Tumor lymphangiogenesis and new drug development

Advanced Drug Delivery Reviews

Volumn 99, Issue , 2016, Pages 148-160

  Dieterich, Lothar C ^a   Detmar, Michael ^a  

^a ETH ZURICH   (Switzerland)

Author keywords

Anti lymphangiogenic drug; Clinical trial; Lymph node; Lymphatic endothelial cell; Metastasis; Tumor associated inflammation

Indexed keywords

DISEASE CONTROL; DISEASES; ENDOTHELIAL CELLS; PATHOLOGY; TRANSPORT PROPERTIES;

ANTI-LYMPHANGIOGENIC DRUG; CLINICAL TRIAL; INTERSTITIAL FLUIDS; LYMPH NODE; METASTASIS; METASTATIC DISEASE; THERAPEUTIC APPLICATION; THERAPEUTIC TARGETS;

TUMORS;

AMG 208; AMG 337; AMG 780; ANGIOPOIETIN RECEPTOR; ANGIOTENSIN I; ANGIOTENSIN II; ANTINEOPLASTIC AGENT; CAPMATINIB; CHEMOKINE RECEPTOR CXCR4; CRIZOTINIB; CVX 060; FICLATUZUMAB; FORETINIB; IMC 3C5; MK 8033; ONARTUZUMAB; PF 04217903; RILOTUMUMAB; SCATTER FACTOR; SCATTER FACTOR RECEPTOR; SPHINGOSINE 1 PHOSPHATE; THROMBOSPONDIN 1; TIVANTINIB; TREBANANIB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASCULOTROPIN A; VASCULOTROPIN C; VASCULOTROPIN RECEPTOR 3; VGX 100; VOLITINIB;

ADAPTIVE IMMUNITY; ANTIGEN PRESENTING CELL; ANTIGEN SPECIFICITY; BREAST CANCER; CANCER GROWTH; CARCINOGENESIS; CD4+ T LYMPHOCYTE; CD8+ T LYMPHOCYTE; CELL PROLIFERATION; CELL RENEWAL; CIRCULATION; COLORECTAL CANCER; CORRELATION ANALYSIS; HUMAN; IMMUNE RESPONSE; IMMUNOLOGICAL TOLERANCE; IMMUNOREGULATION; LYMPHANGIOGENESIS; LYMPHATIC SYSTEM; MELANOMA; NON SMALL CELL LUNG CANCER; NONHUMAN; OVERALL SURVIVAL; PRIORITY JOURNAL; PROGRESSION FREE SURVIVAL; PROSTATE CANCER; PROTEIN CLEAVAGE; PROTEIN CROSS LINKING; PROTEIN FUNCTION; PROTEIN TARGETING; REVIEW; SKIN CANCER; STOMACH CANCER; ANIMAL; DRUG DEVELOPMENT; DRUG EFFECTS; LYMPH NODE METASTASIS; LYMPH VESSEL; NEOPLASMS; PATHOLOGY; PROCEDURES;

ANIMALS; ANTINEOPLASTIC AGENTS; DRUG DISCOVERY; HUMANS; LYMPHANGIOGENESIS; LYMPHATIC METASTASIS; LYMPHATIC VESSELS; NEOPLASMS;

EID: 84953268831     PISSN: 0169409X     EISSN: 18728294     Source Type: Journal    
DOI: 10.1016/j.addr.2015.12.011     Document Type: Review

References (216)

1. Alitalo K. The lymphatic vasculature in disease. Nat. Med. 2011, 17:1371-1380.
2. Hirakawa S., Detmar M., Karaman S. Lymphatics in nanophysiology. Adv. Drug Deliv. Rev. 2014, 74:12-18.
3. Dieterich L.C., Seidel C.D., Detmar M. Lymphatic vessels: new targets for the treatment of inflammatory diseases. Angiogenesis 2014, 17:359-371.
4. Stacker S.A., Williams S.P., Karnezis T., Shayan R., Fox S.B., Achen M.G. Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat. Rev. Cancer 2014, 14:159-172.
5. Padera T.P., Kadambi A., di Tomaso E., Carreira C.M., Brown E.B., Boucher Y., Choi N.C., Mathisen D., Wain J., Mark E.J., Munn L.L., Jain R.K. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 2002, 296:1883-1886.
6. 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. 2000, 60:4324-4327.
7. Stanczyk M., Olszewski W.L., Gewartowska M., Domaszewska-Szostek A. Lack of functioning lymphatics and accumulation of tissue fluid/lymph in interstitial "lakes" in colon cancer tissue. Lymphology 2010, 43:158-167.
8. Olszewski W.L., Stanczyk M., Gewartowska M., Domaszewska-Szostek A., Durlik M. Lack of functioning intratumoral lymphatics in colon and pancreas cancer tissue. Lymphat. Res. Biol. 2012, 10:112-117.
9. Agarwal B., Saxena R., Morimiya A., Mehrotra S., Badve S. Lymphangiogenesis does not occur in breast cancer. Am. J. Surg. Pathol. 2005, 29:1449-1455.
10. Roma A.A., Magi-Galluzzi C., Kral M.A., Jin T.T., Klein E.A., Zhou M. Peritumoral lymphatic invasion is associated with regional lymph node metastases in prostate adenocarcinoma. Mod. Pathol. 2006, 19:392-398.
11. Hirakawa S., Kodama S., Kunstfeld R., Kajiya K., Brown L.F., Detmar M. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J. Exp. Med. 2005, 201:1089-1099.
12. Hirakawa S., Brown L.F., 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.
13. 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. 2012, 41:2073-2078.
14. Angeli V., Ginhoux F., Llodra J., Quemeneur L., Frenette P.S., Skobe M., Jessberger R., Merad M., Randolph G.J. B cell-driven lymphangiogenesis in inflamed lymph nodes enhances dendritic cell mobilization. Immunity 2006, 24:203-215.
15. Kataru R.P., Jung K., Jang C., Yang H., Schwendener R.A., Baik J.E., Han S.H., Alitalo K., Koh G.Y. Critical role of CD11b + macrophages and VEGF in inflammatory lymphangiogenesis, antigen clearance, and inflammation resolution. Blood 2009, 113:5650-5659.
16. Huggenberger R., Ullmann S., Proulx S.T., Pytowski B., Alitalo K., Detmar M. Stimulation of lymphangiogenesis via VEGFR-3 inhibits chronic skin inflammation. J. Exp. Med. 2010, 207:2255-2269.
17. Huggenberger R., Siddiqui S.S., Brander D., Ullmann S., Zimmermann K., Antsiferova M., Werner S., Alitalo K., Detmar M. An important role of lymphatic vessel activation in limiting acute inflammation. Blood 2011, 117:4667-4678.
18. Gundem G., Van Loo P., Kremeyer B., Alexandrov L.B., Tubio J.M., Papaemmanuil E., Brewer D.S., Kallio H.M., Hognas G., Annala M., Kivinummi K., Goody V., Latimer C., O'Meara S., Dawson K.J., Isaacs W., Emmert-Buck M.R., Nykter M., Foster C., Kote-Jarai Z., Easton D., Whitaker H.C., Neal D.E., Cooper C.S., Eeles R.A., Visakorpi T., Campbell P.J., McDermott U., Wedge D.C., Bova G.S. The evolutionary history of lethal metastatic prostate cancer. Nature 2015, 520:353-357.
19. Hong M.K., Macintyre G., Wedge D.C., Van Loo P., Patel K., Lunke S., Alexandrov L.B., Sloggett C., Cmero M., Marass F., Tsui D., Mangiola S., Lonie A., Naeem H., Sapre N., Phal P.M., Kurganovs N., Chin X., Kerger M., Warren A.Y., Neal D., Gnanapragasam V., Rosenfeld N., Pedersen J.S., Ryan A., Haviv I., Costello A.J., Corcoran N.M., Hovens C.M. Tracking the origins and drivers of subclonal metastatic expansion in prostate cancer. Nat. Commun. 2015, 6:6605.
20. Nathanson S.D., Shah R., Rosso K. Sentinel lymph node metastases in cancer: causes, detection and their role in disease progression. Semin. Cell Dev. Biol. 2015, 38:106-116.
21. Pastushenko I., Vermeulen P.B., Carapeto F.J., Van den Eynden G., Rutten A., Ara M., Dirix L.Y., Van Laere S. Blood microvessel density, lymphatic microvessel density and lymphatic invasion in predicting melanoma metastases: systematic review and meta-analysis. Br. J. Dermatol. 2014, 170:66-77.
22. Chen Y., Yan J., Yuan Z., Yu S., Yang C., Wang Z., Zheng Q. A meta-analysis of the relationship between lymphatic microvessel density and clinicopathological parameters in breast cancer. Bull. Cancer 2013, 100:1-10.
23. Yu M., Liu L., Liang C., Li P., Ma X., Zhang Q., Wei Y. Intratumoral vessel density as prognostic factors in head and neck squamous cell carcinoma: a meta-analysis of literature. Head Neck 2014, 36:596-602.
24. Clevers H. The cancer stem cell: premises, promises and challenges. Nat. Med. 2011, 17:313-319.
25. Plaks V., Kong N., Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells?. Cell Stem Cell 2015, 16:225-238.
26. Mendez-Ferrer S., Michurina T.V., Ferraro F., Mazloom A.R., Macarthur B.D., Lira S.A., Scadden D.T., Ma'ayan A., Enikolopov G.N., Frenette P.S. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 2010, 466:829-834.
27. Boyle S.T., Ingman W.V., Poltavets V., Faulkner J.W., Whitfield R.J., McColl S.R., Kochetkova M. The chemokine receptor CCR7 promotes mammary tumorigenesis through amplification of stem-like cells. Oncogene 2015, 10.1038/onc.2015.66.
28. Cabioglu N., Yazici M.S., Arun B., Broglio K.R., Hortobagyi G.N., Price J.E., Sahin A. CCR7 and CXCR4 as novel biomarkers predicting axillary lymph node metastasis in T1 breast cancer. Clin. Cancer Res. 2005, 11:5686-5693.
29. Kim M., Koh Y.J., Kim K.E., Koh B.I., Nam D.H., Alitalo K., Kim I., Koh G.Y. CXCR4 signaling regulates metastasis of chemoresistant melanoma cells by a lymphatic metastatic niche. Cancer Res. 2010, 70:10411-10421.
30. Cohen J.N., Guidi C.J., Tewalt E.F., Qiao H., Rouhani S.J., Ruddell A., Farr A.G., Tung K.S., Engelhard V.H. Lymph node-resident lymphatic endothelial cells mediate peripheral tolerance via Aire-independent direct antigen presentation. J. Exp. Med. 2010, 207:681-688.
31. Tewalt E.F., Cohen J.N., Rouhani S.J., Guidi C.J., Qiao H., Fahl S.P., Conaway M.R., Bender T.P., Tung K.S., Vella A.T., Adler A.J., Chen L., Engelhard V.H. Lymphatic endothelial cells induce tolerance via PD-L1 and lack of costimulation leading to high-level PD-1 expression on CD8 T cells. Blood 2012, 120:4772-4782.
32. Cohen J.N., Tewalt E.F., Rouhani S.J., Buonomo E.L., Bruce A.N., Xu X., Bekiranov S., Fu Y.X., Engelhard V.H. Tolerogenic properties of lymphatic endothelial cells are controlled by the lymph node microenvironment. PLoS One 2014, 9.
33. Hirosue S., Vokali E., Raghavan V.R., Rincon-Restrepo M., Lund A.W., Corthesy-Henrioud P., Capotosti F., Halin Winter C., Hugues S., Swartz M.A. Steady-state antigen scavenging, cross-presentation, and CD8+ T cell priming: a new role for lymphatic endothelial cells. J. Immunol. 2014, 192:5002-5011.
34. Lund A.W., Duraes F.V., Hirosue S., Raghavan V.R., Nembrini C., Thomas S.N., Issa A., Hugues S., Swartz M.A. VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. Cell Rep. 2012, 1:191-199.
35. Tamburini B.A., Burchill M.A., Kedl R.M. Antigen capture and archiving by lymphatic endothelial cells following vaccination or viral infection. Nat. Commun. 2014, 5:3989.
36. Rouhani S.J., Eccles J.D., Riccardi P., Peske J.D., Tewalt E.F., Cohen J.N., Liblau R., Makinen T., Engelhard V.H. Roles of lymphatic endothelial cells expressing peripheral tissue antigens in CD4 T-cell tolerance induction. Nat. Commun. 2015, 6:6771.
37. Dubrot J., Duraes F.V., Potin L., Capotosti F., Brighouse D., Suter T., LeibundGut-Landmann S., Garbi N., Reith W., Swartz M.A., Hugues S. Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4(+) T cell tolerance. J. Exp. Med. 2014, 211:1153-1166.
38. Karkkainen M.J., Haiko P., Sainio K., Partanen J., Taipale J., Petrova T.V., Jeltsch M., Jackson D.G., Talikka M., Rauvala H., Betsholtz C., Alitalo K. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat. Immunol. 2004, 5:74-80.
39. Baldwin M.E., Halford M.M., Roufail S., Williams R.A., Hibbs M.L., Grail D., Kubo H., Stacker S.A., Achen M.G. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol. Cell. Biol. 2005, 25:2441-2449.
40. Rissanen T.T., Markkanen J.E., Gruchala M., Heikura T., Puranen A., Kettunen M.I., Kholova I., Kauppinen R.A., Achen M.G., Stacker S.A., Alitalo K., Yla-Herttuala S. VEGF-D is the strongest angiogenic and lymphangiogenic effector among VEGFs delivered into skeletal muscle via adenoviruses. Circ. Res. 2003, 92:1098-1106.
41. Schoppmann S.F., 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.
42. Ji H., Cao R., Yang Y., Zhang Y., Iwamoto H., Lim S., Nakamura M., Andersson P., Wang J., Sun Y., Dissing S., He X., Yang X., Cao Y. TNFR1 mediates TNF-alpha-induced tumour lymphangiogenesis and metastasis by modulating VEGF-C-VEGFR3 signalling. Nat. Commun. 2014, 5:4944.
43. Riabov V., Gudima A., Wang N., Mickley A., Orekhov A., Kzhyshkowska J. Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis. Front. Physiol. 2014, 5:75.
44. Ji R.C. Hypoxia and lymphangiogenesis in tumor microenvironment and metastasis. Cancer Lett. 2014, 346:6-16.
45. Morfoisse F., Kuchnio A., Frainay C., Gomez-Brouchet A., Delisle M.B., Marzi S., Helfer A.C., Hantelys F., Pujol F., Guillermet-Guibert J., Bousquet C., Dewerchin M., Pyronnet S., Prats A.C., Carmeliet P., Garmy-Susini B. Hypoxia induces VEGF-C expression in metastatic tumor cells via a HIF-1alpha-independent translation-mediated mechanism. Cell Rep. 2014, 6:155-167.
46. Valtola R., Salven P., Heikkila P., Taipale J., Joensuu H., Rehn M., Pihlajaniemi T., Weich H., deWaal R., Alitalo K. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am. J. Pathol. 1999, 154:1381-1390.
47. Schmeisser A., Christoph M., Augstein A., Marquetant R., Kasper M., Braun-Dullaeus R.C., Strasser R.H. Apoptosis of human macrophages by Flt-4 signaling: implications for atherosclerotic plaque pathology. Cardiovasc. Res. 2006, 71:774-784.
48. Zhang Y., Lu Y., Ma L., Cao X., Xiao J., Chen J., Jiao S., Gao Y., Liu C., Duan Z., Li D., He Y., Wei B., Wang H. Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-kappaB signaling and protects against endotoxin shock. Immunity 2014, 40:501-514.
49. Karaman S., Hollmen M., Robciuc M.R., Alitalo A., Nurmi H., Morf B., Buschle D., Alkan H.F., Ochsenbein A.M., Alitalo K., Wolfrum C., Detmar M. Blockade of VEGF-C and VEGF-D modulates adipose tissue inflammation and improves metabolic parameters under high-fat diet. Mol. Metab. 2015, 4:93-105.
50. Joukov V., Sorsa T., Kumar V., Jeltsch M., Claesson-Welsh L., Cao Y., Saksela O., Kalkkinen N., Alitalo K. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J. 1997, 16:3898-3911.
51. Stacker S.A., Stenvers K., Caesar C., Vitali A., Domagala T., Nice E., Roufail S., Simpson R.J., Moritz R., Karpanen T., Alitalo K., Achen M.G. Biosynthesis of vascular endothelial growth factor-D involves proteolytic processing which generates non-covalent homodimers. J. Biol. Chem. 1999, 274:32127-32136.
52. McColl B.K., Baldwin M.E., Roufail S., Freeman C., Moritz R.L., Simpson R.J., Alitalo K., Stacker S.A., Achen M.G. Plasmin activates the lymphangiogenic growth factors VEGF-C and VEGF-D. J. Exp. Med. 2003, 198:863-868.
53. Jeltsch M., Jha S.K., Tvorogov D., Anisimov A., Leppanen V.M., Holopainen T., Kivela R., Ortega S., Karpanen T., Alitalo K. CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. Circulation 2014, 129:1962-1971.
54. Joukov V., Pajusola K., Kaipainen A., Chilov D., Lahtinen I., Kukk E., Saksela O., Kalkkinen N., Alitalo K. 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. 1996, 15:290-298.
55. Bjorndahl M.A., Cao R., Burton J.B., Brakenhielm E., Religa P., Galter D., Wu L., Cao Y. Vascular endothelial growth factor-a promotes peritumoral lymphangiogenesis and lymphatic metastasis. Cancer Res. 2005, 65:9261-9268.
56. Tawada M., Hayashi S., Ikegame Y., Nakashima S., Yoshida K. Possible involvement of tumor-producing VEGF-A in the recruitment of lymphatic endothelial progenitor cells from bone marrow. Oncol. Rep. 2014, 32:2359-2364.
57. Van den Eynden G.G., Van der Auwera I., Van Laere S.J., Trinh X.B., Colpaert C.G., van Dam P., Dirix L.Y., Vermeulen P.B., Van Marck E.A. Comparison of molecular determinants of angiogenesis and lymphangiogenesis in lymph node metastases and in primary tumours of patients with breast cancer. J. Pathol. 2007, 213:56-64.
58. Eklund L., Saharinen P. Angiopoietin signaling in the vasculature. Exp. Cell Res. 2013, 319:1271-1280.
59. Schulz P., Fischer C., Detjen K.M., Rieke S., Hilfenhaus G., von Marschall Z., Bohmig M., Koch I., Kehrberger J., Hauff P., Thierauch K.H., Alves F., Wiedenmann B., Scholz A. Angiopoietin-2 drives lymphatic metastasis of pancreatic cancer. FASEB J. 2011, 25:3325-3335.
60. Fagiani E., Lorentz P., Kopfstein L., Christofori G. Angiopoietin-1 and -2 exert antagonistic functions in tumor angiogenesis, yet both induce lymphangiogenesis. Cancer Res. 2011, 71:5717-5727.
61. Holopainen T., Saharinen P., D'Amico G., Lampinen A., Eklund L., Sormunen R., Anisimov A., Zarkada G., Lohela M., Helotera H., Tammela T., Benjamin L.E., Yla-Herttuala S., Leow C.C., Koh G.Y., Alitalo K. Effects of angiopoietin-2-blocking antibody on endothelial cell-cell junctions and lung metastasis. J. Natl. Cancer Inst. 2012, 104:461-475.
62. Zheng W., Nurmi H., Appak S., Sabine A., Bovay E., Korhonen E.A., Orsenigo F., Lohela M., D'Amico G., Holopainen T., Leow C.C., Dejana E., Petrova T.V., Augustin H.G., Alitalo K. Angiopoietin 2 regulates the transformation and integrity of lymphatic endothelial cell junctions. Genes Dev. 2014, 28:1592-1603.
63. Shojaei F., Lee J.H., Simmons B.H., Wong A., Esparza C.O., Plumlee P.A., Feng J., Stewart A.E., Hu-Lowe D.D., Christensen J.G. HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors. Cancer Res. 2010, 70:10090-10100.
64. 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.
65. Jiang W.G., Davies G., Martin T.A., Parr C., Watkins G., Mansel R.E., Mason M.D. The potential lymphangiogenic effects of hepatocyte growth factor/scatter factor in vitro and in vivo. Int. J. Mol. Med. 2005, 16:723-728.
66. Cao R., Bjorndahl M.A., Gallego M.I., Chen S., Religa P., Hansen A.J., Cao Y. Hepatocyte growth factor is a lymphangiogenic factor with an indirect mechanism of action. Blood 2006, 107:3531-3536.
67. Zhang Q.H., Qian K., Li X.J., Pu J., Wu X.T. Experimental study of the hepatocyte growth factor contributing to lymphangiogenesis and lymphatic metastasis in gastric cancer. Zhonghua Wei Chang Wai Ke Za Zhi 2007, 10:212-216.
68. Cao R., Ji H., Feng N., Zhang Y., Yang X., Andersson P., Sun Y., Tritsaris K., Hansen A.J., Dissing S., Cao Y. Collaborative interplay between FGF-2 and VEGF-C promotes lymphangiogenesis and metastasis. Proc. Natl. Acad. Sci. U. S. A. 2012, 109:15894-15899.
69. Larrieu-Lahargue F., Welm A.L., Bouchecareilh M., Alitalo K., Li D.Y., Bikfalvi A., Auguste P. Blocking Fibroblast Growth Factor receptor signaling inhibits tumor growth, lymphangiogenesis, and metastasis. PLoS One 2012, 7.
70. Platonova N., Miquel G., Regenfuss B., Taouji S., Cursiefen C., Chevet E., Bikfalvi A. Evidence for the interaction of fibroblast growth factor-2 with the lymphatic endothelial cell marker LYVE-1. Blood 2013, 121:1229-1237.
71. Marino D., Angehrn Y., Klein S., Riccardi S., Baenziger-Tobler N., Otto V.I., Pittelkow M., Detmar M. Activation of the epidermal growth factor receptor promotes lymphangiogenesis in the skin. J. Dermatol. Sci. 2013, 71:184-194.
72. Bracher A., Cardona A.S., Tauber S., Fink A.M., Steiner A., Pehamberger H., Niederleithner H., Petzelbauer P., Groger M., Loewe R. Epidermal growth factor facilitates melanoma lymph node metastasis by influencing tumor lymphangiogenesis. J. Invest. Dermatol. 2013, 133:230-238.
73. Cao R., Bjorndahl M.A., Religa P., Clasper S., Garvin S., Galter D., Meister B., Ikomi F., Tritsaris K., Dissing S., Ohhashi T., Jackson D.G., Cao Y. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell 2004, 6:333-345.
74. Bjorndahl M., Cao R., Nissen L.J., Clasper S., Johnson L.A., Xue Y., Zhou Z., Jackson D., Hansen A.J., Cao Y. Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo. Proc. Natl. Acad. Sci. U. S. A. 2005, 102:15593-15598.
75. Li Z.J., Ying X.J., Chen H.L., Ye P.J., Chen Z.L., Li G., Jiang H.F., Liu J., Zhou S.Z. Insulin-like growth factor-1 induces lymphangiogenesis and facilitates lymphatic metastasis in colorectal cancer. World J. Gastroenterol. 2013, 19:7788-7794.
76. Mantovani A., Allavena P., Sica A., Balkwill F. Cancer-related inflammation. Nature 2008, 454:436-444.
77. Lyons T.R., O'Brien J., Borges V.F., Conklin M.W., Keely P.J., Eliceiri K.W., Marusyk A., Tan A.C., Schedin P. Postpartum mammary gland involution drives progression of ductal carcinoma in situ through collagen and COX-2. Nat. Med. 2011, 17:1109-1115.
78. Lyons T.R., Borges V.F., Betts C.B., Guo Q., Kapoor P., Martinson H.A., Jindal S., Schedin P. Cyclooxygenase-2-dependent lymphangiogenesis promotes nodal metastasis of postpartum breast cancer. J. Clin. Invest. 2014, 124:3901-3912.
79. Barnes N.L., Warnberg F., Farnie G., White D., Jiang W., Anderson E., Bundred N.J. Cyclooxygenase-2 inhibition: effects on tumour growth, cell cycling and lymphangiogenesis in a xenograft model of breast cancer. Br. J. Cancer 2007, 96:575-582.
80. Liu H., Yang Y., Xiao J., Lv Y., Liu Y., Yang H., Zhao L. COX-2-mediated regulation of VEGF-C in association with lymphangiogenesis and lymph node metastasis in lung cancer. Anat. Rec. (Hoboken) 2010, 293:1838-1846.
81. Morita Y., Hata K., Nakanishi M., Nishisho T., Yura Y., Yoneda T. Cyclooxygenase-2 promotes tumor lymphangiogenesis and lymph node metastasis in oral squamous cell carcinoma. Int. J. Oncol. 2012, 41:885-892.
82. Karnezis T., Shayan R., Caesar C., Roufail S., Harris N.C., Ardipradja K., Zhang Y.F., Williams S.P., Farnsworth R.H., Chai M.G., Rupasinghe T.W., Tull D.L., Baldwin M.E., Sloan E.K., Fox S.B., Achen M.G., Stacker S.A. VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell 2012, 21:181-195.
83. Ogawa F., Amano H., Eshima K., Ito Y., Matsui Y., Hosono K., Kitasato H., Iyoda A., Iwabuchi K., Kumagai Y., Satoh Y., Narumiya S., Majima M. Prostanoid induces premetastatic niche in regional lymph nodes. J. Clin. Invest. 2014, 124:4882-4894.
84. Karpinich N.O., Kechele D.O., Espenschied S.T., Willcockson H.H., Fedoriw Y., Caron K.M. Adrenomedullin gene dosage correlates with tumor and lymph node lymphangiogenesis. FASEB J. 2013, 27:590-600.
85. Klein K.R., Karpinich N.O., Espenschied S.T., Willcockson H.H., Dunworth W.P., Hoopes S.L., Kushner E.J., Bautch V.L., Caron K.M. Decoy receptor CXCR7 modulates adrenomedullin-mediated cardiac and lymphatic vascular development. Dev. Cell 2014, 30:528-540.
86. Pham T.H., Baluk P., Xu Y., Grigorova I., Bankovich A.J., Pappu R., Coughlin S.R., McDonald D.M., Schwab S.R., Cyster J.G. Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning. J. Exp. Med. 2010, 207:17-27.
87. Nagahashi M., Ramachandran S., Kim E.Y., Allegood J.C., Rashid O.M., Yamada A., Zhao R., Milstien S., Zhou H., Spiegel S., Takabe K. Sphingosine-1-phosphate produced by sphingosine kinase 1 promotes breast cancer progression by stimulating angiogenesis and lymphangiogenesis. Cancer Res. 2012, 72:726-735.
88. Lejmi E., Leconte L., Pedron-Mazoyer S., Ropert S., Raoul W., Lavalette S., Bouras I., Feron J.G., Maitre-Boube M., Assayag F., Feumi C., Alemany M., Jie T.X., Merkulova T., Poupon M.F., Ruchoux M.M., Tobelem G., Sennlaub F., Plouet J. Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B. Proc. Natl. Acad. Sci. U. S. A. 2008, 105:12491-12496.
89. Eveno C., Broqueres-You D., Feron J.G., Rampanou A., Tijeras-Raballand A., Ropert S., Leconte L., Levy B.I., Pocard M. Netrin-4 delays colorectal cancer carcinomatosis by inhibiting tumor angiogenesis. Am. J. Pathol. 2011, 178:1861-1869.
90. Larrieu-Lahargue F., Welm A.L., Thomas K.R., Li D.Y. Netrin-4 induces lymphangiogenesis in vivo. Blood 2010, 115:5418-5426.
91. Brideau G., Makinen M.J., Elamaa H., Tu H., Nilsson G., Alitalo K., Pihlajaniemi T., Heljasvaara R. Endostatin overexpression inhibits lymphangiogenesis and lymph node metastasis in mice. Cancer Res. 2007, 67:11528-11535.
92. Weckmann M., Moir L.M., Heckman C.A., Black J.L., Oliver B.G., Burgess J.K. Lamstatin-a novel inhibitor of lymphangiogenesis derived from collagen IV. J. Cell. Mol. Med. 2012, 16:3062-3073.
93. Hwang-Bo J., Yoo K.H., Park J.H., Jeong H.S., Chung I.S. Recombinant canstatin inhibits angiopoietin-1-induced angiogenesis and lymphangiogenesis. Int. J. Cancer 2012, 131:298-309.
94. Cursiefen C., Maruyama K., Bock F., Saban D., Sadrai Z., Lawler J., Dana R., Masli S. Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J. Exp. Med. 2011, 208:1083-1092.
95. Hawighorst T., Oura H., Streit M., Janes L., Nguyen L., Brown L.F., Oliver G., Jackson D.G., Detmar M. Thrombospondin-1 selectively inhibits early-stage carcinogenesis and angiogenesis but not tumor lymphangiogenesis and lymphatic metastasis in transgenic mice. Oncogene 2002, 21:7945-7956.
96. Albuquerque R.J., Hayashi T., Cho W.G., Kleinman M.E., Dridi S., Takeda A., Baffi J.Z., Yamada K., Kaneko H., Green M.G., Chappell J., Wilting J., Weich H.A., Yamagami S., Amano S., Mizuki N., Alexander J.S., Peterson M.L., Brekken R.A., Hirashima M., Capoor S., Usui T., Ambati B.K., Ambati J. Alternatively spliced vascular endothelial growth factor receptor-2 is an essential endogenous inhibitor of lymphatic vessel growth. Nat. Med. 2009, 15:1023-1030.
97. Becker J., Pavlakovic H., Ludewig F., Wilting F., Weich H.A., Albuquerque R., Ambati J., Wilting J. Neuroblastoma progression correlates with downregulation of the lymphangiogenesis inhibitor sVEGFR-2. Clin. Cancer Res. 2010, 16:1431-1441.
98. Singh N., Tiem M., Watkins R., Cho Y.K., Wang Y., Olsen T., Uehara H., Mamalis C., Luo L., Oakey Z., Ambati B.K. Soluble vascular endothelial growth factor receptor 3 is essential for corneal alymphaticity. Blood 2013, 121:4242-4249.
99. Heishi T., Hosaka T., Suzuki Y., Miyashita H., Oike Y., Takahashi T., Nakamura T., Arioka S., Mitsuda Y., Takakura T., Hojo K., Matsumoto M., Yamauchi C., Ohta H., Sonoda H., Sato Y. Endogenous angiogenesis inhibitor vasohibin1 exhibits broad-spectrum antilymphangiogenic activity and suppresses lymph node metastasis. Am. J. Pathol. 2010, 176:1950-1958.
100. Oka M., Iwata C., Suzuki H.I., Kiyono K., Morishita Y., Watabe T., Komuro A., Kano M.R., Miyazono K. Inhibition of endogenous TGF-beta signaling enhances lymphangiogenesis. Blood 2008, 111:4571-4579.
101. Mumblat Y., Kessler O., Ilan N., Neufeld G. Full-length semaphorin-3C is an inhibitor of tumor lymphangiogenesis and metastasis. Cancer Res. 2015, 75:2177-2186.
102. Doci C.L., Mikelis C.M., Lionakis M.S., Molinolo A.A., Gutkind J.S. Genetic identification of SEMA3F as an anti-lymphangiogenic metastasis suppressor gene in head and neck squamous carcinoma. Cancer Res. 2015, 75(14):2937-2948.
103. Kataru R.P., Kim H., Jang C., Choi D.K., Koh B.I., Kim M., Gollamudi S., Kim Y.K., Lee S.H., Koh G.Y. T lymphocytes negatively regulate lymph node lymphatic vessel formation. Immunity 2011, 34:96-107.
104. Savetsky I.L., Ghanta S., Gardenier J.C., Torrisi J.S., Garcia Nores G.D., Hespe G.E., Nitti M.D., Kataru R.P., Mehrara B.J. Th2 cytokines inhibit lymphangiogenesis. PLoS One 2015, 10.
105. Shin K., Kataru R.P., Park H.J., Kwon B.I., Kim T.W., Hong Y.K., Lee S.H. TH2 cells and their cytokines regulate formation and function of lymphatic vessels. Nat. Commun. 2015, 6:6196.
106. Karpanen T., Egeblad M., Karkkainen M.J., Kubo H., Yla-Herttuala S., Jaattela M., Alitalo K. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res. 2001, 61:1786-1790.
107. 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.
108. Shimizu K., Kubo H., Yamaguchi K., Kawashima K., Ueda Y., Matsuo K., Awane M., Shimahara Y., Takabayashi A., Yamaoka Y., Satoh S. Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci. 2004, 95:328-333.
109. Burton J.B., Priceman S.J., Sung J.L., Brakenhielm E., An D.S., 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. Persaud K., Tille J.C., Liu M., Zhu Z., Jimenez X., Pereira D.S., Miao H.Q., Brennan L.A., Witte L., Pepper M.S., Pytowski B. 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. 2004, 117:2745-2756.
111. Goldman J., Rutkowski J.M., Shields J.D., Pasquier M.C., Cui Y., Schmokel H.G., Willey S., Hicklin D.J., Pytowski B., Swartz M.A. Cooperative and redundant roles of VEGFR-2 and VEGFR-3 signaling in adult lymphangiogenesis. FASEB J. 2007, 21:1003-1012.
112. Rinderknecht M., Villa A., Ballmer-Hofer K., Neri D., Detmar M. Phage-derived fully human monoclonal antibody fragments to human vascular endothelial growth factor-C block its interaction with VEGF receptor-2 and 3. PLoS One 2010, 5.
113. Jimenez X., Lu D., Brennan L., Persaud K., Liu M., Miao H., Witte L., Zhu Z. A recombinant, fully human, bispecific antibody neutralizes the biological activities mediated by both vascular endothelial growth factor receptors 2 and 3. Mol. Cancer Ther. 2005, 4:427-434.
114. Achen M.G., Roufail S., Domagala T., Catimel B., Nice E.C., Geleick D.M., Murphy R., Scott A.M., Caesar C., Makinen T., Alitalo K., Stacker S.A. Monoclonal antibodies to vascular endothelial growth factor-D block its interactions with both VEGF receptor-2 and VEGF receptor-3. Eur. J. Biochem. 2000, 267:2505-2515.
115. Caunt M., Mak J., Liang W.C., Stawicki S., Pan Q., Tong R.K., Kowalski J., Ho C., Reslan H.B., Ross J., Berry L., Kasman I., Zlot C., Cheng Z., Le Couter J., Filvaroff E.H., Plowman G., Peale F., French D., Carano R., Koch A.W., Wu Y., Watts R.J., Tessier-Lavigne M., Bagri A. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 2008, 13:331-342.
116. Alam A., Blanc I., Gueguen-Dorbes G., Duclos O., Bonnin J., Barron P., Laplace M.C., Morin G., Gaujarengues F., Dol F., Herault J.P., Schaeffer P., Savi P., Bono F. SAR131675, a potent and selective VEGFR-3-TK inhibitor with antilymphangiogenic, antitumoral, and antimetastatic activities. Mol. Cancer Ther. 2012, 11:1637-1649.
117. Lin J., Lalani A.S., Harding T.C., Gonzalez M., Wu W.W., Luan B., Tu G.H., Koprivnikar K., VanRoey M.J., He Y., Alitalo K., Jooss K. Inhibition of lymphogenous metastasis using adeno-associated virus-mediated gene transfer of a soluble VEGFR-3 decoy receptor. Cancer Res. 2005, 65:6901-6909.
118. Gherardi E., Birchmeier W., Birchmeier C., Vande Woude G. Targeting MET in cancer: rationale and progress. Nat. Rev. Cancer 2012, 12:89-103.
119. Kieran M.W., Kalluri R., Cho Y.J. The VEGF pathway in cancer and disease: responses, resistance, and the path forward. Cold Spring Harb. Perspect. Med. 2012, 2:a006593.
120. Chen H.M., Tsai C.H., Hung W.C. Foretinib inhibits angiogenesis, lymphangiogenesis and tumor growth of pancreatic cancer in vivo by decreasing VEGFR-2/3 and TIE-2 signaling. Oncotarget 2015, 6(17):14940-14952.
121. Yiannakopoulou E. Modulation of lymphangiogenesis: a new target for aspirin and other nonsteroidal anti-inflammatory agents? A systematic review. J. Clin. Pharmacol. 2012, 52:1749-1754.
122. Yano A., Fujii Y., Iwai A., Kawakami S., Kageyama Y., Kihara K. Glucocorticoids suppress tumor lymphangiogenesis of prostate cancer cells. Clin. Cancer Res. 2006, 12:6012-6017.
123. Shinriki S., Jono H., Ueda M., Ota K., Ota T., Sueyoshi T., Oike Y., Ibusuki M., Hiraki A., Nakayama H., Shinohara M., Ando Y. Interleukin-6 signalling regulates vascular endothelial growth factor-C synthesis and lymphangiogenesis in human oral squamous cell carcinoma. J. Pathol. 2011, 225:142-150.
124. Proulx S.T., Luciani P., Dieterich L.C., Karaman S., Leroux J.C., Detmar M. Expansion of the lymphatic vasculature in cancer and inflammation: new opportunities for in vivo imaging and drug delivery. J. Control. Release 2013, 172:550-557.
125. Moncayo V.M., Aarsvold J.N., Alazraki N.P. Lymphoscintigraphy and sentinel nodes. J. Nucl. Med. 2015, 56:901-907.
126. Kitai T., Inomoto T., Miwa M., Shikayama T. Fluorescence navigation with indocyanine green for detecting sentinel lymph nodes in breast cancer. Breast Cancer 2005, 12:211-215.
127. Proulx S.T., Luciani P., Christiansen A., Karaman S., Blum K.S., Rinderknecht M., Leroux J.C., Detmar M. Use of a PEG-conjugated bright near-infrared dye for functional imaging of rerouting of tumor lymphatic drainage after sentinel lymph node metastasis. Biomaterials 2013, 34:5128-5137.
128. Blum K.S., Proulx S.T., Luciani P., Leroux J.C., Detmar M. Dynamics of lymphatic regeneration and flow patterns after lymph node dissection. Breast Cancer Res. Treat. 2013, 139:81-86.
129. Dadras S.S., Paul T., Bertoncini J., Brown L.F., Muzikansky A., Jackson D.G., Ellwanger U., Garbe C., Mihm M.C., Detmar M. Tumor lymphangiogenesis: a novel prognostic indicator for cutaneous melanoma metastasis and survival. Am. J. Pathol. 2003, 162:1951-1960.
130. Valencak J., Heere-Ress E., Kopp T., Schoppmann S.F., Kittler H., Pehamberger H. Selective immunohistochemical staining shows significant prognostic influence of lymphatic and blood vessels in patients with malignant melanoma. Eur. J. Cancer 2004, 40:358-364.
131. Dadras S.S., Lange-Asschenfeldt B., Velasco P., Nguyen L., Vora A., Muzikansky A., Jahnke K., Hauschild A., Hirakawa S., Mihm M.C., Detmar M. Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod. Pathol. 2005, 18:1232-1242.
132. Doeden K., Ma Z., Narasimhan B., Swetter S.M., Detmar M., Dadras S.S. Lymphatic invasion in cutaneous melanoma is associated with sentinel lymph node metastasis. J. Cutan. Pathol. 2009, 36:772-780.
133. Shayan R., Karnezis T., Murali R., Wilmott J.S., Ashton M.W., Taylor G.I., Thompson J.F., Hersey P., Achen M.G., Scolyer R.A., Stacker S.A. Lymphatic vessel density in primary melanomas predicts sentinel lymph node status and risk of metastasis. Histopathology 2012, 61:702-710.
134. Heindl L.M., Hofmann-Rummelt C., Adler W., Bosch J.J., Holbach L.M., Naumann G.O., Kruse F.E., Cursiefen C. Prognostic significance of tumor-associated lymphangiogenesis in malignant melanomas of the conjunctiva. Ophthalmology 2011, 118:2351-2360.
135. Bono P., Wasenius V.M., Heikkila P., Lundin J., Jackson D.G., Joensuu H. High LYVE-1-positive lymphatic vessel numbers are associated with poor outcome in breast cancer. Clin. Cancer Res. 2004, 10:7144-7149.
136. El-Gohary Y.M., Metwally G., Saad R.S., Robinson M.J., Mesko T., Poppiti R.J. Prognostic significance of intratumoral and peritumoral lymphatic density and blood vessel density in invasive breast carcinomas. Am. J. Clin. Pathol. 2008, 129:578-586.
137. 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 2008, 25:717-725.
138. Kandemir N.O., Barut F., Bektas S., Ozdamar S.O. Can lymphatic vascular density be used in determining metastatic spreading potential of tumor in invasive ductal carcinomas?. Pathol. Oncol. Res. 2012, 18:253-262.
139. 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. 2009, 113:261-273.
140. 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.
141. Schoppmann S.F., Birner P., Studer P., Breiteneder-Geleff S. Lymphatic microvessel density and lymphovascular invasion assessed by anti-podoplanin immunostaining in human breast cancer. Anticancer Res. 2001, 21:2351-2355.
142. Zhao Y.C., Ni X.J., Li Y., Dai M., Yuan Z.X., Zhu Y.Y., Luo C.Y. Peritumoral lymphangiogenesis induced by vascular endothelial growth factor C and D promotes lymph node metastasis in breast cancer patients. World J. Surg. Oncol. 2012, 10:165.
143. Kato T., Prevo R., Steers G., Roberts H., Leek R.D., Kimura T., Kameoka S., Nishikawa T., Kobayashi M., Jackson D.G., Harris A.L., Gatter K.C., Pezzella F. A quantitative analysis of lymphatic vessels in human breast cancer, based on LYVE-1 immunoreactivity. Br. J. Cancer 2005, 93:1168-1174.
144. Van der Auwera I., Van den Eynden G.G., Colpaert C.G., Van Laere S.J., van Dam P., Van Marck E.A., Dirix L.Y., Vermeulen P.B. Tumor lymphangiogenesis in inflammatory breast carcinoma: a histomorphometric study. Clin. Cancer Res. 2005, 11:7637-7642.
145. van der Schaft D.W., Pauwels P., Hulsmans S., Zimmermann M., van de Poll-Franse L.V., Griffioen A.W. Absence of lymphangiogenesis in ductal breast cancer at the primary tumor site. Cancer Lett. 2007, 254:128-136.
146. Williams C.S., Leek R.D., Robson A.M., Banerji S., Prevo R., Harris A.L., Jackson D.G. Absence of lymphangiogenesis and intratumoural lymph vessels in human metastatic breast cancer. J. Pathol. 2003, 200:195-206.
147. Hurst N.J., Dominello M., Dyson G., Jaratli H., Sharma M., Ahmed Y.K., Melkane A.E., Rose C., Jacobs J., Giorgadze T., Kim H. Intratumoral lymphatic vessel density as a predictor of progression-free and overall survival in locally advanced laryngeal/hypopharyngeal cancer. Head Neck 2015, 10.1002/hed.24011.
148. Hinojar-Gutierrez A., Fernandez-Contreras M.E., Alvarez-Carrillo S., Quintanilla M., Gamallo C. Role of intratumoral lymphatic vessels in the lymph node dissemination of laryngopharyngeal squamous cell carcinoma. Head Neck 2010, 32:757-762.
149. Chung M.K., Min J.Y., So Y.K., Ko Y.H., Jeong H.S., Son Y.I., Baek C.H. Correlation between lymphatic vessel density and regional metastasis in squamous cell carcinoma of the tongue. Head Neck 2010, 32:445-451.
150. Frech S., Hormann K., Riedel F., Gotte K. Lymphatic vessel density in correlation to lymph node metastasis in head and neck squamous cell carcinoma. Anticancer Res. 2009, 29:1675-1679.
151. Zhao D., Pan J., Li X.Q., Wang X.Y., Tang C., Xuan M. Intratumoral lymphangiogenesis in oral squamous cell carcinoma and its clinicopathological significance. J. Oral Pathol. Med. 2008, 37:616-625.
152. Hinojar-Gutierrez A., Fernandez-Contreras M.E., Gonzalez-Gonzalez R., Fernandez-Luque M.J., Hinojar-Arzadun 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.
153. Audet N., Beasley N.J., MacMillan C., Jackson D.G., Gullane P.J., Kamel-Reid S. Lymphatic vessel density, nodal metastases, and prognosis in patients with head and neck cancer. Arch. Otolaryngol. Head Neck Surg. 2005, 131:1065-1070.
154. Kyzas P.A., Geleff S., Batistatou A., Agnantis N.J., Stefanou D. Evidence for lymphangiogenesis and its prognostic implications in head and neck squamous cell carcinoma. J. Pathol. 2005, 206:170-177.
155. Munoz-Guerra M.F., Marazuela E.G., Martin-Villar E., Quintanilla M., Gamallo C. Prognostic significance of intratumoral lymphangiogenesis in squamous cell carcinoma of the oral cavity. Cancer 2004, 100:553-560.
156. Maula S.M., Luukkaa M., Grenman R., Jackson D., Jalkanen S., Ristamaki 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.
157. Beasley N.J., Prevo R., Banerji S., Leek R.D., Moore J., van Trappen P., Cox G., Harris A.L., Jackson D.G. Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res. 2002, 62:1315-1320.
158. Longatto Filho A., Oliveira T.G., Pinheiro C., de Carvalho M.B., Curioni O.A., Mercante A.M., Schmitt F.C., Gattas G.J. How useful is the assessment of lymphatic vascular density in oral carcinoma prognosis?. World J. Surg. Oncol. 2007, 5:140.
159. 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.
160. Heindl L.M., Hofmann-Rummelt C., Adler W., Holbach L.M., Naumann G.O., Kruse F.E., Cursiefen C. Tumor-associated lymphangiogenesis in the development of conjunctival squamous cell carcinoma. Ophthalmology 2010, 117:649-658.
161. Adachi Y., Nakamura H., Kitamura Y., Taniguchi Y., Araki K., Shomori K., Horie Y., Kurozawa Y., Ito H., Hayashi K. 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. 2007, 57:171-177.
162. Takanami I. Lymphatic microvessel density using D2-40 is associated with nodal metastasis in non-small cell lung cancer. Oncol. Rep. 2006, 15:437-442.
163. 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.
164. Kadota K., Huang C.L., Liu D., Ueno M., Kushida Y., Haba R., Yokomise H. The clinical significance of lymphangiogenesis and angiogenesis in non-small cell lung cancer patients. Eur. J. Cancer 2008, 44:1057-1067.
165. Sun J.G., Wang Y., Chen Z.T., Zhuo W.L., Zhu B., Liao R.X., Zhang S.X. Detection of lymphangiogenesis in non-small cell lung cancer and its prognostic value. J. Exp. Clin. Cancer Res. 2009, 28:21.
166. Jin S., Zhu W., Shi Q., Zhang Z., Guo R. Clinicopathological significance of lymphatic vessel density marked by D2-40 and E-cadherin expression in non-small-cell lung cancer. Med. Oncol. 2012, 29:3157-3161.
167. Wang J., Li K., Wang B., Bi J. Lymphatic microvessel density as a prognostic factor in non-small cell lung carcinoma: a meta-analysis of the literature. Mol. Biol. Rep. 2012, 39:5331-5338.
168. Faoro L., Hutto J.Y., Salgia R., El-Zayaty S.A., Ferguson M.K., Cheney R.T., Reid M.E., Armato S.G., Krausz T., Husain A.N. Lymphatic vessel density is not associated with lymph node metastasis in non-small cell lung carcinoma. Arch. Pathol. Lab. Med. 2008, 132:1882-1888.
169. Algars A., Irjala H., Vaittinen S., Huhtinen H., Sundstrom J., Salmi M., Ristamaki R., Jalkanen S. Type and location of tumor-infiltrating macrophages and lymphatic vessels predict survival of colorectal cancer patients. Int. J. Cancer 2012, 131:864-873.
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. 2011, 64:6-12.
171. 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.
172. Matsumoto K., Nakayama Y., Inoue Y., Minagawa N., Katsuki T., Shibao K., Tsurudome Y., Hirata K., Nagata N., Itoh H. Lymphatic microvessel density is an independent prognostic factor in colorectal cancer. Dis. Colon Rectum 2007, 50:308-314.
173. Kaneko I., Tanaka S., Oka S., Kawamura T., Hiyama T., Ito M., Yoshihara M., Shimamoto F., Chayama K. Lymphatic vessel density at the site of deepest penetration as a predictor of lymph node metastasis in submucosal colorectal cancer. Dis. Colon Rectum 2007, 50:13-21.
174. Saad R.S., Kordunsky L., Liu Y.L., Denning K.L., Kandil H.A., Silverman J.F. Lymphatic microvessel density as prognostic marker in colorectal cancer. Mod. Pathol. 2006, 19:1317-1323.
175. Liang P., Hong J.W., Ubukata H., Liu H.R., Watanabe Y., Katano M., Motohashi G., Kasuga T., Nakada I., Tabuchi T. Increased density and diameter of lymphatic microvessels correlate with lymph node metastasis in early stage invasive colorectal carcinoma. Virchows Arch. 2006, 448:570-575.
176. Kuroyama S., Kobayashi N., Ohbu M., Ohtani Y., Okayasu I., Kakita A. Enzyme histochemical analysis of lymphatic vessels in colon carcinoma: occurrence of lymphangiogenesis within the tumor. Hepato-Gastroenterology 2005, 52:1057-1061.
177. Lin M., Ma S.P., Lin H.Z., Ji P., Xie D., Yu J.X. Intratumoral as well as peritumoral lymphatic vessel invasion correlates with lymph node metastasis and unfavourable outcome in colorectal cancer. Clin. Exp. Metastasis 2010, 27:123-132.
178. 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.
179. 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.
180. Wang X.L., Fang J.P., Tang R.Y., Chen X.M. Different significance between intratumoral and peritumoral lymphatic vessel density in gastric cancer: a retrospective study of 123 cases. BMC Cancer 2010, 10:299.
181. Coskun U., Akyurek N., Dursun A., Yamac D. Peritumoral lymphatic microvessel density associated with tumor progression and poor prognosis in gastric carcinoma. J. Surg. Res. 2010, 164:110-115.
182. Gao P., Zhou G.Y., Zhang Q.H., Xiang L., Zhang S.L., Li C., Sun Y.L. Clinicopathological significance of peritumoral lymphatic vessel density in gastric carcinoma. Cancer Lett. 2008, 263:223-230.
183. Donizy P., Rudno-Rudzinska J., Halon A., Dziegala M., Kabarowski J., Frejlich E., Dziegiel P., Kielan W., Matkowski R. Intratumoral but not peritumoral lymphatic vessel density measured by D2-40 expression predicts poor outcome in gastric cancer-ROC curve analysis to find cut-off point. Anticancer Res. 2014, 34:3113-3118.
184. Lee K., Park do J., Choe G., Kim H.H., Kim W.H., Lee H.S. Increased intratumoral lymphatic vessel density correlates with lymph node metastasis in early gastric carcinoma. Ann. Surg. Oncol. 2010, 17:73-80.
185. Rudno-Rudzinska J., Kielan W., Grzebieniak Z., Dziegiel P., Donizy P., Mazur G., Knakiewicz M., Frejlich E., Halon A. High density of peritumoral lymphatic vessels measured by D2-40/podoplanin and LYVE-1 expression in gastric cancer patients: an excellent prognostic indicator or a false friend?. Gastric Cancer 2013, 16:513-520.
186. Debinski P., Dembowski J., Kowal P., Szydelko T., Kolodziej A., Malkiewicz B., Tupikowski K., Zdrojowy R. The clinical significance of lymphangiogenesis in renal cell carcinoma. Med. Sci. Monit. 2013, 19:606-611.
187. Ozardili I., Guldur M.E., Ciftci H., Bitiren M., Altunkol A. Correlation between lymphangiogenesis and clinicopathological parameters in renal cell carcinoma. Singap. Med. J. 2012, 53:332-335.
188. 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.
189. Baldewijns M.M., Roskams T., Ballet V., Van den Eynden G.G., Van Laere S.J., Van der Auwera I., Lerut E., De Bruine A.P., Thijssen V.L., Vermeulen P.B., van Poppel H. A low frequency of lymph node metastasis in clear-cell renal cell carcinoma is related to low lymphangiogenic activity. BJU Int. 2009, 103:1626-1631.
190. Iwata T., Miyata Y., Kanda S., Nishikido M., Hayashi T., Sakai H., Kanetake H. Lymphangiogenesis and angiogenesis in conventional renal cell carcinoma: association with vascular endothelial growth factors A to D immunohistochemistry. Urology 2008, 71:749-754.
191. Ma Y., Hou Y., Liu B., Li X., Yang S., Ma J. Intratumoral lymphatics and lymphatic vessel invasion detected by D2-40 are essential for lymph node metastasis in bladder transitional cell carcinoma. Anat. Rec. (Hoboken) 2010, 293:1847-1854.
192. Fernandez M.I., Bolenz C., Trojan L., Steidler A., Weiss C., Alken P., Grobholz R., Michel M.S. Prognostic implications of lymphangiogenesis in muscle-invasive transitional cell carcinoma of the bladder. Eur. Urol. 2008, 53:571-578.
193. Bolenz C., Auer M., Strobel P., Heinzelbecker J., Schubert C., Trojan L. The lymphatic system in clinically localized urothelial carcinoma of the bladder: morphologic characteristics and predictive value. Urol. Oncol. 2013, 31:1606-1614.
194. Bolenz C., Fernandez M.I., Trojan L., Hoffmann K., Herrmann E., Steidler A., Weiss C., Strobel P., Alken P., Michel M.S. Lymphangiogenesis occurs in upper tract urothelial carcinoma and correlates with lymphatic tumour dissemination and poor prognosis. BJU Int. 2009, 103:1040-1046.
195. Cheng L., Bishop E., Zhou H., Maclennan G.T., Lopez-Beltran A., Zhang S., Badve S., Baldridge L.A., Montironi R. Lymphatic vessel density in radical prostatectomy specimens. Hum. Pathol. 2008, 39:610-615.
196. Kostis G., Ioannis L., Helen K., Helen P. The expression of vascular endothelial growth factor-C correlates with lymphatic microvessel density and lymph node metastasis in prostate carcinoma: an immunohistochemical study. Urol. Ann. 2014, 6:224-230.
197. Trojan L., Rensch F., Voss M., Grobholz R., Weiss C., Jackson D.G., Alken P., Michel M.S. The role of the lymphatic system and its specific growth factor, vascular endothelial growth factor C, for lymphogenic metastasis in prostate cancer. BJU Int. 2006, 98:903-906.
198. Zeng Y., Opeskin K., Horvath L.G., Sutherland R.L., Williams E.D. Lymphatic vessel density and lymph node metastasis in prostate cancer. Prostate 2005, 65:222-230.
199. Thelen A., Jonas S., Benckert C., Weichert W., Schott E., Botcher C., Dietz E., Wiedenmann B., Neuhaus P., Scholz A. Tumor-associated lymphangiogenesis correlates with prognosis after resection of human hepatocellular carcinoma. Ann. Surg. Oncol. 2009, 16:1222-1230.
200. Sipos B., Klapper W., Kruse M.L., Kalthoff H., Kerjaschki D., Kloppel G. Expression of lymphangiogenic factors and evidence of intratumoral lymphangiogenesis in pancreatic endocrine tumors. Am. J. Pathol. 2004, 165:1187-1197.
201. Rubbia-Brandt L., Terris B., Giostra E., Dousset B., Morel P., Pepper M.S. 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.
202. Choi Y., Park K.J., Ryu S., Kim D.H., Yun J., Kang D.K., Chun M. Papillary thyroid carcinoma involving cervical neck lymph nodes: correlations with lymphangiogenesis and ultrasound features. Endocr. J. 2012, 59:941-948.
203. Chung M.K., Kim J.H., Ko Y.H., Son Y.I. Correlation of lymphatic vessel density and vascular endothelial growth factor with nodal metastasis in papillary thyroid microcarcinoma. Head Neck 2012, 34:846-851.
204. Hall F.T., Freeman J.L., Asa S.L., Jackson D.G., Beasley N.J. Intratumoral lymphatics and lymph node metastases in papillary thyroid carcinoma. Arch. Otolaryngol. Head Neck Surg. 2003, 129:716-719.
205. Eloy C., Santos J., Soares P., Sobrinho-Simoes M. Intratumoural lymph vessel density is related to presence of lymph node metastases and separates encapsulated from infiltrative papillary thyroid carcinoma. Virchows Arch. 2011, 459:595-605.
206. Ramani P., Somerville M.S., May M.T. Podoplanin lymphatic density and invasion correlate with adverse clinicopathologic and biological factors and survival in neuroblastomas. Am. J. Surg. Pathol. 2012, 36:908-915.
207. En-Lin S., Wei-Wei Y., Xiao-Liang X., Juan X. Relationship between high density of peritumoral lymphatic vessels and biological behavior of cervical cancer. Int. J. Gynecol. Cancer 2012, 22:1435-1441.
208. Gombos Z., Xu X., Chu C.S., Zhang P.J., 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.
209. Zhang S.Q., Yu H., Zhang L.L. Clinical implications of increased lymph vessel density in the lymphatic metastasis of early-stage invasive cervical carcinoma: a clinical immunohistochemical method study. BMC Cancer 2009, 9:64.
210. Saad R.S., Ismiil N., Ghorab Z., Nofech-Mozes S., Dube V., Covens A., Khalifa M.A. Lymphatic vessel density as a prognostic marker in clinical stage I endocervical adenocarcinoma. Int. J. Gynecol. Pathol. 2010, 29:386-393.
211. Zaganelli F.L., Carvalho F.M., Almeida B.G., Bacchi C.E., Goes J.C., Calil M.A., Baracat E.C., Carvalho J.P. Intratumoral lymphatic vessel density and clinicopathologic features of patients with early-stage cervical cancer after radical hysterectomy. Int. J. Gynecol. Cancer 2010, 20:1225-1231.
212. Maghraby H.K., Elsarha A.I., Saad R.S. Peritumoral lymphatic vessel density as a prognostic parameter in endometrial carcinoma: an immunohistochemical study. Indian J. Pathol. Microbiol. 2010, 53:465-469.
213. Gao Y., Liu Z., Gao F., Meng X.Y. High density of peritumoral lymphatic vessels is a potential prognostic marker of endometrial carcinoma: a clinical immunohistochemical method study. BMC Cancer 2010, 10:131.
214. Vandenput I., Vanhove T., Calster B.V., Gorp T.V., Moerman P., Verbist G., Vergote I., Amant F. The use of lymph vessel markers to predict endometrial cancer outcome. Int. J. Gynecol. Cancer 2010, 20:363-367.
215. Kawamura L., Carvalho F.M., Alves B.G., Bacchi C.E., Goes J.C., Calil M.A., Baracat E.C., Carvalho J.P. Association between intratumoral lymphatic microvessel density (LMVD) and clinicopathologic features in endometrial cancer: a retrospective cohort study. World J. Surg. Oncol. 2010, 8:89.
216. Heinzelbecker J., Gropp T., Weiss C., Huettl K., Stroebel P., Haecker A., Bolenz C., Trojan L. The role of lymph vessel density and lymphangiogenesis in metastatic tumor spread of nonseminomatous testicular germ cell tumors. Urol. Oncol. 2014, 32:178-185.