Tumor metastasis and the lymphatic vasculature

International Journal of Cancer

Volumn 125, Issue 12, 2009, Pages 2747-2756

  Sleeman, Jonathan P ^a,b   Thiele, Wilko ^a,b  

^a UNIVERSITY OF HEIDELBERG   (Germany)

^b KARLSRUHE INSTITUTE OF TECHNOLOGY   (Germany)

Author keywords

Cancer; Lymph nodes; Lymphangiogenesis; Lymphatic endothelial cells; Lymphatic vessels; Metastasis; VEGF C; VEGF D; VEGFR 3

Indexed keywords

CYCLOOXYGENASE 2; FIBROBLAST GROWTH FACTOR RECEPTOR 3; INTERLEUKIN 3; INTERLEUKIN 7; TRANSFORMING GROWTH FACTOR BETA; VASCULOTROPIN C; VASCULOTROPIN D; VASCULOTROPIN RECEPTOR 3;

CELL INVASION; CELL MIGRATION; HUMAN; LYMPH NODE METASTASIS; LYMPHANGIOGENESIS; METASTASIS; PRIORITY JOURNAL; PROGNOSIS; PROTEIN EXPRESSION; SHORT SURVEY; SIGNAL TRANSDUCTION; TUMOR VASCULARIZATION;

ANIMALS; ENDOTHELIAL CELLS; HUMANS; LYMPHANGIOGENESIS; LYMPHATIC METASTASIS; LYMPHATIC VESSELS; NEOPLASMS;

EID: 70549104050     PISSN: 00207136     EISSN: 10970215     Source Type: Journal    
DOI: 10.1002/ijc.24702     Document Type: Short Survey

References (165)

1. Sporn MB. The war on cancer. Lancet 1996;347:1377-1381
2. Sleeman JP. The lymph node as a bridgehead in the metastatic dissemination of tumors. Recent Results Cancer Res 2000;157:55-81.
3. Cady B. Regional lymph node metastases: a singular manifestation of the process of clinical metastases in cancer: contemporary animal research and clinical reports suggest unifying concepts. Ann Surg Oncol 2007;14:1790-1800 (Pubitemid 46876511)
4. Beahrs O, Myers M. Purpose and principles of staging. In: Beahrs O, Myers M, editors. Manual for staging of cancer. Philadelphia: Lippincott, 1983.3-5.
5. Leong SP, Cady B, Jablons DM, Garcia-Aguilar J, Reintgen D, Jakub J, Pendas S, Duhaime L, Cassell R, Gardner M, Giuliano R, Archie V, et al. Clinical patterns of metastasis. Cancer Metastasis Rev 2006;25:221-232
6. Tanis PJ, Nieweg OE, Valdés Olmos RA, Rutgers EJ Th, Kroon BB. History of sentinel node and validation of the technique. Breast Cancer Res 2001;3:109-112 (Pubitemid 32266279)
7. Sleeman JP, Krishnan J, Kirkin V, Baumann P. Markers for the lymphatic endothelium: in search of the holy grail? Microsc Res Tech 2001;55:61-69
8. Sleeman JP, Schmid A, Thiele W. Tumor lymphatics. Semin Cancer Biol 2009; doi: 10.1016/j.semcancer.2009.05.005.
9. Weiss L. Metastasis of cancer: a conceptual history from antiquity to the 1990s. Cancer Metastasis Rev 2000;19:193-383. (Pubitemid 32436789)
10. 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;60:4324-4327 (Pubitemid 32103603)
11. Wartiovaara U, Salven P, Mikkola H, Lassila R, Kaukonen J, Joukov V, Orpana A, Ristimaki A, Heikinheimo M, Joensuu H, Alitalo K, Palotie A. Peripheral blood platelets express VEGF-C and VEGF which are released during platelet activation. Thromb Haemost 1998;80:171-175 (Pubitemid 28353517)
12. Trikha M, Nakada MT. Platelets and cancer: implications for antiangiogenic therapy. Semin Thromb Hemost 2002;28:39-44. (Pubitemid 34194871)
13. Schoppmann SF, Birner P, Stockl J, Kalt R, Ullrich R, Caucig C, Kriehuber E, Nagy K, Alitalo K, Kerjaschki D. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 2002;161:947-956 (Pubitemid 34988382)
14. Neuchrist C, Erovic BM, Handisurya A, Fischer MB, Steiner GE, Hollemann D, Gedlicka C, Saaristo A, Burian M. Vascular endothelial growth factor C and vascular endothelial growth factor receptor 3 expression in squamous cell carcinomas of the head and neck. Head Neck 2003;25:464-474 (Pubitemid 36577031)
15. Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 2005;201:1089-1099 (Pubitemid 40524677)
16. Hirakawa S, Brown LF, Kodama S, Paavonen K, Alitalo K, Detmar M. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 2007;109:1010-1017 (Pubitemid 46220646)
17. Harrell MI, Iritani BM, Ruddell A. Tumor-induced sentinel lymph node lymphangiogenesis and increased lymph flow precede melanoma metastasis. Am J Pathol 2007;170:774-786 (Pubitemid 47339411)
18. Ruddell A, Kelly-Spratt KS, Furuya M, Parghi SS, Kemp CJ. p19/Arf and p53 suppress sentinel lymph node lymphangiogenesis and carcinoma metastasis. Oncogene 2008;27:3145-3155 (Pubitemid 351693168)
19. Mashino K, Sadanaga N, Yamaguchi H, Tanaka F, Ohta M, Shibuta K, Inoue H, Mori M. Expression of chemokine receptor CCR7 is associated with lymph node metastasis of gastric carcinoma. Cancer Res 2002;62:2937-2941 (Pubitemid 34525782)
20. Shields JD, Emmett MS, Dunn DB, Joory KD, Sage LM, Rigby H, Mortimer PS, Orlando A, Levick JR, Bates DO. Chemokine-mediated migration of melanoma cells towards lymphatics - a mechanism contributing to metastasis. Oncogene 2007;26:2997-3005. (Pubitemid 46733648)
21. 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;11:526-538 (Pubitemid 46856909)
22. 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;69:349-357
23. Laakkonen P, Waltari M, Holopainen T, Takahashi T, Pytowski B, Steiner P, Hicklin D, Persaud K, Tonra JR, Witte L, Alitalo K. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res 2007;67:593-599 (Pubitemid 46192197)
24. Petrova TV, Bono P, Holnthoner W, Chesnes J, Pytowski B, Sihto H, Laakkonen P, Heikkilä P, Joensuu H, Alitalo K. VEGFR-3 expression is restricted to blood and lymphatic vessels in solid tumors. Cancer Cell 2008;13:554-556 (Pubitemid 351763905)
25. Cochran AJ, Wen DR, Farzad Z, Stene MA, McBride W, Lana AM, Hoon DS, Morton DL. Immunosuppression by melanoma cells as a factor in the generation of metastatic disease. Anticancer Res 1989;9:859-864 (Pubitemid 19266318)
26. Reiss CK, Volenec FJ, Humphrey M, Singla O, Humphrey LJ. The role of the regional lymph node in breast cancer: a comparison between nodal and systemic reactivity. J Surg Oncol 1983;22:249-253 (Pubitemid 13130114)
27. Cochran AJ, Huang RR, Lee J, Itakura E, Leong SP, Essner R. Tumour-induced immune modulation of sentinel lymph nodes. Nat Rev Immunol 2006;6:659-670 (Pubitemid 44298215)
28. Huang RR, Wen DR, Guo J, Giuliano AE, Nguyen M, Offodile R, Stern S, Turner R, Cochran AJ. Selective modulation of paracortical dendritic cells and T-lymphocytes in breast cancer sentinel lymph nodes. Breast J 2000;6:225-232 (Pubitemid 30622094)
29. Kohrt HE, Nouri N, Nowels K, Johnson D, Holmes S, Lee PP. Profile of immune cells in axillary lymph nodes predicts disease-free survival in breast cancer. PLoS Med 2005;2:e284.
30. Preynat-Seauve O, Contassot E, Schuler P, Piguet V, French LE, Huard B. Extralymphatic tumors prepare draining lymph nodes to invasion via a T-cell cross-tolerance process. Cancer Res 2007;67:5009-5016
31. Kim R, Emi M, Tanabe K, Arihiro K. Immunobiology of the sentinel lymph node and its potential role for antitumour immunity. Lancet Oncol 2006;7:1006-1016 (Pubitemid 44804142)
32. Breiteneder-Geleff S, Soleiman A, Kowalski H, Horvat R, Amann G, Kriehuber E, Diem K, Weninger W, Tschachler E, Alitalo K, Kerjaschki D. Angiosarcomas express mixed endothelial phenotypes of blood and lymphatic capillaries: podoplanin as a specific marker for lymphatic endothelium. Am J Pathol 1999;154:385-394 (Pubitemid 29094089)
33. Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, Jones M, Jackson DG. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol 1999;144:789-801. (Pubitemid 29234556)
34. Wigle JT, Oliver G. Prox1 function is required for the development of the murine lymphatic system. Cell 1999;98:769-778 (Pubitemid 29446894)
35. Bono P, Wasenius VM, Heikkilä P, Lundin J, Jackson DG, Joensuu H. High LYVE-1-positive lymphatic vessel numbers are associated with poor outcome in breast cancer. Clin Cancer Res 2004;10:7144-7149 (Pubitemid 39487698)
36. Vleugel MM, Bos R, van der Groep P, Greijer AE, Shvarts A, Stel HV, van der Wall E, van Diest PJ. Lack of lymphangiogenesis during breast carcinogenesis. J Clin Pathol 2004;57:746-751
37. Nakamura Y, Yasuoka H, Tsujimoto M, Imabun S, Nakahara M, Nakao K, Nakamura M, Mori I, Kakudo K. Lymph vessel density correlates with nodal status. VEGF-C expression, and prognosis in breast cancer. Breast Cancer Res Treat 2005;91:125-132
38. Zhang GH, Yang WT, Zhou XY, Zeng Y, Lu HF, Shi DR. Study of the correlation between HER-2 gene and lymphangiogenesis and their prognostic significance in human breast cancer. Zhonghua Yi Xue Za Zhi 2007;87:155-160
39. Van der Schaft DW, Pauwels P, Hulsmans S, Zimmermann M, van de Poll-Franse LV, Griffioen AW. Absence of lymphangiogenesis in ductal breast cancer at the primary tumor site. Cancer Lett 2007;254:128-136 (Pubitemid 47058811)
40. Mohammed RA, Ellis IO, Elsheikh S, Paish EC, Martin SG. Lymphatic and angiogenic characteristics in breast cancer: morphometric analysis and prognostic implications. Breast Cancer Res Treat 2009;113:261-273
41. Fernández MI, Bolenz C, Trojan L, Steidler A, Weiss C, Alken P, Grobholz R, Michel MS. Prognostic implications of lymphangiogenesis in muscle-invasive transitional cell carcinoma of the bladder. Eur Urol 2008;53:571-578 (Pubitemid 351178994)
42. Gombos Z, Xu X, Chu CS, Zhang PJ, Acs G. Peritumoral lymphatic vessel density and vascular endothelial growth factor C expression in early-stage squamous cell carcinoma of the uterine cervix. Clin Cancer Res 2005;11:8364-8371 (Pubitemid 41746949)
43. Longatto-Filho A, Pinheiro C, Pereira SM, Etlinger D, Moreira MA, Jubé LF, Queiroz GS, Baltazar F, Schmitt FC. Lymphatic vessel density and epithelial D2-40 immunoreactivity in pre-invasive and invasive lesions of the uterine cervix. Gynecol Oncol 2007;107:45-51. (Pubitemid 47495944)
44. Mou JH, Yan XC, Li ZP, Wang D, Duan GJ, Xiang DB, Xiao HL, Zhang QH. Characteristic and clinicopathologic significance of lymphangiogenesis in colorectal cancer. Zhonghua Bing Li Xue Za Zhi 2005;34:348-352
45. Yang X, Li LR, Pan ZZ, Zhou ZW, Wan DS. Lymphatic vessel density in Dukes' B rectal carcinoma and its correlation to prognosis. Ai Zheng 2006;25:749-752
46. Chen W, Shen W, Chen M, Cai G, Liu X. Study on the relationship between lymphatic vessel density and distal intramural spread of rectal cancer. Eur Surg Res 2007;39:332-339 (Pubitemid 47614358)
47. Yan G, Zhou XY, Cai SJ, Zhang GH, Peng JJ, Du X. Lymphangiogenic and angiogenic microvessel density in human primary sporadic colorectal carcinoma. World J Gastroenterol 2008;14:101-107 (Pubitemid 351314335)
48. Longatto-Filho A, Pinheiro C, Ferreira L, Scapulatempo C, Alves VA, Baltazar F, Schmitt F. Peritumoural, but not intratumoural, lymphatic vessel density and invasion correlate with colorectal carcinoma poor-outcome markers. Virchows Arch 2008;452:133-138
49. Gao J, Knutsen A, Arbman G, Carstensen J, Frånlund B, Sun XF. Clinical and biological significance of angiogenesis and lymphangiogenesis in colorectal cancer. Dig Liver Dis 2009;41:116-122
50. Stefansson IM, Salvesen HB, Akslen LA. Vascular proliferation is important for clinical progress of endometrial cancer. Cancer Res 2006;66:3303-3309
51. Kitadai Y, Kodama M, Cho S, Kuroda T, Ochiumi T, Kimura S, Tanaka S, Matsumura S, Yasui W, Chayama K. Quantitative analysis of lymphangiogenic markers for predicting metastasis of human gastric carcinoma to lymph nodes. Int J Cancer 2005;115:388-392 (Pubitemid 40663742)
52. Nakamura Y, Yasuoka H, Tsujimoto M, Kurozumi K, Nakahara M, Nakao K, Kakudo K. Importance of lymph vessels in gastric cancer: a prognostic indicator in general and a predictor for lymph node metastasis in early stage cancer. J Clin Pathol 2006;59:77-82. (Pubitemid 43076243)
53. Wang TB, Deng MH, Qiu WS, Dong WG. Association of serum vascular endothelial growth factor-C and lymphatic vessel density with lymph node metastasis and prognosis of patients with gastric cancer. World J Gastroenterol 2007;13:1794-1797
54. Yuanming L, Feng G, Lei T, Ying W. Quantitative analysis of lymphangiogenic markers in human gastroenteric tumor. Arch Med Res 2007;38:106-112 (Pubitemid 44894621)
55. Gao P, Zhou GY, Zhang QH, Xiang L, Zhang SL, Li C, Sun YL. Clinicopathological significance of peritumoral lymphatic vessel density in gastric carcinoma. Cancer Lett 2008;263:223-230
56. Thelen A, Scholz A, Benckert C, Weichert W, Dietz E, Wiedenmann B, Neuhaus P, Jonas S. Tumor-associated lymphangiogenesis correlates with lymph node metastases and prognosis in hilar cholangiocarcinoma. Ann Surg Oncol 2008;15:791-799
57. Beasley NJ, Prevo R, Banerji S, Leek RD, Moore J, van Trappen P, Cox G, Harris AL, Jackson DG. Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res 2002;62:1315-1320 (Pubitemid 34407785)
58. Maula SM, Luukkaa M, Grénman R, Jackson D, Jalkanen S, Ristamäki R. Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region. Cancer Res 2003;63:1920-1926 (Pubitemid 36460859)
59. Franchi A, Gallo O, Massi D, Baroni G, Santucci M. Tumor lymphangiogenesis in head and neck squamous cell carcinoma: a morphometric study with clinical correlations. Cancer 2004;101:973-978 (Pubitemid 39100431)
60. Kyzas PA, Geleff S, Batistatou A, Agnantis NJ, Stefanou D. Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma. J Pathol 2005;206:170-177 (Pubitemid 40754020)
61. Straume O, Jackson DG, Akslen LA. Independent prognostic impact of lymphatic vessel density and presence of low-grade lymphangiogenesis in cutaneous melanoma. Clin Cancer Res 2003;9:250-256 (Pubitemid 36109741)
62. Dadras SS, Paul T, Bertoncini J, Brown LF, Muzikansky A, Jackson DG, Ellwanger U, Garbe C, Mihm MC, Detmar M. Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am J Pathol 2003;162:1951-1960 (Pubitemid 36613052)
63. Giorgadze TA, Zhang PJ, Pasha T, Coogan PS, Acs G, Elder DE, Xu X. Lymphatic vessel density is significantly increased in melanoma. J Cutan Pathol 2004;31:672-677 (Pubitemid 39440848)
64. Ohta Y, Shridhar V, Bright RK, Kalemkerian GP, Du W, Carbone M, Watanabe Y, Pass HI. VEGF and VEGF type C play an important role in angiogenesis and lymphangiogenesis in human malignant mesothelioma tumours. Br J Cancer 1999;81:54-61. (Pubitemid 29415491)
65. Li Q, Dong X, Gu W, Qiu X, Wang E. Clinical significance of co-expression of VEGF-C and VEGFR-3 in non-small cell lung cancer. Chin Med J (Engl) 2003;116:727-730 (Pubitemid 36701858)
66. Renyi-Vamos F, Tovari J, Fillinger J, Timar J, Paku S, Kenessey I, Ostoros G, Agocs L, Soltesz I, Dome B. Lymphangiogenesis correlates with lymph node metastasis, prognosis, and angiogenic phenotype in human non-small cell lung cancer. Clin Cancer Res 2005;11:7344-7353 (Pubitemid 41507693)
67. Wang Y, Sun JG, Ye MF, Chen ZT. Clinical and prognostic significance of podoplanin-positive lymphatic vessel density in non-small cell lung carcinoma. Zhonghua Jie He He Hu Xi Za Zhi 2006;29:758-761
68. Faoro L, Hutto JY, Salgia R, El-Zayaty SA, Ferguson MK, Cheney RT, Reid ME, Armato SG, III, Krausz T, Husain AN. Lymphatic vessel density is not associated with lymph node metastasis in non-small cell lung carcinoma. Arch Pathol Lab Med 2008;132:1882-1888
69. Brundler MA, Harrison JA, de Saussure B, de Perrot M, Pepper MS. Lymphatic vessel density in the neoplastic progression of Barrett's oesophagus to adenocarcinoma. J Clin Pathol 2006;59:191-195
70. Mori D, Yamasaki F, Shibaki M, Tokunaga O. Lateral peritumoral lymphatic vessel invasion can predict lymph node metastasis in esophageal squamous cell carcinoma. Mod Pathol 2007;20:694-700. (Pubitemid 46788876)
71. Inoue A, Moriya H, Katada N, Tanabe S, Kobayashi N, Watanabe M, Okayasu I, Ohbu M. Intratumoral lymphangiogenesis of esophageal squamous cell carcinoma and relationship with regulatory factors and prognosis. Pathol Int 2008;58:611-619
72. Saad RS, Lindner JL, Liu Y, Silverman JF. Lymphatic vessel density as prognostic marker in esophageal adenocarcinoma. Am J Clin Pathol 2009;131:92-98
73. Sedivy R, Beck-Mannagetta J, Haverkampf C, Battistutti W, Hönigschnabl S. Expression of vascular endothelial growth factor-C correlates with the lymphatic microvessel density and the nodal status in oral squamous cell cancer. J Oral Pathol Med 2003;32:455-460 (Pubitemid 37039919)
74. Muñoz-Guerra MF, Marazuela EG, Martín-Villar E, Quintanilla M, Gamallo C. Prognostic significance of intratumoral lymphangiogenesis in squamous cell carcinoma of the oral cavity. Cancer 2004;100:553-560
75. Miyahara M, Tanuma J, Sugihara K, Semba I. Tumor lymphangiogenesis correlates with lymph node metastasis and clinicopathologic parameters in oral squamous cell carcinoma. Cancer 2007;110:1287-1294 (Pubitemid 47435600)
76. Hinojar-Gutiérrez A, Fernández-Contreras ME, González-González R, Fernández-Luque MJ, Hinojar-Arzadún A, Quintanilla M, Gamallo C. Intratumoral lymphatic vessels and VEGF-C expression are predictive factors of lymph node relapse in T1-T4 N0 laryngopharyngeal squamous cell carcinoma. Ann Surg Oncol 2007;14:248-257 (Pubitemid 44954296)
77. Zhao D, Pan J, Li XQ, Wang XY, Tang C, Xuan M. Intratumoral lymphangiogenesis in oral squamous cell carcinoma and its clinicopathological significance. J Oral Pathol Med 2008;37:616-625
78. Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Kowalski H, Oberhuber G. Lymphatic microvessel density in epithelial ovarian cancer: its impact on prognosis. Anticancer Res 2000;20:2981-2985 (Pubitemid 30802667)
79. Rubbia-Brandt L, Terris B, Giostra E, Dousset B, Morel P, Pepper MS. Lymphatic vessel density and vascular endothelial growth factor-C expression correlate with malignant behavior in human pancreatic endocrine tumors. Clin Cancer Res 2004;10:6919-6928 (Pubitemid 39383042)
80. Sipos B, Kojima M, Tiemann K, Klapper W, Kruse ML, Kalthoff H, Schniewind B, Tepel J, Weich H, Kerjaschki D, Klöppel G. Lymphatic spread of ductal pancreatic adenocarcinoma is independent of lymphangiogenesis. J Pathol 2005;207:301-312 (Pubitemid 41556454)
81. Trojan L, Michel MS, Rensch F, Jackson DG, Alken P, Grobholz R. Lymph and blood vessel architecture in benign and malignant prostatic tissue: lack of lymphangiogenesis in prostate carcinoma assessed with novel lymphatic marker lymphatic vessel endothelial hyaluronan receptor (LYVE-1). J Urol 2004;172:103-107 (Pubitemid 41615048)
82. Zeng Y, Opeskin K, Horvath LG, Sutherland RL, Williams ED. Lymphatic vessel density and lymph node metastasis in prostate cancer. Prostate 2005;65:222-230
83. Roma AA, Magi-Galluzzi C, Kral MA, Jin TT, Klein EA, Zhou M. Peritumoral lymphatic invasion is associated with regional lymph node metastases in prostate adenocarcinoma. Mod Pathol 2006;19:392-398 (Pubitemid 43276993)
84. Cheng L, Bishop E, Zhou H, Maclennan GT, Lopez-Beltran A, Zhang S, Badve S, Baldridge LA, Montironi R. Lymphatic vessel density in radical prostatectomy specimens. Hum Pathol 2008;39:610-615
85. De la Torre NG, Buley I, Wass JA, Turner HE. Angiogenesis and lymphangiogenesis in thyroid proliferative lesions: relationship to type and tumour behaviour. Endocr Relat Cancer 2006;13:931-944 (Pubitemid 44763268)
86. Horiguchi A, Ito K, Sumitomo M, Kimura F, Asano T, Hayakawa M. Intratumoral lymphatics and lymphatic invasion are associated with tumor aggressiveness and poor prognosis in renal cell carcinoma. Urology 2008;71:928-932
87. Bolenz C, Fernández MI, Trojan L, Hoffmann K, Herrmann E, Steidler A, Weiss C, Ströbel P, Alken P, Michel MS. Lymphangiogenesis occurs in upper tract urothelial carcinoma and correlates with lymphatic tumour dissemination and poor prognosis. BJU Int 2009;103:1040-1046
88. Van den Eynden GG, Van der Auwera I, Van Laere SJ, Huygelen V, Colpaert CG, van Dam P, Dirix LY, Vermeulen PB, Van Marck EA. Induction of lymphangiogenesis in and around axillary lymph node metastases of patients with breast cancer. Br J Cancer 2006;95:1362-1366 (Pubitemid 44760086)
89. He Y, Rajantie I, Ilmonen M, Makinen T, Karkkainen MJ, Haiko P, Salven P, Alitalo K. Preexisting lymphatic endothelium but not endothelial progenitor cells are essential for tumor lymphangiogenesis and lymphatic metastasis. Cancer Res 2004;64:3737-3740 (Pubitemid 38697279)
90. Religa P, Cao R, Bjorndahl M, Zhou Z, Zhu Z, Cao Y. Presence of bone marrow-derived circulating progenitor endothelial cells in the newly formed lymphatic vessels. Blood 2005;106:4184-4190 (Pubitemid 41775925)
91. Schledzewski K, Falkowski M, Moldenhauer G, Metharom P, Kzhyshkowska J, Ganss R, Demory A, Falkowska-Hansen B, Kurzen H, Ugurel S, Geginat G, Arnold B, et al. Lymphatic endothelium-specific hyaluronan receptor LYVE-1 is expressed by stabilin-1+. F4/80+, CD11b+ macrophages in malignant tumours and wound healing tissue in vivo and in bone marrow cultures in vitro: implications for the assessment of lymphangiogenesis. J Pathol 2006;209:67-77.
92. Jiang S, Bailey AS, Goldman DC, Swain JR, Wong MH, Streeter PR, Fleming WH. Hematopoietic stem cells contribute to lymphatic endothelium. PLoS ONE 2008;3:e3812. (Pubitemid 352749428)
93. Maruyama K, Ii M, Cursiefen C, Jackson DG, Keino H, Tomita M, Van Rooijen N, Takenaka H, Dámore PA, Stein-Streilein J, Losordo DW, Streilein JW. Inflammation-induced lymphangiogenesis in the cornea arises from CD11b-positive macrophages. J Clin Invest 2005;115:2363-2372 (Pubitemid 41266198)
94. Kerjaschki D, Huttary N, Raab I, Regele H, Bojarski-Nagy K, Bartel G, Krober SM, Greinix H, Rosenmaier A, Karlhofer F, Wick N, Mazal PR. Lymphatic endothelial progenitor cells contribute to de novo lymphangiogenesis in human renal transplants. Nat Med 2006;12:230-234 (Pubitemid 43214751)
95. Krishnan J, Kirkin V, Steffen A, Hegen M, Weih D, Tomarev S, Wilting J, Sleeman JP. 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 2003;63:713-722 (Pubitemid 36158152)
96. Cao R, Bjorndahl MA, Religa P, Clasper S, Garvin S, Galter D, Meister B, Ikomi F, Tritsaris K, Dissing S, Ohhashi T, Jackson DG, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 2004;6:333-345 (Pubitemid 39361435)
97. Iwata C, Kano MR, Komuro A, Oka M, Kiyono K, Johansson E, Morishita Y, Yashiro M, Hirakawa K, Kaminishi M, Miyazono K. Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis. Cancer Res 2007;67:10181-10189 (Pubitemid 350070790)
98. Shibata MA, Morimoto J, Shibata E, Otsuki Y. Combination therapy with short interfering RNA vectors against VEGF-C and VEGF-A suppresses lymph node and lung metastasis in a mouse immunocompetent mammary cancer model. Cancer Gene Ther 2008;15:776-786
99. Da MX, Wu Z, Tian HW. Tumor lymphangiogenesis and lymphangiogenic growth factors. Arch Med Res 2008;39:365-372
100. Thiele W, Sleeman JP. Tumor-induced lymphangiogenesis: a target for cancer therapy? J Biotechnol 2006;124:224-241
101. Eccles S, Paon L, Sleeman J. Lymphatic metastasis in breast cancer: importance and new insights into cellular and molecular mechanisms. Clin Exp Metastasis 2007;24:619-636 (Pubitemid 50001146)
102. Mandriota SJ, Jussila L, Jeltsch M, Compagni A, Baetens D, Prevo R, Banerji S, Huarte J, Montesano R, Jackson DG, Orci L, Alitalo K, et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 2001;20:672-682 (Pubitemid 32167632)
103. Skobe M, Hawighorst T, Jackson DG, Prevo R, Janes L, Velasco P, Riccardi L, Alitalo K, Claffey K, Detmar M. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 2001;7:192-198 (Pubitemid 32148486)
104. Stacker SA, Caesar C, Baldwin ME, Thornton GE, Williams RA, Prevo R, Jackson DG, Nishikawa S, Kubo H, Achen MG. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 2001;7:186-191 (Pubitemid 32148485)
105. He Y, Kozaki K, Karpanen T, Koshikawa K, Yla-Herttuala S, Takahashi T, Alitalo K. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 2002;94:819-825 (Pubitemid 34705053)
106. Kopfstein L, Veikkola T, Djonov VG, Baeriswyl V, Schomber T, Strittmatter K, Stacker SA, Achen MG, Alitalo K, Christofori G. Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. Am J Pathol 2007;170:1348-1361 (Pubitemid 47339341)
107. He Y, Rajantie I, Pajusola K, Jeltsch M, Holopainen T, Yla-Herttuala S, Harding T, Jooss K, Takahashi T, Alitalo K. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res 2005;65:4739-4746 (Pubitemid 40740810)
108. Matsui J, Funahashi Y, Uenaka T, Watanabe T, Tsuruoka A, Asada M. Multi-kinase inhibitor E7080 suppresses lymph node and lung metastases of human mammary breast tumor MDA-MB-231 via inhibition of vascular endothelial growth factor-receptor (VEGF-R) 2 and VEGF-R3 kinase. Clin Cancer Res 2008;14:5459-5465
109. Burton JB, Priceman SJ, Sung JL, Brakenhielm E, An DS, Pytowski B, Alitalo K, Wu L. Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res 2008;68:7828-7837
110. Johnson NC, Dillard ME, Baluk P, McDonald DM, Harvey NL, Frase SL, Oliver G. Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity. Genes Dev 2008;22:3282-3291
111. Francois M, Caprini A, Hosking B, Orsenigo F, Wilhelm D, Browne C, Paavonen K, Karnezis T, Shayan R, Downes M, Davidson T, Tutt D, et al. Sox18 induces development of the lymphatic vasculature in mice. Nature 2008;456:643-647
112. Gröger M, Loewe R, Holnthoner W, Embacher R, Pillinger M, Herron GS, Wolff K, Petzelbauer P. IL-3 induces expression of lymphatic markers Prox-1 and podoplanin in human endothelial cells. J Immunol 2004;173:7161-7169 (Pubitemid 39628151)
113. Al-Rawi MA, Watkins G, Mansel RE, Jiang WG. The effects of interleukin- 7 on the lymphangiogenic properties of human endothelial cells. Int J Oncol 2005;27:721-730
114. Tammela T, Enholm B, Alitalo K, Paavonen K. The biology of vascular endothelial growth factors. Cardiovasc Res 2005;65:550-563 (Pubitemid 40138976)
115. Hong YK, Harvey N, Noh YH, Schacht V, Hirakawa S, Detmar M, Oliver G. Prox1 is a master control gene in the program specifying lymphatic endothelial cell fate. Dev Dyn 2002;225:351-357 (Pubitemid 35265813)
116. Petrova TV, Makinen T, Makela TP, Saarela J, Virtanen I, Ferrell RE, Finegold DN, Kerjaschki D, Yla-Herttuala S, Alitalo K. Lymphatic endothelial reprogramming of vascular endothelial cells by the Prox-1 homeobox transcription factor. EMBO J 2002;21:4593-4599 (Pubitemid 34984346)
117. Schacht V, Ramirez MI, Hong YK, Hirakawa S, Feng D, Harvey N, Williams M, Dvorak AM, Dvorak HF, Oliver G, Detmar M. T1alpha/podoplanin deficiency disrupts normal lymphatic vasculature formation and causes lymphedema. EMBO J 2003;22:3546-3556 (Pubitemid 36898332)
118. Fu J, Gerhardt H, McDaniel JM, Xia B, Liu X, Ivanciu L, Ny A, Hermans K, Silasi-Mansat R, McGee S, Nye E, Ju T, et al. Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice. J Clin Invest 2008;118:3725-3737
119. Shin JW, Min M, Larrieu-Lahargue F, Canron X, Kunstfeld R, Nguyen L, Henderson JE, Bikfalvi A, Detmar M, Hong YK. Prox1 promotes lineage-specific expression of fibroblast growth factor (FGF) receptor-3 in lymphatic endothelium: a role for FGF signaling in lymphangiogenesis. Mol Biol Cell 2006;17:576-584 (Pubitemid 43191094)
120. Mishima K, Watabe T, Saito A, Yoshimatsu Y, Imaizumi N, Masui S, Hirashima M, Morisada T, Oike Y, Araie M, Niwa H, Kubo H, et al. Prox1 induces lymphatic endothelial differentiation via integrin alpha9 and other signaling cascades. Mol Biol Cell 2007;18:1421-1429 (Pubitemid 46626636)
121. Lee S, Kang J, Yoo J, Ganesan SK, Cook SC, Aguilar B, Ramu S, Lee J, Hong YK. Prox1 physically and functionally interacts with COUP-TFII to specify lymphatic endothelial cell fate. Blood 2009;113:1856-1859
122. Yamazaki T, Yoshimatsu Y, Morishita Y, Miyazono K, Watabe T. COUP-TFII regulates the functions of Prox1 in lymphatic endothelial cells through direct interaction. Genes Cells 2009;14:425-434
123. Kulkarni RM, Greenberg JM, Akeson AL. NFATc1 regulates lymphatic endothelial development. Mech Dev 2009;126:350-365
124. Oka M, Iwata C, Suzuki HI, Kiyono K, Morishita Y, Watabe T, Komuro A, Kano MR, Miyazono K. Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood 2008;111:4571-4579
125. Vlahakis NE, Young BA, Atakilit A, Sheppard D. The lymphangiogenic vascular endothelial growth factors VEGF-C and -D are ligands for the integrin alpha9beta1. J Biol Chem 2005;280:4544-4552 (Pubitemid 40288622)
126. Karpanen T, Heckman CA, Keskitalo S, Jeltsch M, Ollila H, Neufeld G, Tamagnone L, Alitalo K. Functional interaction of VEGF-C and VEGF-D with neuropilin receptors. FASEB J 2006;20:1462-1472 (Pubitemid 44943854)
127. Wirzenius M, Tammela T, Uutela M, He Y, Odorisio T, Zambruno G, Nagy JA, Dvorak HF, Yla-Herttuala S, Shibuya M, Alitalo K. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med 2007;204:1431-1440 (Pubitemid 46919880)
128. Jeltsch M, Kaipainen A, Joukov V, Meng X, Lakso M, Rauvala H, Swartz M, Fukumura D, Jain RK, Alitalo K. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 1997;276:1423-1425 (Pubitemid 27235412)
129. Veikkola T, Jussila L, Makinen T, Karpanen T, Jeltsch M, Petrova TV, Kubo H, Thurston G, McDonald DM, Achen MG, Stacker SA, Alitalo K. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 2001;20:1223-1231 (Pubitemid 32233963)
130. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol 2009;21:154-165
131. Nagy JA, Vasile E, Feng D, Sundberg C, Brown LF, Detmar MJ, Lawitts JA, Benjamin L, Tan X, Manseau EJ, Dvorak AM, Dvorak HF. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 2002;196:1497-1506 (Pubitemid 35424943)
132. Dixelius J, Makinen T, Wirzenius M, Karkkainen MJ, Wernstedt C, Alitalo K, Claesson-Welsh L. Ligand-induced vascular endothelial growth factor receptor-3 (VEGFR-3) heterodimerization with VEGFR-2 in primary lymphatic endothelial cells regulates tyrosine phosphorylation sites. J Biol Chem 2003;278:40973-40979 (Pubitemid 37280919)
133. Makinen T, Veikkola T, Mustjoki S, Karpanen T, Catimel B, Nice EC, Wise L, Mercer A, Kowalski H, Kerjaschki D, Stacker SA, Achen MG, et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 2001;20:4762-4773 (Pubitemid 32848629)
134. Goldman J, Rutkowski JM, Shields JD, Pasquier MC, Cui Y, Schmokel HG, Willey S, Hicklin DJ, Pytowski B, Swartz MA. Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis. FASEB J 2007;21:1003-1012 (Pubitemid 46495690)
135. Gale NW, Thurston G, Hackett SF, Renard R, Wang Q, McClain J, Martin C, Witte C, Witte MH, Jackson D, Suri C, Campochiaro PA, 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
136. Kajiya K, Hirakawa S, Ma B, Drinnenberg I, Detmar M. Hepatocyte growth factor promotes lymphatic vessel formation and function. EMBO J 2005;24:2885-2895 (Pubitemid 43079892)
137. Makinen T, Adams RH, Bailey J, Lu Q, Ziemiecki A, Alitalo K, Klein R, Wilkinson GA. PDZ interaction site in ephrinB2 is required for the remodeling of lymphatic vasculature. Genes Dev 2005;19:397-410. (Pubitemid 40189302)
138. Furtado GC, Marinkovic T, Martin AP, Garin A, Hoch B, Hubner W, Chen BK, Genden E, Skobe M, Lira SA. Lymphotoxin beta receptor signaling is required for inflammatory lymphangiogenesis in the thyroid. Proc Natl Acad Sci USA 2007;104:5026-5031 (Pubitemid 47186170)
139. Chang LK, Garcia-Cardena G, Farnebo F, Fannon M, Chen EJ, Butterfield C, Moses MA, Mulligan RC, Folkman J, Kaipainen A. Dose-dependent response of FGF-2 for lymphangiogenesis. Proc Natl Acad Sci USA 2004;101:11658-11663
140. Achen MG, Stacker SA. Tumor lymphangiogenesis and metastatic spread - new players begin to emerge. Int J Cancer 2006;119:1755-1760
141. Hong YK, Lange-Asschenfeldt B, Velasco P, Hirakawa S, Kunstfeld R, Brown LF, Bohlen P, Senger DR, Detmar M. VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J 2004;18:1111-1113 (Pubitemid 39561540)
142. Dietrich T, Onderka J, Bock F, Kruse FE, Vossmeyer D, Stragies R, Zahn G, Cursiefen C. Inhibition of inflammatory lymphangiogenesis by integrin alpha5 blockade. Am J Pathol 2007;171:361-372 (Pubitemid 47339252)
143. Spessotto P, Cervi M, Mucignat MT, Mungiguerra G, Sartoretto I, Doliana R, Colombatti A. beta 1 Integrin-dependent cell adhesion to EMILIN-1 is mediated by the gC1q domain. J Biol Chem 2003;278:6160-6167 (Pubitemid 36800869)
144. Danussi C, Spessotto P, Petrucco A, Wassermann B, Sabatelli P, Montesi M, Doliana R, Bressan GM, Colombatti A. Emilin1 deficiency causes structural and functional defects of lymphatic vasculature. Mol Cell Biol 2008;28:4026-4039 (Pubitemid 351812988)
145. Salameh A, Galvagni F, Bardelli M, Bussolino F, Oliviero S. Direct recruitment of CRK and GRB2 to VEGFR-3 induces proliferation, migration, and survival of endothelial cells through the activation of ERK, AKT, and JNK pathways. Blood 2005;106:3423-3431 (Pubitemid 41609177)
146. Taniguchi K, Kohno R, Ayada T, Kato R, Ichiyama K, Morisada T, Oike Y, Yonemitsu Y, Maehara Y, Yoshimura A. Spreds are essential for embryonic lymphangiogenesis by regulating vascular endothelial growth factor receptor 3 signaling. Mol Cell Biol 2007;27:4541-4550 (Pubitemid 46906575)
147. Matsuo M, Yamada S, Koizumi K, Sakurai H, Saiki I. Tumour-derived fibroblast growth factor-2 exerts lymphangiogenic effects through Akt/mTOR/p70S6kinase pathway in rat lymphatic endothelial cells. Eur J Cancer 2007;43:1748-1754 (Pubitemid 47042372)
148. Kobayashi S, Kishimoto T, Kamata S, Otsuka M, Miyazaki M, Ishikura H. Rapamycin, a specific inhibitor of the mammalian target of rapamycin, suppresses lymphangiogenesis and lymphatic metastasis. Cancer Sci 2007;98:726-733 (Pubitemid 46563450)
149. Kubo H, Cao R, Brakenhielm E, Makinen T, Cao Y, Alitalo K. 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 (Pubitemid 34693650)
150. Shin JW, Huggenberger R, Detmar M. Transcriptional profiling of VEGF-A and VEGF-C target genes in lymphatic endothelium reveals endothelial-specific molecule-1 as a novel mediator of lymphangiogenesis. Blood 2008;112:2318-2326
151. Achen MG, Mann GB, Stacker SA. Targeting lymphangiogenesis to prevent tumour metastasis. Br J Cancer 2006;94:1355-1360
152. Schomber T, Zumsteg A, Strittmatter K, Crnic I, Antoniadis H, Littlewood-Evans A, Wood J, Christofori G. Differential effects of the vascular endothelial growth factor receptor inhibitor PTK787/ZK222584 on tumor angiogenesis and tumor lymphangiogenesis. Mol Cancer Ther 2009;8:55-63.
153. Pytowski B, Goldman J, Persaud K, Wu Y, Witte L, Hicklin DJ, Skobe M, Boardman KC, Swartz MA. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst 2005;97:14-21.
154. Baluk P, Tammela T, Ator E, Lyubynska N, Achen MG, Hicklin DJ, Jeltsch M, Petrova TV, Pytowski B, Stacker SA, Yla-Herttuala S, Jackson DG, et al. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J Clin Invest 2005;115:247-257 (Pubitemid 40385467)
155. Paavonen K, Puolakkainen P, Jussila L, Jahkola T, Alitalo K. Vascular endothelial growth factor receptor-3 in lymphangiogenesis in wound healing. Am J Pathol 2000;156:1499-1504 (Pubitemid 30646689)
156. Gervasoni JE, Jr, Taneja C, Chung MA, Cady B. Biologic and clinical significance of lymphadenectomy. Surg Clin North Am 2000;80:1631-1673
157. Fisher B, Redmond C, Fisher ER. The contribution of recent NSABP clinical trials of primary breast cancer therapy to an understanding of tumor biology - an overview of findings. Cancer 1980;46:1009-1025 (Pubitemid 10027061)
158. Veronesi U, Orecchia R, Zurrida S, Galimberti V, Luini A, Veronesi P, Gatti G, D'Aiuto G, Cataliotti L, Paolucci R, Piccolo P, Massaioli N, et al. Avoiding axillary dissection in breast cancer surgery: a randomized trial to assess the role of axillary radiotherapy. Ann Oncol 2005;16:383-388 (Pubitemid 40458313)
159. Veronesi U, Marubini E, Mariani L, Valagussa P, Zucali R. The dissection of internal mammary nodes does not improve the survival of breast cancer patients: 30-year results of a randomised trial. Eur J Cancer 1999;35:1320-1325 (Pubitemid 29397430)
160. Pharis DB, Zitelli JA. The management of regional lymph nodes in cancer. Br J Dermatol 2003;149:919-925 (Pubitemid 37541975)
161. Yu XM, Lo CY, Lam AK, Lang BH, Leung P, Luk JM. The potential clinical relevance of serum vascular endothelial growth factor (VEGF) and VEGF-C in recurrent papillary thyroid carcinoma. Surgery 2008;144:934-940
162. Kimura H, Kato H, Tanaka N, Inose T, Faried A, Sohda M, Nakajima M, Fukai Y, Miyazaki T, Masuda N, Manda R, Fukuchi M, et al. Preoperative serum vascular endothelial growth factor-C (VEGF-C) levels predict recurrence in patients with esophageal cancer. Anticancer Res 2008;28:165-169 (Pubitemid 351362897)
163. Alabi AA, Suppiah A, Madden LA, Monson JR, Greenman J. Preoperative serum levels of serum VEGF-C is associated with distant metastasis in colorectal cancer patients. Int J Colorectal Dis 2009;24:269-274
164. Pitchford SC, Furze RC, Jones CP, Wengner AM, Rankin SM. Differential mobilization of subsets of progenitor cells from the bone marrow. Cell Stem Cell 2009;4:62-72.
165. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, MacDonald DD, Jin DK, Shido K, Kerns SA, Zhu Z, Hicklin D, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 2005;438:820-827 (Pubitemid 41753060)