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Lymphangiogenesis and lymphatic vessel remodelling in cancer

Key Points

  • The lymphatic vasculature is essential for immune function, tissue fluid homeostasis and the absorption of dietary fat.

  • The process of lymphangiogenesis involves the formation of new lymphatic vessels from pre-existing lymphatics; this occurs during embryonic development, wound healing and in various pathological contexts, including cancer.

  • Tumour cells and cells of the tumour microenvironment produce growth factors that promote lymphangiogenesis from initial lymphatics, as well as the enlargement of initial and collecting lymphatic vessels in and around solid tumours. The enlargement of collecting lymphatics can involve remodelling of these vessels by smooth muscle cells.

  • Lymphangiogenic factors (such as vascular endothelial growth factor C (VEGFC) and VEGFD) can induce the metastatic spread of tumours in mouse models of cancer.

  • Clinicopathological studies have shown that the production of lymphangiogenic factors, lymphangiogenesis and lymphatic remodelling can correlate with cancer progression.

  • Lymphatic vessels provide a therapeutic target for modulating the immune response to cancer and restricting metastasis; clinical trials of agents that target lymphangiogenic signalling pathways are underway.

  • Mouse models and genome-wide functional screening approaches might identify further important signalling pathways in tumour lymphangiogenesis that could be potential diagnostic and therapeutic targets.

Abstract

The generation of new lymphatic vessels through lymphangiogenesis and the remodelling of existing lymphatics are thought to be important steps in cancer metastasis. The past decade has been exciting in terms of research into the molecular and cellular biology of lymphatic vessels in cancer, and it has been shown that the molecular control of tumour lymphangiogenesis has similarities to that of tumour angiogenesis. Nevertheless, there are significant mechanistic differences between these biological processes. We are now developing a greater understanding of the specific roles of distinct lymphatic vessel subtypes in cancer, and this provides opportunities to improve diagnostic and therapeutic approaches that aim to restrict the progression of cancer.

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Figure 1: Structure of the lymphatic vasculature and of lymphatic endothelial cells from initial lymphatics.
Figure 2: Remodelling of lymphatic vessels in cancer and its contribution to metastasis.
Figure 3: Mechanisms of tumour lymphangiogenesis and interactions between tumour cells and lymphatics.
Figure 4: Lymphangiogenesis and lymphatic remodelling in cancer — implications for diagnostics.

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References

  1. Tuttle, T. M. Technical Advances In Sentinel Lymph Node Biopsy For Breast Cancer. Am. Surg. 70, 407–413 (2004).

    PubMed  Google Scholar 

  2. Stacker, S. A. et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nature Med. 7, 186–191 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Mandriota, S. J. et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J. 20, 672–682 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Skobe, M. et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nature Med. 7, 192–198 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Karpanen, T. et al. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res. 61, 1786–1790 (2001).

    CAS  PubMed  Google Scholar 

  6. Karnezis, T. et al. VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell 21, 181–195 (2012). References 2–6 show the ability of VEGFC and VEGFD to promote tumour angiogenesis, lymphangiogenesis and lymphatic metastasis. They also show the potential of therapeutic approaches that target these growth factors and associated processes.

    Article  CAS  PubMed  Google Scholar 

  7. Gogineni, A. et al. Inhibition of VEGF-C modulates distal lymphatic remodeling and secondary metastasis. PLoS ONE 8, e68755 (2013). References 6 and 7 examine the molecular and cellular mechanisms whereby collecting lymphatics can control the rate of tumour metastasis, both proximal and distal to the sentinel lymph node.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hirakawa, S. et al. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 109, 1010–1017 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Achen, M. G., Mann, G. B. & Stacker, S. A. Targeting lymphangiogenesis to prevent tumour metastasis. Br. J. Cancer 94, 1355–1360 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mumprecht, V. et al. In vivo imaging of inflammation- and tumor-induced lymph node lymphangiogenesis by immuno-positron emission tomography. Cancer Res. 70, 8842–8851 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Asellius, G. De Lacteibus sive lacteis venis Quarto Vasorum Mesaroicum genere novo invente Gasp. Asellii Cremonensis Antomici Ticiensis Qua Sententiae Anatomicae multae, nel perperam receptae illustrantur. (Mediolani, 1627).

    Google Scholar 

  12. Gerli, R., Solito, R., Weber, E. & Agliano, M. Specific adhesion molecules bind anchoring filaments and endothelial cells in human skin initial lymphatics. Lymphology 33, 148–157 (2000).

    CAS  PubMed  Google Scholar 

  13. Baluk, P. et al. Functionally specialized junctions between endothelial cells of lymphatic vessels. J. Exp. Med. 204, 2349–2362 (2007). This manuscript reports on the specialized junctions used by LECs to allow them to participate in fluid transport while maintaining their integrity.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Miteva, D. O. et al. Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ. Res. 106, 920–931 (2010).

    Article  CAS  PubMed  Google Scholar 

  15. Alitalo, K. The lymphatic vasculature in disease. Nature Med. 17, 1371–1380 (2011). This is a comprehensive review of the role of lymphatics and the lymphatic endothelium in human disease.

    Article  CAS  PubMed  Google Scholar 

  16. Tammela, T. & Alitalo, K. Lymphangiogenesis: molecular mechanisms and future promise. Cell 140, 460–476 (2010).

    Article  CAS  PubMed  Google Scholar 

  17. Schulte-Merker, S., Sabine, A. & Petrova, T. V. Lymphatic vascular morphogenesis in development, physiology, and disease. J. Cell Biol. 193, 607–618 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Makinen, T. et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J. 20, 4762–4773 (2001). This study reports the isolation and biological characterization of LECs, including signalling pathways for growth, survival and migration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Shibuya, M. Vascular endothelial growth factor and its receptor system: physiological functions in angiogenesis and pathological roles in various diseases. J. Biochem. 153, 13–19 (2013).

    Article  CAS  PubMed  Google Scholar 

  20. Karpanen, T. et al. Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J. 20, 1462–1472 (2006).

    Article  CAS  PubMed  Google Scholar 

  21. Harris, N. C. 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. 25, 2615–2625 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Chung, A. S. & Ferrara, N. Developmental and pathological angiogenesis. Annu. Rev. Cell Dev. Biol. 27, 563–584 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Tammela, T. et al. VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling. Nature Cell Biol. 13, 1202–1213 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Zheng, W. et al. Notch restricts lymphatic vessel sprouting induced by vascular endothelial growth factor. Blood 118, 1154–1162 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Xu, Y. et al. Neuropilin-2 mediates VEGF-C-induced lymphatic sprouting together with VEGFR3. J. Cell Biol. 188, 115–130 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kriehuber, E. et al. Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J. Exp. Med. 194, 797–808 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Podgrabinska, S. et al. Molecular characterization of lymphatic endothelial cells. Proc. Natl Acad. Sci. USA 99, 16069–16074 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hirakawa, S. et al. Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am. J. Pathol. 162, 575–586 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wick, N. et al. Transcriptomal comparison of human dermal lymphatic endothelial cells ex vivo and in vitro. Physiol. Genomics 28, 179–192 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Kawai, Y. et al. Heterogeneity in immunohistochemical, genomic, and biological properties of human lymphatic endothelial cells between initial and collecting lymph vessels. Lymphat. Res. Biol. 6, 15–27 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Herbert, S. P. & Stainier, D. Y. Molecular control of endothelial cell behaviour during blood vessel morphogenesis. Nature Rev. Mol. Cell. Biol. 12, 551–564 (2011).

    Article  CAS  Google Scholar 

  32. Koltowska, K., Betterman, K. L., Harvey, N. L. & Hogan, B. M. Getting out and about: the emergence and morphogenesis of the vertebrate lymphatic vasculature. Development 140, 1857–1870 (2013).

    Article  CAS  PubMed  Google Scholar 

  33. Hogan, B. M. et al. Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nature Genet. 41, 396–398 (2009).

    Article  CAS  PubMed  Google Scholar 

  34. Farnsworth, R. H., Achen, M. G. & Stacker, S. A. Lymphatic endothelium: an important interactive surface for malignant cells. Pulm. Pharmacol. Ther. 19, 51–60 (2006).

    Article  CAS  PubMed  Google Scholar 

  35. Dadras, S. S. et al. Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am. J. Pathol. 162, 1951–1960 (2003). This paper helps to establish that tumour lymphangiogenesis has prognostic importance in human cancers: in this case, cutaneous melanoma.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Leu, A. J., Berk, D. A., Lymboussaki, A., Alitalo, K. & Jain, R. K. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res. 60, 4324–4327 (2000).

    CAS  PubMed  Google Scholar 

  37. Padera, T. P. et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296, 1883–1886 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Shayan, R. et al. Tumor location and nature of lymphatic vessels are key determinants of cancer metastasis. Clin. Exp. Metastasis 30, 345–356 (2013).

    Article  CAS  PubMed  Google Scholar 

  39. Wong, S. Y. et al. Tumor-secreted vascular endothelial growth factor-C is necessary for prostate cancer lymphangiogenesis, but lymphangiogenesis is unnecessary for lymph node metastasis. Cancer Res. 65, 9789–9798 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. Karpanen, T. & Alitalo, K. Lymphatic vessels as targets of tumor therapy. J. Exp. Med. 194, F37–F42 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Krishnan, J. et al. 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, 713–722 (2003).

    CAS  PubMed  Google Scholar 

  42. Ji, R. C. Lymphatic endothelial cells, tumor lymphangiogenesis and metastasis: new insights into intratumoral and peritumoral lymphatics. Cancer Metastasis Rev. 25, 677–694 (2006).

    Article  PubMed  Google Scholar 

  43. Hoshida, T. 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. 66, 8065–8075 (2006). This study uses mouse models and intravital microscopy to show that factors such as VEGFC can increase the delivery of cancer cells to lymph nodes, through mechanisms such as hyperplasia of peritumoural lymphatic vessels.

    Article  CAS  PubMed  Google Scholar 

  44. He, Y. 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. 65, 4739–4746 (2005).

    Article  CAS  PubMed  Google Scholar 

  45. Joukov, V. et al. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 16, 3898–3911 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Siegfried, G. et al. The secretory proprotein convertases furin, PC5, and PC7 activate VEGF-C to induce tumorigenesis. J. Clin. Invest. 111, 1723–1732 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Stacker, S. A. et al. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J. Biol. Chem. 274, 32127–32136 (1999).

    Article  CAS  PubMed  Google Scholar 

  48. Baldwin, M. E. et al. Multiple forms of mouse vascular endothelial growth factor-D are generated by RNA splicing and proteolysis. J. Biol. Chem. 276, 44307–44314 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. McColl, B. K. et al. Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. J. Exp. Med. 198, 863–868 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. McColl, B. K. et al. Proprotein convertases promote processing of VEGF-D, a critical step for binding the angiogenic receptor VEGFR-2. FASEB J. 21, 1088–1098 (2007). References 45–50 describe the important role that proteolysis has in the activation of key lymphangiogenic growth factors.

    Article  CAS  PubMed  Google Scholar 

  51. Schoppmann, S. F. et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am. J. Pathol. 161, 947–956 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kerjaschki, D. The crucial role of macrophages in lymphangiogenesis. J. Clin. Invest. 115, 2316–2319 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Debinski, W. et al. VEGF-D is an X-linked/AP-1 regulated putative onco-angiogen in human glioblastoma multiforme. Mol. Med. 7, 598–608 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tvorogov, D. et al. Effective suppression of vascular network formation by combination of antibodies blocking VEGFR ligand binding and receptor dimerization. Cancer Cell 18, 630–640 (2010).

    Article  CAS  PubMed  Google Scholar 

  55. Pytowski, B. et al. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J. Natl Cancer Inst. 97, 14–21 (2005).

    Article  CAS  PubMed  Google Scholar 

  56. Roberts, N. 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. 66, 2650–2657 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. He, Y. et al. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J. Natl Cancer Inst. 94, 819–825 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Lin, J. et al. Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res. 65, 6901–6909 (2005).

    Article  CAS  PubMed  Google Scholar 

  59. Laakkonen, P. et al. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res. 67, 593–599 (2007).

    Article  CAS  PubMed  Google Scholar 

  60. Caunt, M. et al. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13, 331–342 (2008).

    Article  CAS  PubMed  Google Scholar 

  61. Niederleithner, H. et al. Wnt1 is anti-lymphangiogenic in a melanoma mouse model. J. Invest. Dermatol. 132, 2235–2244 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Su, J. L. et al. Cyclooxygenase-2 induces EP1- and HER-2/Neu-dependent vascular endothelial growth factor-C up-regulation: a novel mechanism of lymphangiogenesis in lung adenocarcinoma. Cancer Res. 64, 554–564 (2004).

    Article  CAS  PubMed  Google Scholar 

  63. Timoshenko, A. V., Chakraborty, C., Wagner, G. F. & Lala, P. K. COX-2-mediated stimulation of the lymphangiogenic factor VEGF-C in human breast cancer. Br. J. Cancer 94, 1154–1163 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Soumaoro, L. T. et al. Coexpression of VEGF-C and Cox-2 in human colorectal cancer and its association with lymph node metastasis. Dis. Colon Rectum 49, 392–398 (2006).

    Article  PubMed  Google Scholar 

  65. Kubo, H. et al. Host prostaglandin EP3 receptor signaling relevant to tumor-associated lymphangiogenesis. Biomed. Pharmacother. 64, 101–106 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Hosono, K. et al. Roles of prostaglandin E2-EP3/EP4 receptor signaling in the enhancement of lymphangiogenesis during fibroblast growth factor-2-induced granulation formation. Arterioscler. Thromb. Vasc. Biol. 31, 1049–1058 (2011).

    Article  CAS  PubMed  Google Scholar 

  67. Zhang, X. H. et al. Coexpression of VEGF-C and COX-2 and its association with lymphangiogenesis in human breast cancer. BMC Cancer 8, 4 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Bjorndahl, M. A. et al. Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res. 65, 9261–9268 (2005).

    Article  PubMed  Google Scholar 

  69. Hirakawa, S. et al. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J. Exp. Med. 201, 1089–1099 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Fagiani, E., Lorentz, P., Kopfstein, L. & Christofori, G. Angiopoietin-1 and -2 exert antagonistic functions in tumor angiogenesis, yet both induce lymphangiogenesis. Cancer Res. 71, 5717–5727 (2011).

    Article  CAS  PubMed  Google Scholar 

  71. Holopainen, T. et al. Effects of angiopoietin-2-blocking antibody on endothelial cell-cell junctions and lung metastasis. J. Natl Cancer Inst. 104, 461–475 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Cao, R. et al. Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. Proc. Natl Acad. Sci. USA 109, 15894–15899 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Cao, R. et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 6, 333–345 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Schito, L. et al. Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells. Proc. Natl Acad. Sci. USA 109, E2707–E2716 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  75. Yoo, Y. A. et al. Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. Cancer Res. 71, 7061–7070 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Lee, A. S. et al. Erythropoietin induces lymph node lymphangiogenesis and lymph node tumor metastasis. Cancer Res. 71, 4506–4517 (2011).

    Article  CAS  PubMed  Google Scholar 

  77. Karpinich, N. O. et al. Adrenomedullin gene dosage correlates with tumor and lymph node lymphangiogenesis. FASEB J. 27, 590–600 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Nagahashi, M. et al. Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis. Cancer Res. 72, 726–735 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Bracher, A. et al. Epidermal growth factor facilitates melanoma lymph node metastasis by influencing tumor lymphangiogenesis. J. Invest. Dermatol. 133, 230–238 (2013).

    Article  CAS  PubMed  Google Scholar 

  80. Patel, V. et al. Decreased lymphangiogenesis and lymph node metastasis by mTOR inhibition in head and neck cancer. Cancer Res. 71, 7103–7112 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Oka, M. et al. Inhibition of endogenous TGF-β signaling enhances lymphangiogenesis. Blood 111, 4571–4579 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Garmy-Susini, B. et al. Integrin α4β1 signaling is required for lymphangiogenesis and tumor metastasis. Cancer Res. 70, 3042–3051 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Iwasaki, T. et al. Deletion of tetraspanin CD9 diminishes lymphangiogenesis in vivo and in vitro. J. Biol. Chem. 288, 2118–2131 (2013).

    Article  CAS  PubMed  Google Scholar 

  84. Clasper, S. et al. A novel gene expression profile in lymphatics associated with tumor growth and nodal metastasis. Cancer Res. 68, 7293–7303 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Forster, R., Davalos-Misslitz, A. C. & Rot, A. CCR7 and its ligands: balancing immunity and tolerance. Nature Rev. Immunol. 8, 362–371 (2008).

    Article  CAS  Google Scholar 

  86. Shields, J. D. et al. Chemokine-mediated migration of melanoma cells towards lymphatics — a mechanism contributing to metastasis. Oncogene 26, 2997–3005 (2007).

    Article  CAS  PubMed  Google Scholar 

  87. Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).

    Article  CAS  PubMed  Google Scholar 

  88. Kawada, K. et al. Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes. Cancer Res. 64, 4010–4017 (2004).

    Article  CAS  PubMed  Google Scholar 

  89. Uchida, D. et al. Acquisition of lymph node, but not distant metastatic potentials, by the overexpression of CXCR4 in human oral squamous cell carcinoma. Lab. Invest. 84, 1538–1546 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Kawada, K. et al. Chemokine receptor CXCR3 promotes colon cancer metastasis to lymph nodes. Oncogene 26, 4679–4688 (2007).

    Article  CAS  PubMed  Google Scholar 

  91. Gunther, K. et al. Prediction of lymph node metastasis in colorectal carcinoma by expression of chemokine receptor CCR7. Int. J. Cancer 116, 726–733 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Cabioglu, N. et al. CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clin. Cancer Res. 11, 5686–5693 (2005).

    Article  CAS  PubMed  Google Scholar 

  93. Mashino, K. et al. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res. 62, 2937–2941 (2002).

    CAS  PubMed  Google Scholar 

  94. Schimanski, C. C. et al. Dissemination of hepatocellular carcinoma is mediated via chemokine receptor CXCR4. Br. J. Cancer 95, 210–217 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ishikawa, T. et al. CXCR4 expression is associated with lymph-node metastasis of oral squamous cell carcinoma. Int. J. Oncol. 28, 61–66 (2006).

    CAS  PubMed  Google Scholar 

  96. Salvucci, O. et al. The role of CXCR4 receptor expression in breast cancer: a large tissue microarray study. Breast Cancer Res. Treat. 97, 275–283 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Hirakawa, S. et al. Nodal lymphangiogenesis and metastasis: role of tumor-induced lymphatic vessel activation in extramammary Paget's disease. Am. J. Pathol. 175, 2235–2248 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Shields, J. D. et al. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11, 526–538 (2007). This study shows how lymphatic drainage influences interstitial fluid flow and this can direct tumour cell migration through an autocrine CCR7 signalling pathway.

    Article  CAS  PubMed  Google Scholar 

  99. Munson, J. M., Bellamkonda, R. V. & Swartz, M. A. Interstitial flow in a 3D microenvironment increases glioma invasion by a CXCR4-dependent mechanism. Cancer Res. 73, 1536–1546 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Issa, A., Le, T. X., Shoushtari, A. N., Shields, J. D. & Swartz, M. A. Vascular endothelial growth factor-C and C-C chemokine receptor 7 in tumor cell-lymphatic cross-talk promote invasive phenotype. Cancer Res. 69, 349–357 (2009).

    Article  CAS  PubMed  Google Scholar 

  101. Das, S. et al. Tumor cell entry into the lymph node is controlled by CCL1 chemokine expressed by lymph node lymphatic sinuses. J. Exp. Med. 210, 1509–1528 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Wirzenius, M. et al. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J. Exp. Med. 204, 1431–1440 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Hirakawa, S. From tumor lymphangiogenesis to lymphvascular niche. Cancer Sci. 100, 983–989 (2009).

    Article  CAS  PubMed  Google Scholar 

  104. Coultas, L., Chawengsaksophak, K. & Rossant, J. Endothelial cells and VEGF in vascular development. Nature 438, 937–945 (2005).

    Article  CAS  PubMed  Google Scholar 

  105. Farnsworth, R. H. et al. A role for bone morphogenic protein-4 in vascular endothelial growth factor-D mediated tumor growth, metastasis and vessel remodelling. Cancer Res. 71, 6547–6557 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Kim, M. et al. CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche. Cancer Res. 70, 10411–10421 (2010).

    Article  CAS  PubMed  Google Scholar 

  107. Lyden, D. et al. Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nature Med. 7, 1194–1201 (2001).

    Article  CAS  PubMed  Google Scholar 

  108. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438, 820–827 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Tewalt, E. F., Cohen, J. N., Rouhani, S. J. & Engelhard, V. H. Lymphatic endothelial cells — key players in regulation of tolerance and immunity. Front. Immunol. 3, 305 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Tewalt, E. F. et al. Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood 120, 4772–4782 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Lund, A. W. et al. VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. Cell Rep. 1, 191–199 (2012). This paper describes how VEGFC is able to promote immune tolerance in a melanoma model and that the lymphatic endothelium might be a target for immunomodulation in the local microenvironment.

    Article  CAS  PubMed  Google Scholar 

  112. Swartz, M. A. & Lund, A. W. Lymphatic and interstitial flow in the tumour microenvironment: linking mechanobiology with immunity. Nature Rev. Cancer 12, 210–219 (2012). This review brings together several disparate areas — mechanobiology, fluid dynamics, cell biology and the immune system — to try and understand the interplay between these factors in the role of the lymphatics in cancer progression.

    Article  CAS  Google Scholar 

  113. Wang, J. et al. Lymphatic microvessel density and vascular endothelial growth factor-C and -D as prognostic factors in breast cancer: a systematic review and meta-analysis of the literature. Mol. Biol. Rep. 39, 11153–11165 (2012).

    Article  CAS  PubMed  Google Scholar 

  114. Liersch, R., Hirakawa, S., Berdel, W. E., Mesters, R. M. & Detmar, M. Induced lymphatic sinus hyperplasia in sentinel lymph nodes by VEGF-C as the earliest premetastatic indicator. Int. J. Oncol. 41, 2073–2078 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Fisher, B. et al. Relation of number of positive axillary nodes to the prognosis of patients with primary breast cancer. An NSABP update. Cancer 52, 1551–1557 (1983).

    Article  CAS  PubMed  Google Scholar 

  116. Foster, R. S. Jr. The biologic and clinical significance of lymphatic metastases in breast cancer. Surg. Oncol. Clin. N. Am. 5, 79–104 (1996).

    Article  PubMed  Google Scholar 

  117. Wong, S. L. et al. Sentinel lymph node biopsy for melanoma: American Society of Clinical Oncology and Society of Surgical Oncology joint clinical practice guideline. J. Clin. Oncol. 30, 2912–2918 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  118. D'Angelo-Donovan, D. D., Dickson-Witmer, D. & Petrelli, N. J. Sentinel lymph node biopsy in breast cancer: a history and current clinical recommendations. Surg. Oncol. 21, 196–200 (2012).

    Article  PubMed  Google Scholar 

  119. Harouaka, R. A., Nisic, M. & Zheng, S. Y. Circulating tumor cell enrichment based on physical properties. J. Lab. Autom. http://dx.doi.org/10.1177/2211068213494391 (2013).

  120. Gonzalez-Masia, J. A., Garcia-Olmo, D. & Garcia-Olmo, D. C. Circulating nucleic acids in plasma and serum (CNAPS): applications in oncology. Onco. Targets Ther. 6, 819–832 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  121. Peinado, H. et al. Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET. Nature Med. 18, 883–891 (2012).

    Article  CAS  PubMed  Google Scholar 

  122. Ran, S., Volk, L., Hall, K. & Flister, M. J. Lymphangiogenesis and lymphatic metastasis in breast cancer. Pathophysiology 17, 229–251 (2010). This is a comprehensive review of lymphangiogenesis and lymphatic metastasis in relation to breast cancer.

    Article  PubMed  Google Scholar 

  123. Achen, M. G., McColl, B. K. & Stacker, S. A. Focus on lymphangiogenesis in tumor metastasis. Cancer Cell 7, 121–127 (2005).

    Article  CAS  PubMed  Google Scholar 

  124. Alitalo, A. & Detmar, M. Interaction of tumor cells and lymphatic vessels in cancer progression. Oncogene 31, 4499–4508 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Doeden, K. et al. Lymphatic invasion in cutaneous melanoma is associated with sentinel lymph node metastasis. J. Cutan. Pathol. 36, 772–780 (2009).

    Article  PubMed  Google Scholar 

  126. Saad, R. S. et al. Lymphatic microvessel density as prognostic marker in colorectal cancer. Mod. Pathol. 19, 1317–1323 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Van der Auwera, I. et al. Increased angiogenesis and lymphangiogenesis in inflammatory versus noninflammatory breast cancer by real-time reverse transcriptase-PCR gene expression quantification. Clin. Cancer Res. 10, 7965–7971 (2004).

    Article  CAS  PubMed  Google Scholar 

  128. Williams, C. S. et al. Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer. J. Pathol. 200, 195–206 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Sipos, B. et al. Lymphatic spread of ductal pancreatic adenocarcinoma is independent of lymphangiogenesis. J. Pathol. 207, 301–312 (2005).

    Article  CAS  PubMed  Google Scholar 

  130. Stacker, S. A., Williams, R. A. & Achen, M. G. Lymphangiogenic growth factors as markers of tumor metastasis. APMIS 112, 539–549 (2004).

    Article  CAS  PubMed  Google Scholar 

  131. Yonemura, Y. et al. Role of vascular endothelial growth factor C expression in the development of lymph node metastasis in gastric cancer. Clin. Cancer Res. 5, 1823–1829 (1999).

    CAS  PubMed  Google Scholar 

  132. Yokoyama, Y. et al. Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma. Clin. Cancer Res. 9, 1361–1369 (2003).

    CAS  PubMed  Google Scholar 

  133. White, J. D. et al. Vascular endothelial growth factor-D expression is an independent prognostic marker for survival in colorectal carcinoma. Cancer Res. 62, 1669–1675 (2002).

    CAS  PubMed  Google Scholar 

  134. Proulx, S. T. et al. Expansion of the lymphatic vasculature in cancer and inflammation: New opportunities for in vivo imaging and drug delivery. J. Control Release 172, 550–557 (2013).

    Article  CAS  PubMed  Google Scholar 

  135. Mumprecht, V. & Detmar, M. In vivo imaging of lymph node lymphangiogenesis by immuno-positron emission tomography. Methods Mol. Biol. 961, 129–140 (2013).

    Article  CAS  PubMed  Google Scholar 

  136. Mumprecht, V., Roudnicky, F. & Detmar, M. Inflammation-induced lymph node lymphangiogenesis is reversible. Am. J. Pathol. 180, 874–879 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Veikkola, T. et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J. 20, 1223–1231 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Dadras, S. S. et al. Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod. Pathol. 18, 1232–1242 (2005).

    Article  PubMed  Google Scholar 

  139. Tammela, T. et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454, 656–660 (2008).

    Article  CAS  PubMed  Google Scholar 

  140. Siekmann, A. F. & Lawson, N. D. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445, 781–784 (2007).

    Article  CAS  PubMed  Google Scholar 

  141. Madsen, C. D. & Sahai, E. Cancer dissemination-lessons from leukocytes. Dev. Cell 19, 13–26 (2010).

    Article  CAS  PubMed  Google Scholar 

  142. Neal, J. & Wakelee, H. AMG-386, a selective angiopoietin-1/-2-neutralizing peptibody for the potential treatment of cancer. Curr. Opin. Mol. Ther. 12, 487–495 (2010).

    CAS  PubMed  Google Scholar 

  143. Sun, W. & Haller, D. G. Adjuvant therapy of colon cancer. Semin. Oncol. 32, 95–102 (2005).

    Article  CAS  PubMed  Google Scholar 

  144. Matsumoto, M. et al. Signaling for lymphangiogenesis via VEGFR-3 is required for the early events of metastasis. Clin. Exp. Metastasis 30, 819–832 (2013).

    Article  CAS  PubMed  Google Scholar 

  145. Banerji, S. et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J. Cell Biol. 144, 789–801 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Breiteneder-Geleff, S. et al. Podoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis. Am. J. Pathol. 151, 1141–1152 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Makinen, T. et al. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev. 19, 397–410 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Schacht, V. et al. Up-regulation of the lymphatic marker podoplanin, a mucin-type transmembrane glycoprotein, in human squamous cell carcinomas and germ cell tumors. Am. J. Pathol. 166, 913–921 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Boone, B. et al. The role of VEGF-C staining in predicting regional metastasis in melanoma. Virchows Arch. 453, 257–265 (2008).

    Article  CAS  PubMed  Google Scholar 

  150. Schietroma, C. et al. Vascular endothelial growth factor-C expression correlates with lymph node localization of human melanoma metastases. Cancer 98, 789–797 (2003).

    Article  CAS  PubMed  Google Scholar 

  151. Tobler, N. E. & Detmar, M. Tumor and lymph node lymphangiogenesis — impact on cancer metastasis. J. Leukoc. Biol. 80, 691–696 (2006).

    Article  CAS  PubMed  Google Scholar 

  152. Xu, X. et al. Lymphatic invasion is independently prognostic of metastasis in primary cutaneous melanoma. Clin. Cancer Res. 18, 229–237 (2012).

    Article  PubMed  Google Scholar 

  153. Raica, M., Cimpean, A. M., Ceausu, R. & Ribatti, D. Lymphatic microvessel density, VEGF-C, and VEGFR-3 expression in different molecular types of breast cancer. Anticancer Res. 31, 1757–1764 (2011).

    CAS  PubMed  Google Scholar 

  154. Mohammed, R. A. et al. Prognostic significance of vascular endothelial cell growth factors -A, -C and -D in breast cancer and their relationship with angio- and lymphangiogenesis. Br. J. Cancer 96, 1092–1100 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Gu, Y., Qi, X. & Guo, S. Lymphangiogenesis induced by VEGF-C and VEGF-D promotes metastasis and a poor outcome in breast carcinoma: a retrospective study of 61 cases. Clin. Exp. Metastasis 25, 717–725 (2008).

    Article  CAS  PubMed  Google Scholar 

  156. Koyama, Y. et al. Vascular endothelial growth factor-C and vascular endothelial growth factor-d messenger RNA expression in breast cancer: association with lymph node metastasis. Clin. Breast Cancer 4, 354–360 (2003).

    Article  CAS  PubMed  Google Scholar 

  157. Gisterek, I. et al. Evaluation of prognostic value of VEGF-C and VEGF-D in breast cancer — 10 years follow-up analysis. Anticancer Res. 27, 2797–2802 (2007).

    CAS  PubMed  Google Scholar 

  158. Nakamura, Y. et al. Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer. Breast Cancer Res. Treat. 91, 125–132 (2005).

    Article  CAS  PubMed  Google Scholar 

  159. Agarwal, B., Saxena, R., Morimiya, A., Mehrotra, S. & Badve, S. Lymphangiogenesis does not occur in breast cancer. Am. J. Surg. Pathol. 29, 1449–1455 (2005).

    Article  PubMed  Google Scholar 

  160. Bono, P. et al. High LYVE-1-positive lymphatic vessel numbers are associated with poor outcome in breast cancer. Clin. Cancer Res. 10, 7144–7149 (2004).

    Article  CAS  PubMed  Google Scholar 

  161. Mohammed, R. A., Ellis, I. O., Elsheikh, S., Paish, E. C. & Martin, S. G. Lymphatic and angiogenic characteristics in breast cancer: morphometric analysis and prognostic implications. Breast Cancer Res. Treat. 113, 261–273 (2009).

    Article  PubMed  Google Scholar 

  162. Marinho, V. F., Metze, K., Sanches, F. S., Rocha, G. F. & Gobbi, H. Lymph vascular invasion in invasive mammary carcinomas identified by the endothelial lymphatic marker D2-40 is associated with other indicators of poor prognosis. BMC Cancer 8, 64 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Travagli, J. P. et al. Sentinel lymphadenectomy without systematic axillary dissection in breast cancer patients: predictors of non-sentinel lymph node metastasis. Eur. J. Surg. Oncol. 29, 403–406 (2003).

    Article  PubMed  Google Scholar 

  164. Arnaout-Alkarain, A., Kahn, H. J., Narod, S. A., Sun, P. A. & Marks, A. N. Significance of lymph vessel invasion identified by the endothelial lymphatic marker D2-40 in node negative breast cancer. Mod. Pathol. 20, 183–191 (2007).

    Article  CAS  PubMed  Google Scholar 

  165. Moehler, M. et al. VEGF-D expression correlates with colorectal cancer aggressiveness and is downregulated by cetuximab. World J. Gastroenterol. 14, 4156–4167 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Fukunaga, S. et al. Association between expression of vascular endothelial growth factor C, chemokine receptor CXCR4 and lymph node metastasis in colorectal cancer. Oncology 71, 204–211 (2006).

    Article  CAS  PubMed  Google Scholar 

  167. Doekhie, F. S. et al. Sialyl Lewis X expression and lymphatic microvessel density in primary tumors of node-negative colorectal cancer patients predict disease recurrence. Cancer Microenviron. 1, 141–151 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Matsumoto, K. et al. Lymphatic microvessel density is an independent prognostic factor in colorectal cancer. Dis. Colon Rectum 50, 308–314 (2007).

    Article  PubMed  Google Scholar 

  169. Kaneko, I. et al. Lymphatic vessel density at the site of deepest penetration as a predictor of lymph node metastasis in submucosal colorectal cancer. Dis. Colon Rectum 50, 13–21 (2007).

    Article  PubMed  Google Scholar 

  170. Barresi, V., Reggiani-Bonetti, L., Di Gregorio, C., De Leon, M. P. & Barresi, G. Lymphatic vessel density and its prognostic value in stage I colorectal carcinoma. J. Clin. Pathol. 64, 6–12 (2011).

    Article  CAS  PubMed  Google Scholar 

  171. Schoppmann, A. et al. Comparison of lymphangiogenesis between primary colorectal cancer and corresponding liver metastases. Anticancer Res. 31, 4605–4611 (2011).

    PubMed  Google Scholar 

  172. Akagi, Y., Adachi, Y., Ohchi, T., Kinugasa, T. & Shirouzu, K. Prognostic impact of lymphatic invasion of colorectal cancer: a single-center analysis of 1,616 patients over 24 years. Anticancer Res. 33, 2965–2970 (2013).

    PubMed  Google Scholar 

  173. Barresi, V. et al. Immunohistochemical assessment of lymphovascular invasion in stage I colorectal carcinoma: prognostic relevance and correlation with nodal micrometastases. Am. J. Surg. Pathol. 36, 66–72 (2012).

    Article  PubMed  Google Scholar 

  174. Lim, S. B. et al. Prognostic significance of lymphovascular invasion in sporadic colorectal cancer. Dis. Colon Rectum 53, 377–384 (2010).

    Article  PubMed  Google Scholar 

  175. Kojima, H. et al. Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer 104, 1668–1677 (2005).

    Article  CAS  PubMed  Google Scholar 

  176. Ogawa, E. et al. Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients. Br. J. Cancer 91, 498–503 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Takanami, I. Lymphatic microvessel density using D2-40 is associated with nodal metastasis in non-small cell lung cancer. Oncol. Rep. 15, 437–442 (2006).

    PubMed  Google Scholar 

  178. Adachi, Y. et al. Lymphatic vessel density in pulmonary adenocarcinoma immunohistochemically evaluated with anti-podoplanin or anti-D2-40 antibody is correlated with lymphatic invasion or lymph node metastases. Pathol. Int. 57, 171–177 (2007).

    Article  CAS  PubMed  Google Scholar 

  179. Renyi-Vamos, F. et al. Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin. Cancer Res. 11, 7344–7353 (2005).

    Article  CAS  PubMed  Google Scholar 

  180. Higgins, K. A. et al. Lymphovascular invasion in non-small-cell lung cancer: implications for staging and adjuvant therapy. J. Thorac. Oncol. 7, 1141–1147 (2012).

    Article  PubMed  Google Scholar 

  181. Schmid, K., Birner, P., Gravenhorst, V., End, A. & Geleff, S. Prognostic value of lymphatic and blood vessel invasion in neuroendocrine tumors of the lung. Am. J. Surg. Pathol. 29, 324–328 (2005).

    Article  PubMed  Google Scholar 

  182. Hanagiri, T. et al. Prognostic significance of lymphovascular invasion for patients with stage I non-small cell lung cancer. Eur. Surg. Res. 47, 211–217 (2011).

    Article  CAS  PubMed  Google Scholar 

  183. Hajrasouliha, A. R. et al. Vascular endothelial growth factor-C promotes alloimmunity by amplifying antigen-presenting cell maturation and lymphangiogenesis. Invest. Ophthalmol. Vis. Sci. 53, 1244–1250 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Achen, M. G. et al. Monoclonal antibodies to vascular endothelial growth factor-D block its interactions with both VEGF receptor-2 and VEGF receptor-3. Eur. J. Biochem. 267, 2505–2515 (2000).

    Article  CAS  PubMed  Google Scholar 

  185. Davydova, N., Roufail, S., Streltsov, V. A., Stacker, S. A. & Achen, M. G. The VD1 neutralizing antibody to vascular endothelial growth factor-D: binding epitope and relationship to receptor binding. J. Mol. Biol. 407, 581–593 (2011).

    Article  CAS  PubMed  Google Scholar 

  186. Kashima, K. et al. Inhibition of lymphatic metastasis in neuroblastoma by a novel neutralizing antibody to vascular endothelial growth factor-D. Cancer Sci. 103, 2144–2152 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Makinen, T. et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nature Med. 7, 199–205 (2001).

    Article  CAS  PubMed  Google Scholar 

  188. Albuquerque, R. J. et al. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nature Med. 15, 1023–1030 (2009).

    Article  CAS  PubMed  Google Scholar 

  189. Persaud, K. et al. Involvement of the VEGF receptor 3 in tubular morphogenesis demonstrated with a human anti-human VEGFR-3 monoclonal antibody that antagonizes receptor activation by VEGF-C. J. Cell Sci. 117, 2745–2756 (2004).

    Article  CAS  PubMed  Google Scholar 

  190. Procopio, G. et al. Experience with sorafenib in the treatment of advanced renal cell carcinoma. Ther. Adv. Urol. 4, 303–313 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Verweij, J. & Sleijfer, S. Pazopanib, a new therapy for metastatic soft tissue sarcoma. Expert. Opin. Pharmacother. 14, 929–935 (2013).

    Article  CAS  PubMed  Google Scholar 

  192. Mankal, P. & O'Reilly, E. Sunitinib malate for the treatment of pancreas malignancies — where does it fit? Expert. Opin. Pharmacother. 14, 783–792 (2013).

    Article  CAS  PubMed  Google Scholar 

  193. Kodera, Y. et al. Sunitinib inhibits lymphatic endothelial cell functions and lymph node metastasis in a breast cancer model through inhibition of vascular endothelial growth factor receptor 3. Breast Cancer Res. 13, R66 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Grunwald, V. & Merseburger, A. S. Axitinib for the treatment of patients with advanced metastatic renal cell carcinoma (mRCC) after failure of prior systemic treatment. Onco. Targets Ther. 5, 111–117 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  195. Davis, S. L., Eckhardt, S. G., Messersmith, W. A. & Jimeno, A. The development of regorafenib and its current and potential future role in cancer therapy. Drugs Today (Barc) 49, 105–115 (2013).

    Article  CAS  Google Scholar 

  196. Hudkins, R. L. et al. Synthesis and biological profile of the pan-vascular endothelial growth factor receptor/tyrosine kinase with immunoglobulin and epidermal growth factor-like homology domains 2 (VEGF-R/TIE-2) inhibitor 11-(2-methylpropyl)-12,13-dihydro-2-methyl-8-(pyrimidin-2-ylamino)-4H-indazolo[5, 4-a]pyrrolo[3,4-c]carbazol-4-one: a novel oncology therapeutic agent. J. Med. Chem. 55, 903–913 (2012).

    Article  CAS  PubMed  Google Scholar 

  197. Karnezis, T., Shayan, R., Fox, S., Achen, M. G. & Stacker, S. A. The connection between lymphangiogenic signalling and prostaglandin biology: a missing link in the metastatic pathway. Oncotarget 3, 893–906 (2012).

    Article  PubMed  Google Scholar 

  198. Joukov, V. et al. 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, 290–298 (1996); erratum 15, 1751 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Achen, M. G. et al. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc. Natl Acad. Sci. USA 95, 548–553 (1998). References 198 and 199 describe the characterization of VEGFC and VEGFD and their relationship to the VEGF family, as well as their proteolytic cleavage and activity on endothelial cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Qian, C. N. 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. 66, 10365–10376 (2006). References 69 and 200 highlight that primary tumours might prepare future sites of metastasis, such as lymph nodes, by releasing lymphangiogenic growth factors.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

S.A.S., T.K. and M.G.A. are supported by Project Grants, a Program Grant and Research Fellowships from the National Health and Medical Research Council (NHMRC) of Australia, and by funds from the Operational Infrastructure Support Program that is provided by the Victorian Government, Australia. R.S. has been supported by the Raelene Boyle Sporting Chance Cancer Foundation and the Royal Australasian College of Surgeons (RACS) Foundation Scholarship, as well as the RACS Surgeon Scientist Program. S.P.W. has been supported by an Australian National Breast Cancer Foundation Doctoral Research Fellowship. The authors thank M. Macheda for proofreading.

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Correspondence to Steven A. Stacker or Marc G. Achen.

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Competing interests

S.A.S. and M.G.A. have both been consultants for Vegenics Limited, South Yarra, Victoria, Australia, in the area of developing inhibitors of angiogenesis and lymphangiogenesis in human diseases, including cancer. This consultancy ended on 31 December 2012. S.A.S., R.S. and M.G.A. are shareholders in Circadian Technologies (owner of Vegenics), South Yarra, Victoria, Australia, which is a company that develops anticancer therapeutics, and in Ark Therapeutics Group Plc, London, UK, which has been developing therapeutic approaches based on the vascular endothelial growth factor family. S.A.S., S.B.F. and M.G.A. are holders of an Australian National Health and Medical Research Council (NHMRC) Program Grant. S.A.S. and M.G.A. are holders of NHMRC Senior Research Fellowships in this area. S.A.S., S.B.F., T.K. and M.G.A. are holders of NHMRC Project Grants in this area. S.A.S. and M.G.A. are holders of numerous patents in this area. S.P.W. declares no competing interests.

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Glossary

Lymphangiogenesis

The formation of new lymphatic vessels from pre-existing lymphatics.

Lymphatic enlargement

The enlargement of lymphatics, which can occur via proliferation of lymphatic endothelial cells (that is, hyperplasia) or other non-proliferative mechanisms.

Lymphatic hyperplasia

The enlargement of lymphatics by proliferation of lymphatic endothelial cells, which may or may not be accompanied by sprouting.

Initial lymphatics

Small blind-ended lymphatics in the tissue periphery that are adapted for the uptake of fluid and cells.

Collecting lymphatics

Large lymphatics that are characterized by a continuous smooth muscle cell coating and are adapted for the transport of lymph and associated cells.

Lymphatic remodelling in cancer

Alteration to the structure and morphology of lymphatic vessels that are associated with cancer, including lymphangiogenesis and lymphatic enlargement.

Lymphatic invasion

The entry of tumour cells into lymphatics, which is identified clinicopathologically by the detection of tumour cells or tumour cell emboli within lymphatics.

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Stacker, S., Williams, S., Karnezis, T. et al. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer 14, 159–172 (2014). https://doi.org/10.1038/nrc3677

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