Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review
  • Published:

Interaction of tumor cells and lymphatic vessels in cancer progression

Oncogene volume 31, pages 4499–4508 (2012)Cite this article

Subjects

Abstract

Metastatic spread of cancer through the lymphatic system affects hundreds of thousands of patients yearly. Growth of new lymphatic vessels, lymphangiogenesis, is activated in cancer and inflammation, but is largely inactive in normal physiology, and therefore offers therapeutic potential. Key mediators of lymphangiogenesis have been identified in developmental studies. During embryonic development, lymphatic endothelial cells derive from the blood vascular endothelium and differentiate under the guidance of lymphatic-specific regulators, such as the prospero homeobox 1 transcription factor. Vascular endothelial growth factor-C (VEGF-C) and VEGF receptor 3 signaling are essential for the further development of lymphatic vessels and therefore they provide a promising target for inhibition of tumor lymphangiogenesis. Lymphangiogenesis is important for the progression of solid tumors as shown for melanoma and breast cancer. Tumor cells may use chemokine gradients as guidance cues and enter lymphatic vessels through intercellular openings between endothelial cell junctions or, possibly, by inducing larger discontinuities in the endothelial cell layer. Tumor-draining sentinel lymph nodes show enhanced lymphangiogenesis even before cancer metastasis and they may function as a permissive ‘lymphovascular niche’ for the survival of metastatic cells. Although our current knowledge indicates that the development of anti-lymphangiogenic therapies may be beneficial for the treatment of cancer patients, several open questions remain with regard to the frequency, mechanisms and biological importance of lymphatic metastases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Garcia M, Jemal A, Ward EM, Center MM, Hao Y, Sieger RL et al. Global Cancer Facts & Figures 2007. American Cancer Society: Atlanta, GA, 2007.

    Google Scholar 

  2. Siegel R, Ward E, Brawley O, Jemal A . Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin 2011; 61: 212–236.

    PubMed  Google Scholar 

  3. Ferlay J, Parkin DM, Steliarova-Foucher E . Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 2010; 46: 765–781.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  5. Yoshimatsu Y, Yamazaki T, Mihira H, Itoh T, Suehiro J, Yuki K et al. Ets family members induce lymphangiogenesis through physical and functional interaction with Prox1. J Cell Sci 2011; 124: 2753–2762.

    CAS  PubMed  Google Scholar 

  6. Bos FL, Caunt M, Peterson-Maduro J, Planas-Paz L, Kowalski J, Karpanen T et al. CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circ Res 2011; 109: 486–491.

    CAS  PubMed  Google Scholar 

  7. Karkkainen MJ, Haiko P, Sainio K, Partanen J, Taipale J, Petrova TV et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 2004; 5: 74–80.

    CAS  PubMed  Google Scholar 

  8. Kang J, Yoo J, Lee S, Tang W, Aguilar B, Ramu S et al. An exquisite cross-control mechanism among endothelial cell fate regulators directs the plasticity and heterogeneity of lymphatic endothelial cells. Blood 2010; 116: 140–150.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Chen L, Mupo A, Huynh T, Cioffi S, Woods M, Jin C et al. Tbx1 regulates Vegfr3 and is required for lymphatic vessel development. J Cell Biol 2010; 189: 417–424.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Norrmen C, Ivanov KI, Cheng J, Zangger N, Delorenzi M, Jaquet M et al. FOXC2 controls formation and maturation of lymphatic collecting vessels through cooperation with NFATc1. J Cell Biol 2009; 185: 439–457.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Wick N, Haluza D, Gurnhofer E, Raab I, Kasimir MT, Prinz M et al. Lymphatic precollectors contain a novel, specialized subpopulation of podoplanin low, CCL27-expressing lymphatic endothelial cells. Am J Pathol 2008; 173: 1202–1209.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Schacht V, Ramirez MI, Hong YK, Hirakawa S, Feng D, Harvey N et al. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J 2003; 22: 3546–3556.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Bertozzi CC, Hess PR, Kahn ML . Platelets: covert regulators of lymphatic development [Review]. Arterioscler Thromb Vasc Biol 2010; 30: 2368–2371.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Bertozzi CC, Schmaier AA, Mericko P, Hess PR, Zou Z, Chen M et al. Platelets regulate lymphatic vascular development through CLEC-2-SLP-76 signaling. Blood 2010; 116: 661–670.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Cueni LN, Chen L, Zhang H, Marino D, Huggenberger R, Alitalo A et al. Podoplanin-Fc reduces lymphatic vessel formation in vitro and in vivo and causes disseminated intravascular coagulation when transgenically expressed in the skin. Blood 2010; 116: 4376–4384.

    PubMed  PubMed Central  Google Scholar 

  16. Jackson DG . Immunological functions of hyaluronan and its receptors in the lymphatics [Review]. Immunol Rev 2009; 230: 216–231.

    CAS  PubMed  Google Scholar 

  17. Oliver G, Srinivasan RS . Lymphatic vasculature development: current concepts [Review]. Ann NY Acad Sci 2008; 1131: 75–81.

    CAS  PubMed  Google Scholar 

  18. Marino D, Dabouras V, Brandli AW, Detmar M . A role for all-trans-retinoic acid in the early steps of lymphatic vasculature development. J Vasc Res 2011; 48: 236–251.

    CAS  PubMed  Google Scholar 

  19. Pflicke H, Sixt M . Preformed portals facilitate dendritic cell entry into afferent lymphatic vessels. J Exp Med 2009; 206: 2925–2935.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Padera TP, Kadambi A, di Tomaso E, Carreira CM, Brown EB, Boucher Y et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 2002; 296: 1883–1886.

    Article  CAS  PubMed  Google Scholar 

  21. Schledzewski K, Falkowski M, Moldenhauer G, Metharom P, Kzhyshkowska J, Ganss R et al. Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+, F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis. J Pathol 2006; 209: 67–77.

    CAS  PubMed  Google Scholar 

  22. Cho CH, Koh YJ, Han J, Sung HK, Jong Lee H, Morisada T et al. Angiogenic role of LYVE-1-positive macrophages in adipose tissue. Circ Res 2007; 100: e47–e57.

    CAS  PubMed  Google Scholar 

  23. Shaul ME, Bennett G, Strissel KJ, Greenberg AS, Obin MS . Dynamic, M2-like remodeling phenotypes of CD11c+ adipose tissue macrophages during high-fat diet-induced obesity in mice. Diabetes 2010; 59: 1171–1181.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Mouta Carreira C, Nasser SM, di Tomaso E, Padera TP, Boucher Y, Tomarev SI et al. LYVE-1 is not restricted to the lymph vessels: expression in normal liver blood sinusoids and down-regulation in human liver cancer and cirrhosis. Cancer Res 2001; 61: 8079–8084.

    CAS  PubMed  Google Scholar 

  25. Kaipainen A, Korhonen J, Mustonen T, van Hinsbergh VW, Fang GH, Dumont D et al. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci USA 1995; 92: 3566–3570.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Laakkonen P, Waltari M, Holopainen T, Takahashi T, Pytowski B, Steiner P et al. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res 2007; 67: 593–599.

    CAS  PubMed  Google Scholar 

  27. Tammela T, Zarkada G, Wallgard E, Murtomaki A, Suchting S, Wirzenius M et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 2008; 454: 656–660.

    CAS  PubMed  Google Scholar 

  28. Haiko P, Makinen T, Keskitalo S, Taipale J, Karkkainen MJ, Baldwin ME et al. Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol Cell Biol 2008; 28: 4843–4850.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Zhang L, Zhou F, Han W, Shen B, Luo J, Shibuya M et al. VEGFR-3 ligand-binding and kinase activity are required for lymphangiogenesis but not for angiogenesis. Cell Res 2010; 20: 1319–1331.

    CAS  PubMed  Google Scholar 

  30. Karkkainen MJ, Saaristo A, Jussila L, Karila KA, Lawrence EC, Pajusola K et al. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci USA 2001; 98: 12677–12682.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Dumont DJ, Jussila L, Taipale J, Lymboussaki A, Mustonen T, Pajusola K et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 1998; 282: 946–949.

    CAS  PubMed  Google Scholar 

  32. Tammela T, Zarkada G, Nurmi H, Jakobsson L, Heinolainen K, Tvorogov D et al. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nat Cell Biol 2011; 13: 1202–1213.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Galvagni F, Pennacchini S, Salameh A, Rocchigiani M, Neri F, Orlandini M et al. Endothelial cell adhesion to the extracellular matrix induces c-Src-dependent VEGFR-3 phosphorylation without the activation of the receptor intrinsic kinase activity. Circ Res 2010; 106: 1839–1848.

    CAS  PubMed  Google Scholar 

  34. Nilsson I, Bahram F, Li X, Gualandi L, Koch S, Jarvius M et al. VEGF receptor 2/-3 heterodimers detected in situ by proximity ligation on angiogenic sprouts. EMBO J 2010; 29: 1377–1388.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Harris NC, Paavonen K, Davydova N, Roufail S, Sato T, Zhang YF et al. Proteolytic processing of vascular endothelial growth factor-D is essential for its capacity to promote the growth and spread of cancer. FASEB J 2011; 25: 2615–2625.

    CAS  PubMed  Google Scholar 

  36. Skobe M, Hamberg LM, Hawighorst T, Schirner M, Wolf GL, Alitalo K et al. Concurrent induction of lymphangiogenesis, angiogenesis, and macrophage recruitment by vascular endothelial growth factor-C in melanoma. Am J Pathol 2001; 159: 893–903.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Saaristo A, Tammela T, Farkkila A, Karkkainen M, Suominen E, Yla-Herttuala S et al. Vascular endothelial growth factor-C accelerates diabetic wound healing. Am J Pathol 2006; 169: 1080–1087.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Schoppmann SF, Birner P, Stockl J, Kalt R, Ullrich R, Caucig C et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 2002; 161: 947–956.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Gordon EJ, Rao S, Pollard JW, Nutt SL, Lang RA, Harvey NL . Macrophages define dermal lymphatic vessel calibre during development by regulating lymphatic endothelial cell proliferation. Development 2010; 137: 3899–3910.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S et al. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood 2010; 116: 829–840.

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Kim KE, Koh YJ, Jeon BH, Jang C, Han J, Kataru RP et al. Role of CD11b+ macrophages in intraperitoneal lipopolysaccharide-induced aberrant lymphangiogenesis and lymphatic function in the diaphragm. Am J Pathol 2009; 175: 1733–1745.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ et al. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 2002; 196: 1497–1506.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M . VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 2005; 201: 1089–1099.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Halin C, Tobler NE, Vigl B, Brown LF, Detmar M . VEGF-A produced by chronically inflamed tissue induces lymphangiogenesis in draining lymph nodes. Blood 2007; 110: 3158–3167.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF et al. VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J 2004; 18: 1111–1113.

    CAS  PubMed  Google Scholar 

  46. Kunstfeld R, Hirakawa S, Hong YK, Schacht V, Lange-Asschenfeldt B, Velasco P et al. Induction of cutaneous delayed-type hypersensitivity reactions in VEGF-A transgenic mice results in chronic skin inflammation associated with persistent lymphatic hyperplasia. Blood 2004; 104: 1048–1057.

    CAS  PubMed  Google Scholar 

  47. Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, Zambruno G et al. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med 2007; 204: 1431–1440.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Baluk P, Tammela T, Ator E, Lyubynska N, Achen MG, Hicklin DJ et al. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J Clin Invest 2005; 115: 247–257.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova TV et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 2001; 20: 1223–1231.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Zheng W, Tammela T, Yamamoto M, Anisimov A, Holopainen T, Kaijalainen S et al. Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor. Blood 2011; 118: 1154–1162.

    CAS  PubMed  Google Scholar 

  51. Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C et al. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 2004; 113: 1040–1050.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Murakami M, Zheng Y, Hirashima M, Suda T, Morita Y, Ooehara J et al. VEGFR1 tyrosine kinase signaling promotes lymphangiogenesis as well as angiogenesis indirectly via macrophage recruitment. Arterioscler Thromb Vasc Biol 2008; 28: 658–664.

    CAS  PubMed  Google Scholar 

  53. Leppanen VM, Jeltsch M, Anisimov A, Tvorogov D, Aho K, Kalkkinen N et al. Structural determinants of vascular endothelial growth factor-D receptor binding and specificity. Blood 2011; 117: 1507–1515.

    CAS  PubMed  Google Scholar 

  54. Anisimov A, Alitalo A, Korpisalo P, Soronen J, Kaijalainen S, Leppanen VM et al. Activated forms of VEGF-C and VEGF-D provide improved vascular function in skeletal muscle. Circ Res 2009; 104: 1302–1312.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Rissanen TT, Markkanen JE, Gruchala M, Heikura T, Puranen A, Kettunen MI et al. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ Res 2003; 92: 1098–1106.

    CAS  PubMed  Google Scholar 

  56. Xu Y, Yuan L, Mak J, Pardanaud L, Caunt M, Kasman I et al. Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J Cell Biol 2010; 188: 115–130.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Caunt M, Mak J, Liang WC, Stawicki S, Pan Q, Tong RK et al. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 2008; 13: 331–342.

    CAS  PubMed  Google Scholar 

  58. Gluzman-Poltorak Z, Cohen T, Herzog Y, Neufeld G . Neuropilin-2 is a receptor for the vascular endothelial growth factor (VEGF) forms VEGF-145 and VEGF-165 [corrected]. J Biol Chem 2000; 275: 18040–18045.

    CAS  PubMed  Google Scholar 

  59. Yuan L, Moyon D, Pardanaud L, Breant C, Karkkainen MJ, Alitalo K et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 2002; 129: 4797–4806.

    CAS  PubMed  Google Scholar 

  60. Neufeld G, Kessler O . The semaphorins: versatile regulators of tumour progression and tumour angiogenesis [Review]. Nat Rev Cancer 2008; 8: 632–645.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Chang LK, Garcia-Cardena G, Farnebo F, Fannon M, Chen EJ, Butterfield C et al. Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA 2004; 101: 11658–11663.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 2004; 6: 333–345.

    CAS  PubMed  Google Scholar 

  64. Leong SP, Nakakura EK, Pollock R, Choti MA, Morton DL, Henner WD et al. Unique patterns of metastases in common and rare types of malignancy [Review]. J Surg Oncol 2011; 103: 607–614.

    PubMed  Google Scholar 

  65. Hoshida T, Isaka N, Hagendoorn J, di Tomaso E, Chen YL, Pytowski B et al. Imaging steps of lymphatic metastasis reveals that vascular endothelial growth factor-C increases metastasis by increasing delivery of cancer cells to lymph nodes: therapeutic implications. Cancer Res 2006; 66: 8065–8075.

    CAS  PubMed  Google Scholar 

  66. Catalano O, Caraco C, Mozzillo N, Siani A . Locoregional spread of cutaneous melanoma: sonography findings [Review]. Am J Roentgenol 2010; 194: 735–745.

    Google Scholar 

  67. van Akkooi AC, de Wilt JH, Verhoef C, Schmitz PI, van Geel AN, Eggermont AM et al. Clinical relevance of melanoma micrometastases (<0.1 mm) in sentinel nodes: are these nodes to be considered negative? Ann Oncol 2006; 17: 1578–1585.

    CAS  PubMed  Google Scholar 

  68. Moussai D, Mitsui H, Pettersen JS, Pierson KC, Shah KR, Suarez-Farinas M et al. The human cutaneous squamous cell carcinoma microenvironment is characterized by increased lymphatic density and enhanced expression of macrophage-derived VEGF-C. J Invest Dermatol 2011; 131: 229–236.

    CAS  PubMed  Google Scholar 

  69. Yang H, Kim C, Kim MJ, Schwendener RA, Alitalo K, Heston W et al. Soluble vascular endothelial growth factor receptor-3 suppresses lymphangiogenesis and lymphatic metastasis in bladder cancer. Mol Cancer 2011; 10: 36.

    PubMed  PubMed Central  Google Scholar 

  70. Ran S, Volk L, Hall K, Flister MJ . Lymphangiogenesis and lymphatic metastasis in breast cancer. Pathophysiology 2010; 17: 229–251.

    PubMed  Google Scholar 

  71. Rinderknecht M, Detmar M . Tumor lymphangiogenesis and melanoma metastasis [Review]. J Cell Physiol 2008; 216: 347–354.

    CAS  PubMed  Google Scholar 

  72. Thiele W, Sleeman JP . Tumor-induced lymphangiogenesis: a target for cancer therapy? [Review]. J Biotechnol 2006; 124: 224–241.

    CAS  PubMed  Google Scholar 

  73. Rinderknecht M, Detmar M . Molecular mechanisms of lymph node metastasisi. In: Stacker SA, Achen MG (eds). Lymphangiogenesis in Cancer Metastasis. Springer Science+Business Media BV, 2009.

    Google Scholar 

  74. He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S 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 2005; 65: 4739–4746.

    CAS  PubMed  Google Scholar 

  75. Burton JB, Priceman SJ, Sung JL, Brakenhielm E, An DS, Pytowski B et al. Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res 2008; 68: 7828–7837.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001; 7: 192–198.

    CAS  PubMed  Google Scholar 

  77. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 2001; 20: 672–682.

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Karpanen T, Egeblad M, Karkkainen MJ, Kubo H, Yla-Herttuala S, Jaattela M et al. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 2001; 61: 1786–1790.

    CAS  PubMed  Google Scholar 

  79. Tammela T, Saaristo A, Holopainen T, Yla-Herttuala S, Andersson LC, Virolainen S et al. Photodynamic ablation of lymphatic vessels and intralymphatic cancer cells prevents metastasis. Sci Transl Med 2011; 3: 69ra11.

    PubMed  Google Scholar 

  80. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001; 7: 186–191.

    CAS  PubMed  Google Scholar 

  81. Roberts N, Kloos B, Cassella M, Podgrabinska S, Persaud K, Wu Y et al. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res 2006; 66: 2650–2657.

    CAS  PubMed  Google Scholar 

  82. Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M . VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 2007; 109: 1010–1017.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Kyzas PA, Geleff S, Batistatou A, Agnantis NJ, Stefanou D . Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma. J Pathol 2005; 206: 170–177.

    PubMed  Google Scholar 

  84. Dadras SS, Lange-Asschenfeldt B, Velasco P, Nguyen L, Vora A, Muzikansky A et al. Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol 2005; 18: 1232–1242.

    PubMed  Google Scholar 

  85. Van den Eynden GG, Van der Auwera I, Colpaert CG, Dirix LY, Van Marck EA, Vermeulen PB . Letter to the editor: lymphangiogenesis in primary breast cancer. Cancer Lett 2007; 256: 279–281.

    CAS  PubMed  Google Scholar 

  86. Van der Auwera I, Van den Eynden GG, Colpaert CG, Van Laere SJ, van Dam P, Van Marck EA et al. Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study. Clin Cancer Res 2005; 11: 7637–7642.

    CAS  PubMed  Google Scholar 

  87. van der Schaft DW, Pauwels P, Hulsmans S, Zimmermann M, van de Poll-Franse LV, Griffioen AW . Absence of lymphangiogenesis in ductal breast cancer at the primary tumor site. Cancer Lett 2007; 254: 128–136.

    CAS  PubMed  Google Scholar 

  88. Kerjaschki D, Bago-Horvath Z, Rudas M, Sexl V, Schneckenleithner C, Wolbank S et al. Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse. J Clin Invest 2011; 121: 2000–2012.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Wong SY, Haack H, Crowley D, Barry M, Bronson RT, Hynes RO . Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Res 2005; 65: 9789–9798.

    CAS  PubMed  Google Scholar 

  90. Isaka N, Padera TP, Hagendoorn J, Fukumura D, Jain RK . Peritumor lymphatics induced by vascular endothelial growth factor-C exhibit abnormal function. Cancer Res 2004; 64: 4400–4404.

    CAS  PubMed  Google Scholar 

  91. Fukumura D, Duda DG, Munn LL, Jain RK . Tumor microvasculature and microenvironment: novel insights through intravital imaging in pre-clinical models [Review]. Microcirculation 2010; 17: 206–225.

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Azzali G . Tumor cell transendothelial passage in the absorbing lymphatic vessel of transgenic adenocarcinoma mouse prostate. Am J Pathol 2007; 170: 334–346.

    CAS  PubMed  PubMed Central  Google Scholar 

  93. Dadiani M, Kalchenko V, Yosepovich A, Margalit R, Hassid Y, Degani H et al. Real-time imaging of lymphogenic metastasis in orthotopic human breast cancer. Cancer Res 2006; 66: 8037–8041.

    CAS  PubMed  Google Scholar 

  94. Sahai E . Illuminating the metastatic process [Review]. Nat Rev Cancer 2007; 7: 737–749.

    CAS  PubMed  Google Scholar 

  95. Giampieri S, Manning C, Hooper S, Jones L, Hill CS, Sahai E . Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nat Cell Biol 2009; 11: 1287–1296.

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Kabashima K, Shiraishi N, Sugita K, Mori T, Onoue A, Kobayashi M et al. CXCL12-CXCR4 engagement is required for migration of cutaneous dendritic cells. Am J Pathol 2007; 171: 1249–1257.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Kim M, Koh YJ, Kim KE, Koh BI, Nam DH, Alitalo K et al. CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche. Cancer Res 2010; 70: 10411–10421.

    CAS  PubMed  Google Scholar 

  98. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50–56.

    CAS  PubMed  Google Scholar 

  99. Wiley HE, Gonzalez EB, Maki W, Wu MT, Hwang ST . Expression of CC chemokine receptor-7 and regional lymph node metastasis of B16 murine melanoma. J Natl Cancer Inst 2001; 93: 1638–1643.

    CAS  PubMed  Google Scholar 

  100. Christiansen A, Detmar M . Lymphangiogenesis and Cancer. Genes Cancer (e-pub ahead of print 3 October 2011).

    Google Scholar 

  101. Ruddell A, Harrell MI, Minoshima S, Maravilla KR, Iritani BM, White SW et al. Dynamic contrast-enhanced magnetic resonance imaging of tumor-induced lymph flow. Neoplasia 2008; 10: 706–713.

    PubMed  PubMed Central  Google Scholar 

  102. Proulx ST, Luciani P, Derzsi S, Rinderknecht M, Mumprecht V, Leroux JC et al. Quantitative imaging of lymphatic function with liposomal indocyanine green. Cancer Res 2010; 70: 7053–7062.

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Qian CN, Berghuis B, Tsarfaty G, Bruch M, Kort EJ, Ditlev J et al. Preparing the ‘soil’: the primary tumor induces vasculature reorganization in the sentinel lymph node before the arrival of metastatic cancer cells. Cancer Res 2006; 66: 10365–10376.

    CAS  PubMed  Google Scholar 

  104. Hirakawa S . From tumor lymphangiogenesis to lymphvascular niche [Review]. Cancer Sci 2009; 100: 983–989.

    CAS  PubMed  Google Scholar 

  105. Cady B . Regional lymph node metastases; a singular manifestation of the process of clinical metastases in cancer: contemporary animal research and clinical reports suggest unifying concepts [Review]. Ann Surg Oncol 2007; 14: 1790–1800.

    PubMed  Google Scholar 

  106. Viehl CT, Langer I, Guller U, Zanetti-Dallenbach R, Moch H, Wight E et al. Prognostic impact and therapeutic implications of sentinel lymph node micro-metastases in early-stage breast cancer patients [Review]. J Surg Oncol 2011; 103: 531–533.

    PubMed  Google Scholar 

  107. Krag DN, Anderson SJ, Julian TB, Brown AM, Harlow SP, Costantino JP et al. Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial. Lancet Oncol 2010; 11: 927–933.

    PubMed  PubMed Central  Google Scholar 

  108. Louis-Sylvestre C, Clough K, Asselain B, Vilcoq JR, Salmon RJ, Campana F et al. Axillary treatment in conservative management of operable breast cancer: dissection or radiotherapy? Results of a randomized study with 15 years of follow-up. J Clin Oncol 2004; 22: 97–101.

    PubMed  Google Scholar 

  109. Moehrle M, Schippert W, Rassner G, Garbe C, Breuninger H . Micrometastasis of a sentinel lymph node in cutaneous melanoma is a significant prognostic factor for disease-free survival, distant-metastasis-free survival, and overall survival. Dermatol Surg 2004; 30: 1319–1328.

    CAS  PubMed  Google Scholar 

  110. Leong SP, Zuber M, Ferris RL, Kitagawa Y, Cabanas R, Levenback C et al. Impact of nodal status and tumor burden in sentinel lymph nodes on the clinical outcomes of cancer patients [Review]. J Surg Oncol 2011; 103: 518–530.

    PubMed  Google Scholar 

  111. Clinicaltrials. Trial Identifier NCT01288989. US National Institutes of Health: Bethesda, MD.

  112. Lin J, Lalani AS, Harding TC, Gonzalez M, Wu WW, Luan B et al. Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res 2005; 65: 6901–6909.

    CAS  PubMed  Google Scholar 

  113. Maruyama K, Asai J, Ii M, Thorne T, Losordo DW, D’Amore PA . Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Pathol 2007; 170: 1178–1191.

    PubMed  PubMed Central  Google Scholar 

  114. Sung HK, Morisada T, Cho CH, Oike Y, Lee J, Sung EK et al. Intestinal and peri-tumoral lymphatic endothelial cells are resistant to radiation-induced apoptosis. Biochem Biophys Res Commun 2006; 345: 545–551.

    CAS  PubMed  Google Scholar 

  115. Mumprecht V, Honer M, Vigl B, Proulx ST, Trachsel E, Kaspar M et al. In vivo imaging of inflammation- and tumor-induced lymph node lymphangiogenesis by immuno-positron emission tomography. Cancer Res 2010; 70: 8842–8851.

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Work in the authors’ lab is supported by the Swiss National Science Foundation (grant numbers 3100A0108207and 31003A-130627); Commission of the European Communities (grant number LSHCCT2005518178); Advanced European Research Council (grant LYVICAM); and Oncosuisse and Krebsliga Zurich (to MD).

Author information

Authors and Affiliations

  1. Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland

    A Alitalo & M Detmar

Authors
  1. A Alitalo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M Detmar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M Detmar.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Alitalo, A., Detmar, M. Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 31, 4499–4508 (2012). https://doi.org/10.1038/onc.2011.602

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2011.602

This article is cited by

Search

Advanced search

Quick links