Soleima A, Breitenecker G, Karner B, Birner P (2001b) Inflammatory stromal reaction correlates with lymphatic microvessel density in early-stage cervical cancer. Anticancer Res 21:3419–3423PubMedGoogle Scholar
  80. Schoppmann SF, Birner P, Stockl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D (2002) Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 161:947–956PubMedGoogle Scholar
  81. Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K, Detmar M (2001a) Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol 159:893–903PubMedGoogle Scholar
  82. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M (2001b) Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7:192–198CrossRefPubMedGoogle Scholar
  83. Sleeman JP, Krishnan J, Kirkin V, Baumann P (2001) Markers for the lymphatic endothelium: in search of the holy grail? Microsc Res Tech 55:61–69Google Scholar
  84. Stacker SA, Stenvers K, Caesar C, Vitali A, Domagala T, Nice E, Roufail S, Simpson RJ, Moritz R, Karpanen T, Alitalo K, Achen MG (1999) Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J Biol Chem 274:32127–32136CrossRefPubMedGoogle Scholar
  85. 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 7:186–191CrossRefPubMedGoogle Scholar
  86. Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K (2002) Metastasis: lymphangiogenesis and cancer metastasis. Nat Rev Cancer 2:573–583CrossRefPubMedGoogle Scholar
  87. Straume O, Jackson DG, Akslen LA (2003) Independent prognostic impact of lymphatic vessel density and presence of low-grade lymphangiogenesis in cutaneous melanoma. Clin Cancer Res 9:250–256PubMedGoogle Scholar
  88. Swartz MA, Skobe M (2001) Lymphatic function, lymphangiogenesis, and cancer metastasis. Microsc Res Tech 55:92–99CrossRefPubMedGoogle Scholar
  89. 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
  90. Takahashi A, Kono K, Itakura J, Amemiya H, Feng Tang R, Iizuka H, Fujii H, Matsumoto Y (2002) Correlation of vascular endothelial growth factor-C expression with tumor-infiltrating dendritic cells in gastric cancer. Oncology 62:121–127CrossRefPubMedGoogle Scholar
  91. Tanaka K, Sonoo H, Kurebayashi J, Nomura T, Ohkubo S, Yamamoto Y, Yamamoto S (2002a) Inhibition of infiltration and angiogenesis by thrombospondin-1 in papillary thyroid carcinoma. Clin Cancer Res 8:1125–1131PubMedGoogle Scholar
  92. Tanaka K, Kurebayashi J, Sonoo H, Otsuki T, Yamamoto Y, Ohkubo S, Yamamoto S, Shimozuma K (2002b) Expression of vascular endothelial growth factor family messenger RNA in diseased thyroid tissues. Surg Today 32:761–768CrossRefPubMedGoogle Scholar
  93. Tang RF, Itakura J, Aikawa T, Matsuda K, Fujii H, Korc M, Matsumoto Y (2001) Overexpression of lymphangiogenic growth factor VEGF-C in human pancreatic cancer. Pancreas 22:285–292CrossRefPubMedGoogle Scholar
  94. Tsurusaki T, Kanda S, Sakai H, Kanetake H, Saito Y, Alitalo K, Koji T (1999) Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis. Br J Cancer 80:309–313CrossRefPubMedGoogle Scholar
  95. Ueda M, Terai Y, Yamashita Y, Kumagai K, Ueki K, Yamaguchi H, Akise D, Hung YC, Ueki M (2002) Correlation between vascular endothelial growth factor-C expression and invasion phenotype in cervical carcinomas. Int J Cancer 98:335–343CrossRefPubMedGoogle Scholar
  96. Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova TV, Kubo H, Thurston G, McDonald DM, Achen MG, Stacker SA, Alitalo K (2001) Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 20:1223–1231CrossRefPubMedGoogle Scholar
  97. Weiss L, Schmid-Schonbein GW (1989) Biomechanical interactions of cancer cells with the microvasculature during metastasis. Cell Biophys 14:187–215PubMedGoogle Scholar
  98. White JD, Hewett PW, Kosuge D, McCulloch T, Enholm BC, Carmichael J, Murray JC (2002) Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res 62:1669–1675PubMedGoogle Scholar
  99. Wigle JT, Oliver G (1999) Prox1 function is required for the development of the murine lymphatic system. Cell 98:769–778PubMedGoogle Scholar
  100. Witte MH, Way DL, Witte CL, Bernas M (1997) Lymphangiogenesis: mechanisms, significance and clinical implications. EXS 79:65–112PubMedGoogle Scholar
  101. Yang W, Klos K, Yang Y, Smith TL, Shi D, Yu D (2002) ErbB2 overexpression correlates with increased expression of vascular endothelial growth factors A, C, and D in human breast carcinoma. Cancer 94:2855–2861CrossRefPubMedGoogle Scholar
  102. Yokoyama Y, Sato S, Futagami M, Fukushi Y, Sakamoto T, Umemoto M, Saito Y (2000) Prognostic significance of vascular endothelial growth factor and its receptors in endometrial carcinoma. Gynecol Oncol 77:413–418CrossRefPubMedGoogle Scholar
  103. Yokoyama Y, Charnock-Jones DS, Licence D, Yanaihara A, Hastings JM, Holland CM, Emoto M, Umemoto M, Sakamoto T, Sato S, Mizunuma H, Smith SK (2003) Vascular endothelial growth factor-D is an independent prognostic factor in epithelial ovarian carcinoma. Br J Cancer 88:237–244CrossRefPubMedGoogle Scholar
  104. Yonemura Y, Endo Y, Fujita H, Fushida S, Ninomiya I, Bandou E, Taniguchi K, Miwa K, Ohoyama S, Sugiyama K, Sasaki T (1999) Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer. Clin Cancer Res 5:1823–1829PubMedGoogle Scholar
  105. Yonemura Y, Fushida S, Bando E, Kinoshita K, Miwa K, Endo Y, Sugiyama K, Partanen T, Yamamoto H, Sasaki T (2001) Lymphangiogenesis and the vascular endothelial growth factor receptor (VEGFR)-3 in gastric cancer. Eur J Cancer 37:918–923CrossRefPubMedGoogle Scholar
  106. Yoon YS, Murayama T, Gravereaux E, Tkebuchava T, Silver M, Curry C, Wecker A, Kirchmair R, Hu CS, Kearney M, Ashare A, Jackson DG, Kubo H, Isner JM, Losordo DW (2003) VEGF-C gene therapy augments postnatal lymphangiogenesis and ameliorates secondary lymphedema. J Clin Invest 111:717–725CrossRefPubMedGoogle Scholar
  107. 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
  108. Zetter BR (1993) Adhesion molecules in tumor metastasis. Semin Cancer Biol 4:219–229PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2003

Authors and Affiliations

  • Michael S. Pepper
    • 1
    Email author
  • Jean-Christophe Tille
    • 1
  • Riccardo Nisato
    • 1
  • Mihaela Skobe
    • 2
  1. 1.Department of MorphologyUniversity Medical CenterGeneva 4Switzerland
  2. 2.Derald H. Ruttenberg Cancer CenterMount Sinai School of MedicineNew YorkUSA

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