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Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?

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Journal of Mammary Gland Biology and Neoplasia Aims and scope Submit manuscript

Abstract

Research in lymphatic biology and cancer immunology may soon intersect as emerging evidence implicates the lymphatics in the progression of chronic inflammation and autoimmunity as well as in tumor metastasis and immune escape. Like the blood vasculature, the lymphatic system comprises a highly dynamic conduit system that regulates fluid homeostasis, antigen transport and immune cell trafficking, which all play important roles in the progression and resolution of inflammation, autoimmune diseases, and cancer. This review presents emerging evidence that lymphatic vessels are active modulators of immunity, perhaps fine-tuning the response to adjust the balance between peripheral tolerance and immunity. This suggests that the tumor-associated lymphatic vessels and draining lymph node may be important in tumor immunity which in turn governs metastasis.

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Figure 1
Figure 2

Abbreviations

APC:

antigen‐presenting cell

CCL19/21:

C‐C chemokine ligand 19/21

CCR7:

C-C chemokine receptor 7

CXCL13:

C-X-C Chemokine ligand 13

DC:

dendritic cell

FRC:

fibroblastic reticular cell

LN:

lymph node

TLO:

tertiary lymphoid organ

TReg cell:

regulatory T cell

VEGF:

vascular endothelial growth factor

References

  1. Tammela T, Alitalo K. Lymphangiogenesis: molecular mechanisms and future promise. Cell. 2010;140(4):460–76.

    Article  PubMed  CAS  Google Scholar 

  2. Itano AA, McSorley SJ, Reinhardt RL, Ehst BD, Ingulli E, Rudensky AY, et al. Distinct dendritic cell populations sequentially present antigen to CD4 T cells and stimulate different aspects of cell-mediated immunity. Immunity. 2003;19(1):47–57.

    Article  PubMed  CAS  Google Scholar 

  3. Pape KA, Catron DM, Itano AA, Jenkins MK. The humoral immune response is initiated in lymph nodes by B cells that acquire soluble antigen directly in the follicles. Immunity. 2007;26(4):491–502.

    Article  PubMed  CAS  Google Scholar 

  4. Wilson NS, El-Sukkari D, Belz GT, Smith CM, Steptoe RJ, Heath WR, et al. Most lymphoid organ dendritic cell types are phenotypically and functionally immature. Blood. 2003;102(6):2187–94.

    Article  PubMed  CAS  Google Scholar 

  5. Randolph GJ, Angeli V, Swartz MA. Dendritic-cell trafficking to lymph nodes through lymphatic vessels. Nat Rev Immunol. 2005;5(8):617–28.

    Article  PubMed  CAS  Google Scholar 

  6. Förster R, Davalos-Misslitz A, Rot A. CCR7 and its ligands: balancing immunity and tolerance. Nat Rev Immunol. 2008;8(5):362–71.

    Article  PubMed  CAS  Google Scholar 

  7. Reynoso ED, Lee JW, Turley SJ. Peripheral tolerance induction by lymph node stroma. Adv Exp Med Biol. 2009;633:113–27.

    Article  PubMed  Google Scholar 

  8. Cohen JN, Guidi CJ, Tewalt EF, Qiao H, Rouhani SJ, Ruddell A, et al. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J Exp Med. 2010;207(4):681–8.

    Article  PubMed  CAS  Google Scholar 

  9. Kraal G, Samsom JN, Mebius RE. The importance of regional lymph nodes for mucosal tolerance. Immunol Rev. 2006;213:119–30.

    Article  PubMed  Google Scholar 

  10. Ji RC. Lymphatic endothelial cells, inflammatory lymphangiogenesis, and prospective players. Curr Med Chem. 2007;14(22):2359–68.

    Article  PubMed  CAS  Google Scholar 

  11. Patel SP, Dana R. Corneal lymphangiogenesis: implications in immunity. Semin Ophthalmol. 2009;24(3):135–8.

    Article  PubMed  Google Scholar 

  12. Kerjaschki D, Regele HM, Moosberger I, Nagy-Bojarski K, Watschinger B, Soleiman A, et al. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol. 2004;15(3):603–12.

    Article  PubMed  CAS  Google Scholar 

  13. Nasr IW, Reel M, Oberbarnscheidt MH, Mounzer RH, Baddoura FK, Ruddle NH, et al. Tertiary lymphoid tissues generate effector and memory T cells that lead to allograft rejection. Am J Transplant. 2007;7(5):1071–9.

    Article  PubMed  CAS  Google Scholar 

  14. Angeli V, Ginhoux F, Llodra J, Quemeneur L, Frenette PS, Skobe M, et al. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity. 2006;24(2):203–15.

    Article  PubMed  CAS  Google Scholar 

  15. Jell G, Kerjaschki D, Revell P, Al-Saffar N. Lymphangiogenesis in the bone-implant interface of orthopedic implants: importance and consequence. J Biomed Mater Res A. 2006;77A(1):119–27.

    Article  CAS  Google Scholar 

  16. 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(9):3158–67.

    Article  PubMed  CAS  Google Scholar 

  17. Achen MG, McColl BK, Stacker SA. Focus on lymphangiogenesis in tumor metastasis. Cancer Cell. 2005;7(2):121–7.

    Article  PubMed  CAS  Google Scholar 

  18. 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(3):1010–7.

    Article  PubMed  CAS  Google Scholar 

  19. Hirakawa S, Detmar M, Kerjaschki D, Nagamatsu S, Matsuo K, Tanemura A, et al. Nodal lymphangiogenesis and metastasis role of tumor-induced lymphatic vessel activation in extramammary paget’s disease. Am J Pathol. 2009;175(5):2235–48.

    Article  PubMed  Google Scholar 

  20. 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(3):893–903.

    PubMed  CAS  Google Scholar 

  21. Liersch R, Biermann C, Mesters RM, Berdel WE. Lymphangiogenesis in cancer: current perspectives. Recent Results Cancer Res. 2010;180:115–35.

    Article  PubMed  CAS  Google Scholar 

  22. Ohtani O, Shao XJ, Saitoh M, Ohtani Y. Lymphatics of the rat mammary gland during virgin, pregnant, lactating and post-weaning periods. Ital J Anat Embryol. 1998;103(4 Suppl 1):335–42.

    PubMed  CAS  Google Scholar 

  23. Raharison F, Sautet J. The topography of the lymph vessels of mammary glands in female cats. Anat Histol Embryol. 2007;36(6):442–52.

    Article  PubMed  CAS  Google Scholar 

  24. Heath TJ, Kerlin RL. Lymph drainage from the mammary gland in sheep. J Anat. 1986;144:61–70.

    PubMed  CAS  Google Scholar 

  25. Mylona E, Alexandrou P, Mpakali A, Giannopoulou I, Liapis G, Markaki S, et al. Clinicopathological and prognostic significance of vascular endothelial growth factors (VEGF)-C and -D and VEGF receptor 3 in invasive breast carcinoma. Eur J Surg Oncol. 2007;33(3):294–300.

    Article  PubMed  CAS  Google Scholar 

  26. Pereira CT, Rahal SC, de Carvalho Balieiro JC, Ribeiro AA. Lymphatic drainage on healthy and neoplasic mammary glands in female dogs: can it really be altered? Anat Histol Embryol. 2003;32(5):282–90.

    Article  PubMed  CAS  Google Scholar 

  27. Ran S, Volk L, Hall K, Flister MJ. Lymphangiogenesis and lymphatic metastasis in breast cancer. Pathophysiology. 2010;17(4):229–51.

    Article  PubMed  Google Scholar 

  28. Maby-El Hajjami H, Petrova TV. Developmental and pathological lymphangiogenesis: from models to human disease. Histochem Cell Biol. 2008;130(6):1063–78.

    Article  PubMed  CAS  Google Scholar 

  29. Wick N, Saharinen P, Saharinen J, Gurnhofer E, Steiner CW, Raab I, et al. Transcriptomal comparison of human dermal lymphatic endothelial cells ex vivo and in vitro. Physiol Genomics. 2007;28(2):179–92.

    PubMed  CAS  Google Scholar 

  30. Baluk P, Fuxe J, Hashizume H, Romano T, Lashnits E, Butz S, et al. Functionally specialized junctions between endothelial cells of lymphatic vessels. J Exp Med. 2007;204(10):2349–62.

    Article  PubMed  CAS  Google Scholar 

  31. Tammela T, Saaristo A, Holopainen T, Lyytikka J, Kotronen A, Pitkonen M, et al. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat Med. 2007;13(12):1458–66.

    Article  PubMed  CAS  Google Scholar 

  32. Schmid-Schonbein GW. The second valve system in lymphatics. Lymphat Res Biol. 2003;1(1):25–9. discussion 29-31.

    Article  PubMed  Google Scholar 

  33. Schmid-Schonbein GW. Microlymphatics and lymph flow. Physiol Rev. 1990;70(4):987–1028.

    PubMed  CAS  Google Scholar 

  34. Zawieja DC. Contractile physiology of lymphatics. Lymphat Res Biol. 2009;7(2):87–96.

    Article  PubMed  Google Scholar 

  35. Bazigou E, Xie S, Chen C, Weston A, Miura N, Sorokin L, et al. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell. 2009;17(2):175–86.

    Article  PubMed  CAS  Google Scholar 

  36. Quick CM, Venugopal AM, Gashev AA, Zawieja DC, Stewart RH. Intrinsic pump-conduit behavior of lymphangions. Am J Physiol Regul Integr Comp Physiol. 2007;292(4):R1510–8.

    PubMed  CAS  Google Scholar 

  37. 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(4):1202–9.

    Article  PubMed  CAS  Google Scholar 

  38. Baluk P, Yao LC, Feng J, Romano T, Jung SS, Schreiter JL, et al. TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice. J Clin Invest. 2009;119(10):2954–64.

    PubMed  CAS  Google Scholar 

  39. 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(4):1733–45.

    Article  PubMed  CAS  Google Scholar 

  40. Miteva DO, Rutkowski JM, Dixon JB, Kilarski W, Shields JD, Swartz MA. Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ Res. 2010;106(5):920–31.

    Article  PubMed  CAS  Google Scholar 

  41. Tomei AA, Siegert S, Britschgi MR, Luther SA, Swartz MA. Fluid flow regulates stromal cell organization and CCL21 expression in a tissue-engineered lymph node microenvironment. J Immunol. 2009;183(7):4273–83.

    Article  PubMed  CAS  Google Scholar 

  42. Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell. 2007;11(6):526–38.

    Article  PubMed  CAS  Google Scholar 

  43. Fleury ME, Boardman KC, Swartz MA. Autologous morphogen gradients by subtle interstitial flow and matrix interactions. Biophys J. 2006;91(1):113–21.

    Article  PubMed  CAS  Google Scholar 

  44. Roozendaal R, Mempel TR, Pitcher LA, Gonzalez SF, Verschoor A, Mebius RE, et al. Conduits mediate transport of low-molecular-weight antigen to lymph node follicles. Immunity. 2009;30(2):264–76.

    Article  PubMed  CAS  Google Scholar 

  45. Boardman KC, Swartz MA. Interstitial flow as a guide for lymphangiogenesis. Circ Res. 2003;92(7):801–8.

    Article  PubMed  CAS  Google Scholar 

  46. Rutkowski JM, Boardman KC, Swartz MA. Characterization of lymphangiogenesis in a model of adult skin regeneration. Am J Physiol Heart Circ Physiol. 2006;291(3):H1402–10.

    Article  PubMed  CAS  Google Scholar 

  47. Ng CP, Helm CL, Swartz MA. Interstitial flow differentially stimulates blood and lymphatic endothelial cell morphogenesis in vitro. Microvasc Res. 2004;68(3):258–64.

    Article  PubMed  Google Scholar 

  48. Helm CL, Fleury ME, Zisch AH, Boschetti F, Swartz MA. Synergy between interstitial flow and VEGF directs capillary morphogenesis in vitro through a gradient amplification mechanism. Proc Natl Acad Sci USA. 2005;102(44):15779–84.

    Article  PubMed  CAS  Google Scholar 

  49. Helm CL, Zisch A, Swartz MA. Engineered blood and lymphatic capillaries in 3-D VEGF-fibrin-collagen matrices with interstitial flow. Biotechnol Bioeng. 2007;96(1):167–76.

    Article  PubMed  CAS  Google Scholar 

  50. Rutkowski JM, Moya M, Johannes J, Goldman J, Swartz MA. Secondary lymphedema in the mouse tail: Lymphatic hyperplasia, VEGF-C upregulation, and the protective role of MMP-9. Microvasc Res. 2006;72(3):161–71.

    Article  PubMed  CAS  Google Scholar 

  51. Angeli V, Randolph GJ. Inflammation, lymphatic function, and dendritic cell migration. Lymphat Res Biol. 2006;4(4):217–28.

    Article  PubMed  CAS  Google Scholar 

  52. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009;21(2):154–65.

    Article  PubMed  CAS  Google Scholar 

  53. Adams RH, Alitalo K. Molecular regulation of angiogenesis and lymphangiogenesis. Nat Rev Mol Cell Biol. 2007;8(6):464–78.

    Article  PubMed  CAS  Google Scholar 

  54. Pytowski B, Goldman J, Persaud K, Wu Y, Witte L, Hicklin DJ, et al. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst. 2005;97(1):14–21.

    Article  PubMed  CAS  Google Scholar 

  55. Alitalo K, Tammela T, Petrova TV. Lymphangiogenesis in development and human disease. Nature. 2005;438(7070):946–53.

    Article  PubMed  CAS  Google Scholar 

  56. Bajenoff M, Germain RN. B-cell follicle development remodels the conduit system and allows soluble antigen delivery to follicular dendritic cells. Blood. 2009;114(24):4989–97.

    Article  PubMed  CAS  Google Scholar 

  57. Sixt M, Kanazawa N, Selg M, Samson T, Roos G, Reinhardt DP, et al. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity. 2005;22(1):19–29.

    Article  PubMed  CAS  Google Scholar 

  58. Schumann K, Lammermann T, Bruckner M, Legler DF, Polleux J, Spatz JP, et al. Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns of dendritic cells. Immunity. 2010;32(5):703–13.

    Article  PubMed  CAS  Google Scholar 

  59. Stachowiak AN, Wang Y, Huang YC, Irvine DJ. Homeostatic lymphoid chemokines synergize with adhesion ligands to trigger T and B lymphocyte chemokinesis. J Immunol. 2006;177(4):2340–8.

    PubMed  CAS  Google Scholar 

  60. Angel CE, Chen CJ, Horlacher OC, Winkler S, John T, Browning J, et al. Distinctive localization of antigen-presenting cells in human lymph nodes. Blood. 2009;113(6):1257–67.

    Article  PubMed  CAS  Google Scholar 

  61. Mebius RE, Streeter PR, Breve J, Duijvestijn AM, Kraal G. The influence of afferent lymphatic vessel interruption on vascular addressin expression. J Cell Biol. 1991;115(1):85–95.

    Article  PubMed  CAS  Google Scholar 

  62. Drayton DL, Liao S, Mounzer RH, Ruddle NH. Lymphoid organ development: from ontogeny to neogenesis. Nat Immunol. 2006;7(4):344–53.

    Article  PubMed  CAS  Google Scholar 

  63. Mebius RE. Organogenesis of lymphoid tissues. Nat Rev Immunol. 2003;3(4):292–303.

    Article  PubMed  CAS  Google Scholar 

  64. Mori S, Nakano H, Aritomi K, Wang CR, Gunn MD, Kakiuchi T. Mice lacking expression of the chemokines CCL21-ser and CCL19 (plt mice) demonstrate delayed but enhanced T cell immune responses. J Exp Med. 2001;193(2):207–18.

    Article  PubMed  CAS  Google Scholar 

  65. Luther SA, Bidgol A, Hargreaves DC, Schmidt A, Xu Y, Paniyadi J, et al. Differing activities of homeostatic chemokines CCL19, CCL21, and CXCL12 in lymphocyte and dendritic cell recruitment and lymphoid neogenesis. J Immunol. 2002;169(1):424–33.

    PubMed  CAS  Google Scholar 

  66. Ohl L, Henning G, Krautwald S, Lipp M, Hardtke S, Bernhardt G, et al. Cooperating mechanisms of CXCR5 and CCR7 in development and organization of secondary lymphoid organs. J Exp Med. 2003;197(9):1199–204.

    Article  PubMed  CAS  Google Scholar 

  67. Mueller SN, Ahmed R. Lymphoid stroma in the initiation and control of immune responses. Immunol Rev. 2008;224:284–94.

    Article  PubMed  CAS  Google Scholar 

  68. Pabst O, Wahl B, Bernhardt G, Hammerschmidt SI. Mesenteric lymph node stroma cells in the generation of intestinal immune responses. J Mol Med. 2009;87(10):945–51.

    Article  PubMed  Google Scholar 

  69. Hammerschmidt SI, Ahrendt M, Bode U, Wahl B, Kremmer E, Forster R, et al. Stromal mesenteric lymph node cells are essential for the generation of gut-homing T cells in vivo. J Exp Med. 2008;205(11):2483–90.

    Article  PubMed  CAS  Google Scholar 

  70. Davalos-Misslitz AC, Rieckenberg J, Willenzon S, Worbs T, Kremmer E, Bernhardt G, et al. Generalized multi-organ autoimmunity in CCR7-deficient mice. Eur J Immunol. 2007;37(3):613–22.

    Article  PubMed  CAS  Google Scholar 

  71. Achtman AH, Hopken UE, Bernert C, Lipp M. CCR7-deficient mice develop atypically persistent germinal centers in response to thymus-independent type 2 antigens. J Leukoc Biol. 2009;85(3):409–17.

    Article  PubMed  CAS  Google Scholar 

  72. Henning G, Ohl L, Junt T, Reiterer P, Brinkmann V, Nakano H, et al. CC chemokine receptor 7-dependent and -independent pathways for lymphocyte homing: modulation by FTY720. J Exp Med. 2001;194(12):1875–81.

    Article  PubMed  CAS  Google Scholar 

  73. Gunn MD, Kyuwa S, Tam C, Kakiuchi T, Matsuzawa A, Williams LT, et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med. 1999;189(3):451–60.

    Article  PubMed  CAS  Google Scholar 

  74. Nakano H, Mori S, Yonekawa H, Nariuchi H, Matsuzawa A, Kakiuchi T. A novel mutant gene involved in T-lymphocyte-specific homing into peripheral lymphoid organs on mouse chromosome 4. Blood. 1998;91(8):2886–95.

    PubMed  CAS  Google Scholar 

  75. Stein JV, Rot A, Luo Y, Narasimhaswamy M, Nakano H, Gunn MD, et al. The CC chemokine thymus-derived chemotactic agent 4 (TCA-4, secondary lymphoid tissue chemokine, 6Ckine, exodus-2) triggers lymphocyte function-associated antigen 1-mediated arrest of rolling T lymphocytes in peripheral lymph node high endothelial venules. J Exp Med. 2000;191(1):61–76.

    Article  PubMed  CAS  Google Scholar 

  76. Warnock RA, Campbell JJ, Dorf ME, Matsuzawa A, McEvoy LM, Butcher EC. The role of chemokines in the microenvironmental control of T versus B cell arrest in Peyer’s patch high endothelial venules. J Exp Med. 2000;191(1):77–88.

    Article  PubMed  CAS  Google Scholar 

  77. Hofmann J, Greter M, Du Pasquier L, Becher B. B-cells need a proper house, whereas T-cells are happy in a cave: the dependence of lymphocytes on secondary lymphoid tissues during evolution. Trends Immunol. 2010;31(4):144–53.

    Article  PubMed  CAS  Google Scholar 

  78. Ochando JC, Yopp AC, Yang Y, Garin A, Li Y, Boros P, et al. Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells. J Immunol. 2005;174(11):6993–7005.

    PubMed  CAS  Google Scholar 

  79. Menning A, Hopken UE, Siegmund K, Lipp M, Hamann A, Huehn J. Distinctive role of CCR7 in migration and functional activity of naive- and effector/memory-like Treg subsets. Eur J Immunol. 2007;37(6):1575–83.

    Article  PubMed  CAS  Google Scholar 

  80. Schneider MA, Meingassner JG, Lipp M, Moore HD, Rot A. CCR7 is required for the in vivo function of CD4+ CD25+ regulatory T cells. J Exp Med. 2007;204(4):735–45.

    Article  PubMed  CAS  Google Scholar 

  81. Zhang N, Schroppel B, Lal G, Jakubzick C, Mao X, Chen D, et al. Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. Immunity. 2009;30(3):458–69.

    Article  PubMed  CAS  Google Scholar 

  82. Ueha S, Yoneyama H, Hontsu S, Kurachi M, Kitabatake M, Abe J, et al. CCR7 mediates the migration of Foxp3+ regulatory T cells to the paracortical areas of peripheral lymph nodes through high endothelial venules. J Leukoc Biol. 2007;82(5):1230–8.

    Article  PubMed  CAS  Google Scholar 

  83. Eller K, Weber T, Pruenster M, Wolf AM, Mayer G, Rosenkranz AR, et al. CCR7 deficiency exacerbates injury in acute nephritis due to aberrant localization of regulatory T cells. J Am Soc Nephrol. 2010;21(1):42–52.

    Article  PubMed  CAS  Google Scholar 

  84. Jin Y, Chauhan SK, Saban DR, Dana R. Role of CCR7 in facilitating direct allosensitization and regulatory T-cell function in high-risk corneal transplantation. Invest Ophthalmol Vis Sci. 2010;51(2):816–21.

    Article  PubMed  Google Scholar 

  85. Ahrendt M, Hammerschmidt SI, Pabst O, Pabst R, Bode U. Stromal cells confer lymph node-specific properties by shaping a unique microenvironment influencing local immune responses. J Immunol. 2008;181(3):1898–907.

    PubMed  CAS  Google Scholar 

  86. Wolvers DA, Coenen-de Roo CJ, Mebius RE, van der Cammen MJ, Tirion F, Miltenburg AM, et al. Intranasally induced immunological tolerance is determined by characteristics of the draining lymph nodes: studies with OVA and human cartilage gp-39. J Immunol. 1999;162(4):1994–8.

    PubMed  CAS  Google Scholar 

  87. Lee JW, Epardaud M, Sun J, Becker JE, Cheng AC, Yonekura AR, et al. Peripheral antigen display by lymph node stroma promotes T cell tolerance to intestinal self. Nat Immunol. 2007;8(2):181–90.

    Article  PubMed  CAS  Google Scholar 

  88. Kyewski B, Klein L. A central role for central tolerance. Annu Rev Immunol. 2006;24:571–606.

    Article  PubMed  CAS  Google Scholar 

  89. Collier AY, Lee JW, Turley SJ. Self-encounters of the third kind: lymph node stroma promotes tolerance to peripheral tissue antigens. Mucosal Immunol. 2008;1(4):248–51.

    Article  PubMed  CAS  Google Scholar 

  90. Fletcher AL, Lukacs-Kornek V, Reynoso ED, Pinner SE, Bellemare-Pelletier A, Curry MS, et al. Lymph node fibroblastic reticular cells directly present peripheral tissue antigen under steady-state and inflammatory conditions. J Exp Med. 2010;207(4):689–97.

    Article  PubMed  CAS  Google Scholar 

  91. Turley SJ, Lee JW, Dutton-Swain N, Mathis D, Benoist C. Endocrine self and gut non-self intersect in the pancreatic lymph nodes. Proc Natl Acad Sci USA. 2005;102(49):17729–33.

    Article  PubMed  CAS  Google Scholar 

  92. Shrestha B, Hashiguchi T, Ito T, Miura N, Takenouchi K, Oyama Y, et al. B cell-derived vascular endothelial growth factor a promotes lymphangiogenesis and high endothelial venule expansion in lymph nodes. J Immunol. 2010;184(9):4819–26.

    Article  PubMed  CAS  Google Scholar 

  93. Liao S, Ruddle NH. Synchrony of high endothelial venules and lymphatic vessels revealed by immunization. J Immunol. 2006;177(5):3369–79.

    PubMed  CAS  Google Scholar 

  94. Vondenhoff MF, Greuter M, Goverse G, Elewaut D, Dewint P, Ware CF, et al. LTbetaR signaling induces cytokine expression and up-regulates lymphangiogenic factors in lymph node anlagen. J Immunol. 2009;182(9):5439–45.

    Article  PubMed  CAS  Google Scholar 

  95. Ruddle NH, Akirav EM. Secondary lymphoid organs: responding to genetic and environmental cues in ontogeny and the immune response. J Immunol. 2009;183(4):2205–12.

    Article  PubMed  CAS  Google Scholar 

  96. Aloisi F, Pujol-Borrell R. Lymphoid neogenesis in chronic inflammatory diseases. Nat Rev Immunol. 2006;6(3):205–17.

    Article  PubMed  CAS  Google Scholar 

  97. Martin AP, Coronel EC, Sano G, Chen SC, Vassileva G, Canasto-Chibuque C, et al. A novel model for lymphocytic infiltration of the thyroid gland generated by transgenic expression of the CC chemokine CCL21. J Immunol. 2004;173(8):4791–8.

    PubMed  CAS  Google Scholar 

  98. Heller F, Lindenmeyer MT, Cohen CD, Brandt U, Draganovici D, Fischereder M, et al. The contribution of B cells to renal interstitial inflammation. Am J Pathol. 2007;170(2):457–68.

    Article  PubMed  CAS  Google Scholar 

  99. Fan L, Reilly CR, Luo Y, Dorf ME, Lo D. Cutting edge: ectopic expression of the chemokine TCA4/SLC is sufficient to trigger lymphoid neogenesis. J Immunol. 2000;164(8):3955–9.

    PubMed  CAS  Google Scholar 

  100. Chen SC, Vassileva G, Kinsley D, Holzmann S, Manfra D, Wiekowski MT, et al. Ectopic expression of the murine chemokines CCL21a and CCL21b induces the formation of lymph node-like structures in pancreas, but not skin, of transgenic mice. J Immunol. 2002;168(3):1001–8.

    PubMed  CAS  Google Scholar 

  101. Thaunat O, Kerjaschki D, Nicoletti A. Is defective lymphatic drainage a trigger for lymphoid neogenesis? Trends Immunol. 2006;27(10):441–5.

    Article  PubMed  CAS  Google Scholar 

  102. Flister MJ, Wilber A, Hall KL, Iwata C, Miyazono K, Nisato RE, et al. Inflammation induces lymphangiogenesis through up-regulation of VEGFR-3 mediated by NF-kappaB and Prox1. Blood. 2009;115(2):418–29.

    Article  PubMed  CAS  Google Scholar 

  103. 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(2):247–57.

    PubMed  CAS  Google Scholar 

  104. Watari K, Nakao S, Fotovati A, Basaki Y, Hosoi F, Bereczky B, et al. Role of macrophages in inflammatory lymphangiogenesis: enhanced production of vascular endothelial growth factor C and D through NF-kappaB activation. Biochem Biophys Res Commun. 2008;377(3):826–31.

    Article  PubMed  CAS  Google Scholar 

  105. Kajiya K, Detmar M. An important role of lymphatic vessels in the control of UVB-induced edema formation and inflammation. J Invest Dermatol. 2006;126(4):919–21.

    Article  PubMed  CAS  Google Scholar 

  106. 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(4):1048–57.

    Article  PubMed  CAS  Google Scholar 

  107. Leong TT, Fearon U, Veale DJ. Angiogenesis in psoriasis and psoriatic arthritis: clues to disease pathogenesis. Curr Rheumatol Rep. 2005;7(4):325–9.

    Article  PubMed  CAS  Google Scholar 

  108. Danese S, Sans M, de la Motte C, Graziani C, West G, Phillips MH, et al. Angiogenesis as a novel component of inflammatory bowel disease pathogenesis. Gastroenterology. 2006;130(7):2060–73.

    Article  PubMed  CAS  Google Scholar 

  109. Schonthaler HB, Huggenberger R, Wculek SK, Detmar M, Wagner EF. Systemic anti-VEGF treatment strongly reduces skin inflammation in a mouse model of psoriasis. Proc Natl Acad Sci USA. 2009;106(50):21264–9.

    Article  PubMed  CAS  Google Scholar 

  110. Yao LC, Baluk P, Feng J, McDonald DM. Steroid-resistant lymphatic remodeling in chronically inflamed mouse airways. Am J Pathol. 2010;176(3):1525–41.

    Article  PubMed  CAS  Google Scholar 

  111. Stuht S, Gwinner W, Franz I, Schwarz A, Jonigk D, Kreipe H, et al. Lymphatic neoangiogenesis in human renal allografts: results from sequential protocol biopsies. Am J Transplant. 2007;7(2):377–84.

    Article  PubMed  CAS  Google Scholar 

  112. Ling S, Qi C, Li W, Xu J, Kuang W. Crucial role of corneal lymphangiogenesis for allograft rejection in alkali-burned cornea bed. Clin Experiment Ophthalmol. 2009;37(9):874–83.

    Article  PubMed  Google Scholar 

  113. Ling S, Qi C, Li W, Xu J, Kuang W. The expression of vascular endothelial growth factor C in transplanted corneas. Curr Eye Res. 2009;34(7):553–61.

    Article  PubMed  CAS  Google Scholar 

  114. Chung ES, Saban DR, Chauhan SK, Dana R. Regulation of blood vessel versus lymphatic vessel growth in the cornea. Invest Ophthalmol Vis Sci. 2009;50(4):1613–8.

    Article  PubMed  Google Scholar 

  115. Nathanson SD. Insights into the mechanisms of lymph node metastasis. Cancer. 2003;98(2):413–23.

    Article  PubMed  Google Scholar 

  116. Amioka T, Kitadai Y, Tanaka S, Haruma K, Yoshihara M, Yasui W, et al. Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa. Eur J Cancer. 2002;38(10):1413–9.

    Article  PubMed  CAS  Google Scholar 

  117. Arinaga M, Noguchi T, Takeno S, Chujo M, Miura T, Uchida Y. Clinical significance of vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 in patients with nonsmall cell lung carcinoma. Cancer. 2003;97(2):457–64.

    Article  PubMed  CAS  Google Scholar 

  118. Clarijs R, Schalkwijk L, Ruiter DJ, de Waal RM. Lack of lymphangiogenesis despite coexpression of VEGF-C and its receptor Flt-4 in uveal melanoma. Invest Ophthalmol Vis Sci. 2001;42(7):1422–8.

    PubMed  CAS  Google Scholar 

  119. Leu AJ, Berk DA, Lymboussaki A, Alitalo K, Jain RK. Absence of functional lymphatics within a murine sarcoma: a molecular and functional evaluation. Cancer Res. 2000;60(16):4324–7.

    PubMed  CAS  Google Scholar 

  120. 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(5574):1883–6.

    Article  PubMed  CAS  Google Scholar 

  121. Issa A, Le TX, Shoushtari AN, Shields JD, Swartz MA. Vascular endothelial growth factor-C and C-C chemokine receptor 7 in tumor cell-lymphatic cross-talk promote invasive phenotype. Cancer Res. 2009;69(1):349–57.

    Article  PubMed  CAS  Google Scholar 

  122. Sipos B, Kojima M, Tiemann K, Klapper W, Kruse ML, Kalthoff H, et al. Lymphatic spread of ductal pancreatic adenocarcinoma is independent of lymphangiogenesis. J Pathol. 2005;207(3):301–12.

    Article  PubMed  CAS  Google Scholar 

  123. 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(21):9789–98.

    Article  PubMed  CAS  Google Scholar 

  124. Kataru RP, Jung K, Jang C, Yang H, Schwendener RA, Baik JE, et al. Critical role of CD11b+ macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood. 2009;113(22):5650–9.

    Article  PubMed  CAS  Google Scholar 

  125. Jennbacken K, Vallbo C, Wang WZ, et al. Expression of vascular endothelial growth factor C (VEGF‐C) and VEGF receptor‐3 in human prostate cancer is associated with regional lymph node metastasis. Prostate. 2005;65(2):110–116.

    Google Scholar 

  126. Jenny B, Harrison JA, Baetens D, et al. Expression and localization of VEGF‐C and VEGFR‐3 in glioblastomas and haemangioblastomas. J Pathol. 2006;209(1):34–43.

    Google Scholar 

  127. Li J, Hong M, Pan T. Clinical significance of VEGF‐C and VEGFR‐3 expression in non‐small cell lung cancer. J Huazhong Univ Sci Technolog Med Sci. 2006;26(5):587–90.

    Google Scholar 

  128. Filho AL, Martins A, Costa SMA, et al. VEGFR‐3 expression in breast cancer tissue is not restricted to lymphatic vessels. Pathology Research and Practice. 2005;201(2):93–99.

    Google Scholar 

  129. Su JL, Yang PC, Shih JY, et al. The VEGF‐C/Flt‐4 axis promotes invasion and metastasis of cancer cells. Cancer Cell. 2006;9(3):209–23.

    Google Scholar 

  130. Shields JD, Kourtis IC, Tomei AA, et al. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science. 2010;328(5979):749–52.

    Article  PubMed  CAS  Google Scholar 

  131. Harrell MI, Iritani BM, Ruddell A. Tumor‐induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am J Pathol. 2007;170(2):774–86.

    Google Scholar 

  132. Ruddell RG, Knight B, Tirnitz‐Parker JE, et al. Lymphotoxin‐beta receptor signaling regulates hepatic stellate cell function and wound healing in a murine model of chronic liver injury. Hepatology. 2009;49(1):227–39.

    Google Scholar 

  133. Ruddell A, Harrell MI, Minoshima S, et al. Dynamic contrast‐enhanced magnetic resonance imaging of tumor‐induced lymph flow. Neoplasia. 2008;10(7):706–U4.

    Google Scholar 

  134. Herber DL, Cao W, Nefedova Y, et al. Lipid accumulation and dendritic cell dysfunction in cancer. Nat Med. 2010;16(8):880–6.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Institute of Bioengineering and Swiss Institute of Experimental Cancer Research (ISREC), École Polytechnique Fédérale de Lausanne, Lausanne, 1015, Switzerland

    Amanda W. Lund & Melody A. Swartz

  2. Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Station 15, Lausanne, CH 1015, Switzerland

    Melody A. Swartz

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  1. Amanda W. Lund
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Correspondence to Melody A. Swartz.

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Lund, A.W., Swartz, M.A. Role of Lymphatic Vessels in Tumor Immunity: Passive Conduits or Active Participants?. J Mammary Gland Biol Neoplasia 15, 341–352 (2010). https://doi.org/10.1007/s10911-010-9193-x

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