Lymphangiogenesis in development and disease

Ruediger Liersch; Michael Detmar

doi:10.1160/TH07-04-0238

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 98(02): 304-310
DOI: 10.1160/TH07-04-0238

Theme Issue Article

Schattauer GmbH

Lymphangiogenesis in development and disease

Authors

Ruediger Liersch

¹Department of Medicine, Hematology and Oncology, University Hospital Muenster, Muenster, Germany
Michael Detmar

²Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology, ETH Zurich, Zurich, Switzerland

Abstract

Summary

The lymphatic vascular system plays an important role in the maintenance of fluid homeostasis, in the afferent immune response, in the intestinal lipid uptake and in the metastatic spread of malignant cells. The recent discovery of specific markers and growth factors for lymphatic endothelium and the establishment of genetic mouse models with impairment of lymphatic function have provided novel insights into the molecular control of the lymphatic system in physiology and in embryonic development. They have also identified molecular pathways whose mutational inactivation leads to human diseases associated with lymphedema. Moreover, the lymphatic system plays a major role in chronic inflammatory diseases and in transplant rejection. Importantly, malignant tumors can directly promote lymphangiogenesis within the primary tumor and in draining lymph nodes, leading to enhanced cancer metastasis to lymph nodes and beyond. Based upon these findings, novel therapeutic strategies are currently being developed that aim at inhibiting or promoting the formation and function of lymphatic vessels in disease.

Keywords

Lymphatic endothelium - lymphangiogenesis - lymphedema - inflammation - cancer metastasis

Full Text

References

References
1 Asellius G. De lactibus sive lacteis venis. JB Bidellium, Milan. 1627
2 Cueni LN, Detmar M. New insights into the molecular control of the lymphatic vascular system and its role in disease. J Invest Dermatol 2006; 126: 2167-2177.
3 Witte MH, Bernas MJ, Martin CP, Witte CL. Lymphangiogenesis and lymphangiodysplasia: from molecular to clinical lymphology. Microsc Res Tech 2001; 55: 122-145.
4 Sauter B, Foedinger D, Sterniczky B. et al. Immunoelectron microscopic characterization of human dermal lymphatic microvascular endothelial cells. Differential expression of CD31, CD34, and type IV collagen with lymphatic endothelial cells vs blood capillary endothelial cells in normal human skin, lymphangioma, and hemangioma in situ. J Histochem Cytochem 1998; 46: 165-176.
5 Leak LV, Burke JF. Electron microscopic study of lymphatic capillaries in the removal of connective tissue fluids and particulate substances. Lymphology 1968; 1: 39-52.
6 Barsky SH, Baker A, Siegal GP. et al. Use of antibasement membrane antibodies to distinguish blood vessel capillaries from lymphatic capillaries. Am J Surg Pathol 1983; 7: 667-677.
7 Leak LV, Burke JF. Fine structure of the lymphatic capillary and the adjoining connective tissue area. Am J Anat 1966; 118: 785-809.
8 Shirasawa Y, Ikomi F, Ohhashi T. Physiological roles of endogenous nitric oxide in lymphatic pump activity of rat mesentery in vivo. Am J Physiol Gastrointest Liver Physiol 2000; 278: G551-556.
9 von der Weid PY. Review article: lymphatic vessel pumping and inflammation--the role of spontaneous constrictions and underlying electrical pacemaker potentials. Aliment Pharmacol Ther 2001; 15: 1115-1129.
10 Okada S, Albrecht RM, Aharinejad S. et al. Structural aspects of the lymphocyte traffic in rat submandibular lymph node. Microsc Microanal 2002; 8: 116-133.
11 Sabin F. On the origin of the lymphatics system from the veins and the development of the lymph hearts and thorarcic duct in the pig. Am J Anat 1902; 1: 367-391.
12 Sabin F. On the development of the superficial lymphatics in the skin of the pig. Am J Anat 1904; 3: 183-195.
13 Wigle JT, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell 1999; 98: 769-778.
14 Oliver G. Lymphatic vasculature development. Nat Rev Immunol 2004; 4: 35-45.
15 Wigle JT, Harvey N, Detmar M. et al. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. Embo J 2002; 21: 1505-1513.
16 Hong YK, Harvey N, Noh YH. et al. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn 2002; 225: 351-357.
17 Petrova TV, Makinen T, Makela TP. et al. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. Embo J 2002; 21: 4593-4599.
18 Hong YK, Foreman K, Shin JW. et al. Lymphatic reprogramming of blood vascular endothelium by Kaposi sarcoma-associated herpesvirus. Nat Genet 2004; 36: 683-685.
19 Wang HW, Trotter MW, Lagos D. et al. Kaposi sarcoma herpesvirus-induced cellular reprogramming contributes to the lymphatic endothelial gene expression in Kaposi sarcoma. Nat Genet 2004; 36: 687-693.
20 Karkkainen MJ, Haiko P, Sainio K. 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.
21 Ny A, Koch M, Schneider M. et al. A genetic Xenopus laevis tadpole model to study lymphangiogenesis. Nat Med 2005; 11: 998-1004.
22 Dumont DJ, Jussila L, Taipale J. et al. Cardiovascular failure in mouse embryos deficient in VEGF receptor- 3. Science 1998; 282: 946-949.
23 Schacht V, Ramirez MI, Hong YK. et al. T1alpha/ podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. Embo J 2003; 22: 3546-3556.
24 Yuan L, Moyon D, Pardanaud L. et al. Abnormal lymphatic vessel development in neuropilin 2 mutant mice. Development 2002; 129: 4797-4806.
25 Gale NW, Thurston G, Hackett SF. et al. Angiopoietin- 2 is required for postnatal angiogenesis and lymphatic patterning, and only the latter role is rescued by Angiopoietin-1. Dev Cell 2002; 3: 411-423.
26 Makinen T, Adams RH, Bailey J. et al. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev 2005; 19: 397-410.
27 Wang JF, Zhang XF, Groopman JE. Stimulation of beta 1 integrin induces tyrosine phosphorylation of vascular endothelial growth factor receptor-3 and modulates cell migration. J Biol Chem 2001; 276: 41950-41957.
28 Huang XZ, Wu JF, Ferrando R. et al. Fatal bilateral chylothorax in mice lacking the integrin alpha9beta1. Mol Cell Biol 2000; 20: 5208-5215.
29 Huntington G, McClure C. The anatomy and development of the jugular lymph sac in the domestic cat (Felis domestica). Am J Anat 1910; 10: 177-311.
30 Schneider M, Othman-Hassan K, Christ B. et al. Lymphangioblasts in the avian wing bud. Dev Dyn 1999; 216: 311-319.
31 Liersch R, Nay F, Lu L. et al. Induction of lymphatic endothelial cell differentiation in embryoid bodies. Blood 2006; 107: 1214-1216.
32 Kreuger J, Nilsson I, Kerjaschki D. et al. Early lymph vessel development from embryonic stem cells. Arterioscler Thromb Vasc Biol 2006; 26: 1073-1078.
33 Veikkola T, Jussila L, Makinen T. et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. Embo J 2001; 20: 1223-1231.
34 Oh SJ, Jeltsch MM, Birkenhager R. et al. VEGF and VEGF-C: specific induction of angiogenesis and lymphangiogenesis in the differentiated avian chorioallantoic membrane. Dev Biol 1997; 188: 96-109.
35 Jeltsch M, Kaipainen A, Joukov V. et al. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997; 276: 1423-1425.
36 Kaipainen A, Korhonen J, Mustonen T. 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.
37 Partanen TA, Arola J, Saaristo A. et al. VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. Faseb J 2000; 14: 2087-2096.
38 Hamrah P, Chen L, Zhang Q. et al. Novel expression of vascular endothelial growth factor receptor (VEGFR)-3 and VEGF-C on corneal dendritic cells. Am J Pathol 2003; 163: 57-68.
39 Schoppmann SF, Birner P, Stockl J. et al. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 2002; 161: 947-956.
40 Laakkonen P, Waltari M, Holopainen T. et al. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res 2007; 67: 593-599.
41 Hong YK, Lange-Asschenfeldt B, Velasco P. 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.
42 Nagy JA, Vasile E, Feng D. et al. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 2002; 196: 1497-1506.
43 Kunstfeld R, Hirakawa S, Hong YK. 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.
44 Kriehuber E, Breiteneder-Geleff S, Groeger M. et al. Isolation and characterization of dermal lymphatic and blood endothelial cells reveal stable and functionally specialized cell lineages. J Exp Med 2001; 194: 797-808.
45 Hirakawa S, Hong YK, Harvey N. et al. Identification of vascular lineage-specific genes by transcriptional profiling of isolated blood vascular and lymphatic endothelial cells. Am J Pathol 2003; 162: 575-586.
46 Karpanen T, Heckman CA, Keskitalo S. et al. Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. Faseb J 2006; 20: 1462-1472.
47 Karkkainen MJ, Saaristo A, Jussila L. et al. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci USA 2001; 98: 12677-12682.
48 Chang LK, Garcia-Cardena G, Farnebo F. et al. Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA 2004; 101: 11658-11663.
49 Kubo H, Cao R, Brakenhielm E. et al. Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci USA 2002; 99: 8868-8873.
50 Shin JW, Min M, Larrieu-Lahargue F. et al. Prox1 promotes lineage-specific expression of FGF receptor- 3 in lymphatic endothelium: a role for FGF signaling in lymphangiogenesis. Mol Biol Cell 2006; 17: 576-584.
51 Kajiya K, Hirakawa S, Ma B. et al. Hepatocyte growth factor promotes lymphatic vessel formation and function. Embo J 2005; 24: 2885-2895.
52 Davis S, Aldrich TH, Jones PF. et al. Isolation of angiopoietin- 1, a ligand for the Tie2 receptor, by secretion- trap expression cloning. Cell 1996; 87: 1161-1169.
53 Morisada T, Oike Y, Yamada Y. et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood 2005; 105: 4649-4656.
54 Tammela T, Saaristo A, Lohela M. et al. Angiopoietin- 1 promotes lymphatic sprouting and hyperplasia. Blood 2005; 105: 4642-4648.
55 Witte MH, Erickson R, Bernas M. et al. Phenotypic and genotypic heterogeneity in familial Milroy lymphedema. Lymphology 1998; 31: 145-155.
56 Irrthum A, Karkkainen MJ, Devriendt K. et al. Congenital hereditary lymphedema caused by a mutation that inactivates VEGFR3 tyrosine kinase. Am J Hum Genet 2000; 67: 295-301.
57 Karkkainen MJ, Ferrell RE, Lawrence EC. et al. Missense mutations interfere with VEGFR-3 signal ling in primary lymphoedema. Nat Genet 2000; 25: 153-159.
58 Makinen T, Jussila L, Veikkola T. et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 2001; 7: 199-205.
59 Fang J, Dagenais SL, Erickson RP. et al. Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedemadistichiasis syndrome. Am J Hum Genet 2000; 67: 1382-1388.
60 Hong SE, Shugart YY, Huang DT. et al. Autosomal recessive lissencephaly with cerebellar hypoplasia is associated with human RELN mutations. Nat Genet 2000; 26: 93-96.
61 Irrthum A, Devriendt K, Chitayat D. et al. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema- telangiectasia. Am J Hum Genet 2003; 72: 1470-1478.
62 Rockson SG. Lymphedema. Am J Med 2001; 110: 288-295.
63 Saaristo A, Tammela T, Farkkila A. t al. Vascular endothelial growth factor-C accelerates diabetic wound healing. Am J Pathol 2006; 169: 1080-1087.
64 Saaristo A, Veikkola T, Tammela T. et al. Lymphangiogenic gene therapy with minimal blood vascular side effects. J Exp Med 2002; 196: 719-730.
65 Szuba A, Skobe M, Karkkainen MJ. et al. Therapeutic lymphangiogenesis with human recombinant VEGF-C. Faseb J 2002; 16: 1985-1987.
66 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: 919-921.
67 Kajiya K, Hirakawa S, Detmar M. Vascular endothelial growth factor-A mediates ultraviolet B-induced impairment of lymphatic vessel function. Am J Pathol 2006; 169: 1496-1503.
68 Hamrah P, Huq SO, Liu Y. et al. Corneal immunity is mediated by heterogeneous population of antigenpresenting cells. J Leukoc Biol 2003; 74: 172-178.
69 Yamagami S, Dana MR. The critical role of lymph nodes in corneal alloimmunization and graft rejection. Invest Ophthalmol Vis Sci 2001; 42: 1293-1298.
70 Streilein JW. Peripheral tolerance induction: lessons from immune privileged sites and tissues. Transplant Proc 1996; 28: 2066-2070.
71 Kerjaschki D, Huttary N, Raab I. et al. Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat Med 2006; 12: 230-234.
72 Kerjaschki D, Regele HM, Moosberger I. et al. Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates. J Am Soc Nephrol 2004; 15: 603-612.
73 Cursiefen C, Chen L, Dana MR. et al. Corneal lymphangiogenesis: evidence, mechanisms, and implications for corneal transplant immunology. Cornea 2003; 22: 273-281.
74 Cursiefen C, Cao J, Chen L. et al. Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival. Invest Ophthalmol Vis Sci 2004; 45: 2666-2673.
75 Fisher B, Fisher ER. The interrelationship of hematogenous and lymphatic tumor cell dissemination. Surg Gynecol Obstet 1966; 122: 791-798.
76 Skobe M, Hawighorst T, Jackson DG. et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001; 7: 192-198.
77 Mandriota SJ, Jussila L, Jeltsch M. et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. Embo J 2001; 20: 672-682.
78 Stacker SA, Caesar C, Baldwin ME. et al. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001; 7: 186-191.
79 Stacker SA, Achen MG, Jussila L. et al. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer 2002; 2: 573-583.
80 Dadras SS, Paul T, Bertoncini J. et al. Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 2003; 162: 1951-1960.
81 Dadras SS, Lange-Asschenfeldt B, Velasco P. et al. Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol 2005; 18: 1232-1242.
82 Schoppmann SF, Schindl M, Breiteneder-Geleff S. et al. Inflammatory stromal reaction correlates with lymphatic microvessel density in early-stage cervival cancer. Anticancer Res 2001; 21: 3419-3423.
83 Schoppmann SF, Fenzl A, Nagy K. et al. VEGF-C expressing tumor-associated macrophages in lymph node positive breast cancer: impact on lymphangiogenesis and survival. Surgery 2006; 139: 839-846.
84 Religa P, Cao R, Bjorndahl M. et al. Presence of bone marrow-derived circulating progenitor endothelial cells in the newly formed lymphatic vessels. Blood 2005; 106: 4184-4190.
85 He Y, Rajantie I, Ilmonen M. et al. Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res 2004; 64: 3737-3740.
86 Hirakawa S, Brown LF, Kodama S. et al. VEGFC- induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 2007; 109: 1010-1017.
87 Hirakawa S, Kodama S, Kunstfeld R. et al. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 2005; 201: 1089-1099.
88 Alitalo K, Mohla S, Ruoslahti E. Lymphangiogenesis and cancer: meeting report. Cancer Res 2004; 64: 9225-9229.
89 Gunn MD, Tangemann K, Tam C. et al. A chemokine expressed in lymphoid high endothelial venules promotes the adhesion and chemotaxis of naive T lymphocytes. Proc Natl Acad Sci USA 1998; 95: 258-263.
90 Gunn MD, Kyuwa S, Tam C. et al. Mice lacking expression of secondary lymphoid organ chemokine have defects in lymphocyte homing and dendritic cell localization. J Exp Med 1999; 189: 451-460.
91 Takeuchi H, Fujimoto A, Tanaka M. et al. CCL21 chemokine regulates chemokine receptor CCR7 bearing malignant melanoma cells. Clin Cancer Res 2004; 10: 2351-2358.
92 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: 1638-43.
93 Yan C, Zhu ZG, Yu YY. et al. Expression of vascular endothelial growth factor C and chemokine receptor CCR7 in gastric carcinoma and their values in predicting lymph node metastasis. World J Gastroenterol 2004; 10: 783-790.
94 Mashino K, Sadanaga N, Yamaguchi H. et al. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res 2002; 62: 2937-2941.
95 Muller A, Homey B, Soto H. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 2001; 410: 50-56.
96 Wang J, Xi L, Hunt JL. et al. Expression pattern of chemokine receptor 6 (CCR6) and CCR7 in squamous cell carcinoma of the head and neck identifies a novel metastatic phenotype. Cancer Res 2004; 64: 1861-1866.
97 Takanami I. Overexpression of CCR7 mRNA in nonsmall cell lung cancer: correlation with lymph node metastasis. Int J Cancer 2003; 105: 186-189.
98 Tobler NE, Detmar M. Tumor and lymph node lymphangiogenesis-- impact on cancer metastasis. J Leukoc Biol. 2006; 80: 691-696.
99 Angeli V, Ginhoux F, Llodra J. et al. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 2006; 24: 203-215.
100 Halin C, Detmar M. An unexpected connection: lymph node lymphangiogenesis and dendritic cell migration. Immunity 2006; 24: 129-131.