VEGFs and receptors involved in angiogenesis versus lymphangiogenesis

Current Opinion in Cell Biology

Volumn 21, Issue 2, 2009, Pages 154-165

  Lohela, Marja ^a   Bry, Maija ^a   Tammela, Tuomas ^a   Alitalo, Kari ^a  

^a UNIVERSITY OF HELSINKI   (Finland)

Author keywords

[No Author keywords available]

Indexed keywords

NOTCH RECEPTOR; VASCULOTROPIN; VASCULOTROPIN C; VASCULOTROPIN D; VASCULOTROPIN RECEPTOR 2; VASCULOTROPIN RECEPTOR 3;

ANGIOGENESIS; LYMPH NODE METASTASIS; LYMPHANGIOGENESIS; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PROTEIN TARGETING; REVIEW; SPROUTING;

ANGIOPOIETIN-1; ANIMALS; HUMANS; LYMPHANGIOGENESIS; LYMPHATIC METASTASIS; MEMBRANE PROTEINS; MYOCYTES, CARDIAC; NEOVASCULARIZATION, PHYSIOLOGIC; PROTEIN ISOFORMS; RECEPTOR, TIE-2; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIAL GROWTH FACTORS;

EID: 63749125392     PISSN: 09550674     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.ceb.2008.12.012     Document Type: Review

References (137)

1. Carmeliet P., and Tessier-Lavigne M. Common mechanisms of nerve and blood vessel wiring. Nature 436 (2005) 193-200
2. Avraamides C.J., Garmy-Susini B., and Varner J.A. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer 8 (2008) 604-617
3. Davis G.E., and Senger D.R. Endothelial extracellular matrix: biosynthesis, remodeling, and functions during vascular morphogenesis and neovessel stabilization. Circ Res 97 (2005) 1093-1107
4. Shibuya M., and Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312 (2006) 549-560
5. Carmeliet P., Ferreira V., Breier G., Pollefeyt S., Kieckens L., Gertsenstein M., Fahrig M., Vandenhoeck A., Harpal K., Ebenhardt C., et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 380 (1996) 435-439
6. Ferrara N., Carver-Moore K., Chen H., Dowd M., Lu L., O'Shea K.S., Powell-Braxton L., Hillan K.J., and Moore M.W. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 380 (1996) 439-442
7. Shalaby F., Rossant J., Yamaguchi T.P., Gertsenstein M., Wu X.F., Breitman M.L., and Schuh A.C. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature 376 (1995) 62-66
8. Leung D.W., Cachianes G., Kuang W.J., Goeddel D.V., and Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246 (1989) 1306-1309
9. Folkman J., Merler E., Abernathy C., and Williams G. Isolation of a tumor factor responsible for angiogenesis. J Exp Med 133 (1971) 275-288
10. Larcher F., Murillas R., Bolontrade M., Conti C.J., and Jorcano J.L. VEGF/VPF overexpression in skin of transgenic mice induces angiogenesis, vascular hyperpermeability and accelerated tumor development. Oncogene 17 (1998) 303-311
11. Wilting J., Christ B., and Weich H.A. The effects of growth factors on the day 13 chorioallantoic membrane (CAM): a study of VEGF165 and PDGF-BB. Anat Embryol (Berl) 186 (1992) 251-257
12. Detmar M., Brown L.F., Schon M.P., Elicker B.M., Velasco P., Richard L., Fukumura D., Monsky W., Claffey K.P., and Jain R.K. Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J Invest Dermatol 111 (1998) 1-6
13. Pettersson A., Nagy J.A., Brown L.F., Sundberg C., Morgan E., Jungles S., Carter R., Krieger J.E., Manseau E.J., Harvey V.S., et al. Heterogeneity of the angiogenic response induced in different normal adult tissues by vascular permeability factor/vascular endothelial growth factor. Lab Invest 80 (2000) 99-115
14. Connolly D.T., Heuvelman D.M., Nelson R., Olander J.V., Eppley B.L., Delfino J.J., Siegel N.R., Leimgruber R.M., and Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest 84 (1989) 1470-1478
15. Ng Y.S., Krilleke D., and Shima D.T. VEGF function in vascular pathogenesis. Exp Cell Res 312 (2006) 527-537
16. Weinstein B.M. What guides early embryonic blood vessel formation?. Dev Dyn 215 (1999) 2-11
17. Lee S., Chen T.T., Barber C.L., Jordan M.C., Murdock J., Desai S., Ferrara N., Nagy A., Roos K.P., and Iruela-Arispe M.L. Autocrine VEGF signaling is required for vascular homeostasis. Cell 130 (2007) 691-703. This paper demonstrates that, surprisingly, VEGF produced by endothelial cells is essential for endothelial stability, but does not have a role in angiogenesis.
18. Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev 25 (2004) 581-611
19. Pugh C.W., and Ratcliffe P.J. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9 (2003) 677-684
20. Arany Z., Foo S.Y., Ma Y., Ruas J.L., Bommi-Reddy A., Girnun G., Cooper M., Laznik D., Chinsomboon J., Rangwala S.M., et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC-1alpha. Nature 451 (2008) 1008-1012. This study identifies a mechanism of VEGF upregulation in response to oxygen and nutrient deprivation that is independent of the canonical hypoxia response pathway.
21. Dougher M., and Terman B.I. Autophosphorylation of KDR in the kinase domain is required for maximal VEGF-stimulated kinase activity and receptor internalization. Oncogene 18 (1999) 1619-1627
22. Matsumoto T., Bohman S., Dixelius J., Berge T., Dimberg A., Magnusson P., Wang L., Wikner C., Qi J.H., Wernstedt C., et al. VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. EMBO J 24 (2005) 2342-2353
23. Guo D., Jia Q., Song H.Y., Warren R.S., and Donner D.B. Vascular endothelial cell growth factor promotes tyrosine phosphorylation of mediators of signal transduction that contain SH2 domains. Association with endothelial cell proliferation. J Biol Chem 270 (1995) 6729-6733
24. Xia P., Aiello L.P., Ishii H., Jiang Z.Y., Park D.J., Robinson G.S., Takagi H., Newsome W.P., Jirousek M.R., and King G.L. Characterization of vascular endothelial growth factor's effect on the activation of protein kinase C, its isoforms, and endothelial cell growth. J Clin Invest 98 (1996) 2018-2026
25. Takahashi T., Yamaguchi S., Chida K., and Shibuya M. A single autophosphorylation site on KDR/Flk-1 is essential for VEGF-A-dependent activation of PLC-gamma and DNA synthesis in vascular endothelial cells. EMBO J 20 (2001) 2768-2778
26. Sakurai Y., Ohgimoto K., Kataoka Y., Yoshida N., and Shibuya M. Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc Natl Acad Sci U S A 102 (2005) 1076-1081
27. Wang S., Li X., Parra M., Verdin E., Bassel-Duby R., and Olson E.N. Control of endothelial cell proliferation and migration by VEGF signaling to histone deacetylase 7. Proc Natl Acad Sci U S A 105 (2008) 7738-7743
28. Fulton D., Gratton J.P., McCabe T.J., Fontana J., Fujio Y., Walsh K., Franke T.F., Papapetropoulos A., and Sessa W.C. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 399 (1999) 597-601
29. Gerber H.P., McMurtrey A., Kowalski J., Yan M., Keyt B.A., Dixit V., and Ferrara N. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem 273 (1998) 30336-30343
30. Fukumura D., Gohongi T., Kadambi A., Izumi Y., Ang J., Yun C.O., Buerk D.G., Huang P.L., and Jain R.K. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A 98 (2001) 2604-2609
31. Yu J., deMuinck E.D., Zhuang Z., Drinane M., Kauser K., Rubanyi G.M., Qian H.S., Murata T., Escalante B., and Sessa W.C. Endothelial nitric oxide synthase is critical for ischemic remodeling, mural cell recruitment, and blood flow reserve. Proc Natl Acad Sci U S A 102 (2005) 10999-11004
32. Holmqvist K., Cross M.J., Rolny C., Hagerkvist R., Rahimi N., Matsumoto T., Claesson-Welsh L., and Welsh M. The adaptor protein shb binds to tyrosine 1175 in vascular endothelial growth factor (VEGF) receptor-2 and regulates VEGF-dependent cellular migration. J Biol Chem 279 (2004) 22267-22275
33. Dayanir V., Meyer R.D., Lashkari K., and Rahimi N. Identification of tyrosine residues in vascular endothelial growth factor receptor-2/FLK-1 involved in activation of phosphatidylinositol 3-kinase and cell proliferation. J Biol Chem 276 (2001) 17686-17692
34. Gavard J., and Gutkind J.S. VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol 8 (2006) 1223-1234
35. Gallicchio M., Mitola S., Valdembri D., Fantozzi R., Varnum B., Avanzi G.C., and Bussolino F. Inhibition of vascular endothelial growth factor receptor 2-mediated endothelial cell activation by Axl tyrosine kinase receptor. Blood 105 (2005) 1970-1976
36. Guo D.Q., Wu L.W., Dunbar J.D., Ozes O.N., Mayo L.D., Kessler K.M., Gustin J.A., Baerwald M.R., Jaffe E.A., Warren R.S., et al. Tumor necrosis factor employs a protein-tyrosine phosphatase to inhibit activation of KDR and vascular endothelial cell growth factor-induced endothelial cell proliferation. J Biol Chem 275 (2000) 11216-11221
37. Bellomo D., Headrick J.P., Silins G.U., Paterson C.A., Thomas P.S., Gartside M., Mould A., Cahill M.M., Tonks I.D., Grimmond S.M., et al. Mice lacking the vascular endothelial growth factor-B gene (Vegfb) have smaller hearts, dysfunctional coronary vasculature, and impaired recovery from cardiac ischemia. Circ Res 86 (2000) E29-E35
38. Carmeliet P., Moons L., Luttun A., Vincenti V., Compernolle V., De Mol M., Wu Y., Bono F., Devy L., Beck H., et al. Synergism between vascular endothelial growth factor and placental growth factor contributes to angiogenesis and plasma extravasation in pathological conditions. Nat Med 7 (2001) 575-583
39. Fischer C., Mazzone M., Jonckx B., and Carmeliet P. FLT1 and its ligands VEGFB and PlGF: drug targets for anti-angiogenic therapy?. Nat Rev Cancer 8 (2008) 942-956. A comprehensive review of the recently updated knowledge of the properties and functions of VEGFR-1 and its ligands PlGF and VEGF-B.
40. Fong G.H., Rossant J., Gertsenstein M., and Breitman M.L. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature 376 (1995) 66-70
41. Fong G.H., Zhang L., Bryce D.M., and Peng J. Increased hemangioblast commitment, not vascular disorganization, is the primary defect in flt-1 knock-out mice. Development 126 (1999) 3015-3025
42. Hiratsuka S., Minowa O., Kuno J., Noda T., and Shibuya M. Flt-1 lacking the tyrosine kinase domain is sufficient for normal development and angiogenesis in mice. Proc Natl Acad Sci U S A 95 (1998) 9349-9354
43. Hiratsuka S., Nakao K., Nakamura K., Katsuki M., Maru Y., and Shibuya M. Membrane fixation of vascular endothelial growth factor receptor 1 ligand-binding domain is important for vasculogenesis and angiogenesis in mice. Mol Cell Biol 25 (2005) 346-354
44. Levine R.J., Maynard S.E., Qian C., Lim K.H., England L.J., Yu K.F., Schisterman E.F., Thadhani R., Sachs B.P., Epstein F.H., et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med 350 (2004) 672-683
45. Jinnin M., Medici D., Park L., Limaye N., Liu Y., Boscolo E., Bischoff J., Vikkula M., Boye E., and Olsen B.R. Suppressed NFAT-dependent VEGFR1 expression and constitutive VEGFR2 signaling in infantile hemangioma. Nat Med 14 (2008) 1236-1246. This paper demonstrated that a defective balance in the positive and negative regulation of VEGF/VEGFR-2 signalling is behind the endothelial overproliferation in haemangiomas and identifies the transcription factor NFAT as a regulator of VEGFR-1 expression.
46. Autiero M., Waltenberger J., Communi D., Kranz A., Moons L., Lambrechts D., Kroll J., Plaisance S., De Mol M., Bono F., et al. Role of PlGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9 (2003) 936-943
47. Huang K., Andersson C., Roomans G.M., Ito N., and Claesson-Welsh L. Signaling properties of VEGF receptor-1 and -2 homo- and heterodimers. Int J Biochem Cell Biol 33 (2001) 315-324
48. Barleon B., Sozzani S., Zhou D., Weich H.A., Mantovani A., and Marme D. Migration of human monocytes in response to vascular endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood 87 (1996) 3336-3343
49. Clauss M., Weich H., Breier G., Knies U., Rockl W., Waltenberger J., and Risau W. The vascular endothelial growth factor receptor Flt-1 mediates biological activities. Implications for a functional role of placenta growth factor in monocyte activation and chemotaxis. J Biol Chem 271 (1996) 17629-17634
50. Luttun A., Tjwa M., Moons L., Wu Y., Angelillo-Scherrer A., Liao F., Nagy J.A., Hooper A., Priller J., De Klerck B., et al. Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat Med 8 (2002) 831-840
51. Mould A.W., Tonks I.D., Cahill M.M., Pettit A.R., Thomas R., Hayward N.K., and Kay G.F. Vegfb gene knockout mice display reduced pathology and synovial angiogenesis in both antigen-induced and collagen-induced models of arthritis. Arthritis Rheum 48 (2003) 2660-2669
52. Li X., Tjwa M., Van Hove I., Enholm B., Neven E., Paavonen K., Jeltsch M., Diez Juan T., Sievers R.E., Chorianopoulos E., et al. Reevaluation of the role of VEGF-B suggests a restricted role in the revascularization of the ischemic myocardium. Arterioscler Thromb Vasc Biol 28 (2008) 1614-1620
53. Karpanen T., Bry M., Ollila H.M., Seppanen-Laakso T., Liimatta E., Leskinen H., Kivela R., Helkamaa T., Merentie M., Jeltsch M., et al. Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy. Circ Res 103 (2008) 1018-1026. This study identifies a novel role for VEGF-B in the regulation of cardiac lipid metabolism, opening up avenues for further research into the physiological functions of this mysterious member of the VEGF family.
54. Lähteenvuo J.E., Lähteenvuo M.T., Kivelä A., Rosenlew C., Falkevall A., Klar J., Heikura T., Rissanen T.T., Vähäkangas E., Korpisalo P., et al. Vascular endothelial growth factor-B induces myocardium-specific angiogenesis and arteriogenesis via vascular endothelial growth factor receptor-1- and neuropilin receptor-1-dependent mechanisms. Circulation 119 (2009) 845-856
55. Kukk E., Lymboussaki A., Taira S., Kaipainen A., Jeltsch M., Joukov V., and Alitalo K. VEGF-C receptor binding and pattern of expression with VEGFR-3 suggests a role in lymphatic vascular development. Development 122 (1996) 3829-3837
56. Karkkainen M.J., Haiko P., Sainio K., Partanen J., Taipale J., Petrova T.V., Jeltsch M., Jackson D.G., Talikka M., Rauvala H., et al. Vascular endothelial growth factor C is required for sprouting of the first lymphatic vessels from embryonic veins. Nat Immunol 5 (2004) 74-80
57. Baldwin M.E., Roufail S., Halford M.M., Alitalo K., Stacker S.A., and Achen M.G. Multiple forms of mouse vascular endothelial growth factor-D are generated by RNA splicing and proteolysis. J Biol Chem 276 (2001) 44307-44314
58. Achen M.G., Jeltsch M., Kukk E., Makinen T., Vitali A., Wilks A.F., Alitalo K., and Stacker S.A. Vascular endothelial growth factor D (VEGF-D) is a ligand for the tyrosine kinases VEGF receptor 2 (Flk1) and VEGF receptor 3 (Flt4). Proc Natl Acad Sci U S A 95 (1998) 548-553
59. Avantaggiato V., Orlandini M., Acampora D., Oliviero S., and Simeone A. Embryonic expression pattern of the murine figf gene, a growth factor belonging to platelet-derived growth factor/vascular endothelial growth factor family. Mech Dev 73 (1998) 221-224
60. Joukov V., Sorsa T., Kumar V., Jeltsch M., Claesson-Welsh L., Cao Y., Saksela O., Kalkkinen N., and Alitalo K. Proteolytic processing regulates receptor specificity and activity of VEGF-C. EMBO J 16 (1997) 3898-3911
61. Baldwin M.E., Catimel B., Nice E.C., Roufail S., Hall N.E., Stenvers K.L., Karkkainen M.J., Alitalo K., Stacker S.A., and Achen M.G. The specificity of receptor binding by vascular endothelial growth factor-d is different in mouse and man. J Biol Chem 276 (2001) 19166-19171
62. Karkkainen M.J., Saaristo A., Jussila L., Karila K.A., Lawrence E.C., Pajusola K., Bueler H., Eichmann A., Kauppinen R., Kettunen M.I., et al. A model for gene therapy of human hereditary lymphedema. Proc Natl Acad Sci U S A 98 (2001) 12677-12682
63. Baldwin M.E., Halford M.M., Roufail S., Williams R.A., Hibbs M.L., Grail D., Kubo H., Stacker S.A., and Achen M.G. Vascular endothelial growth factor D is dispensable for development of the lymphatic system. Mol Cell Biol 25 (2005) 2441-2449
64. Jeltsch M., Kaipainen A., Joukov V., Meng X., Lakso M., Rauvala H., Swartz M., Fukumura D., Jain R.K., and Alitalo K. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science 276 (1997) 1423-1425
65. Veikkola T., Jussila L., Makinen T., Karpanen T., Jeltsch M., Petrova T.V., Kubo H., Thurston G., McDonald D.M., Achen M.G., et al. Signalling via vascular endothelial growth factor receptor-3 is sufficient for lymphangiogenesis in transgenic mice. EMBO J 20 (2001) 1223-1231
66. Saaristo A., Veikkola T., Tammela T., Enholm B., Karkkainen M.J., Pajusola K., Bueler H., Yla-Herttuala S., and Alitalo K. Lymphangiogenic gene therapy with minimal blood vascular side effects. J Exp Med 196 (2002) 719-730
67. Stacker S.A., Caesar C., Baldwin M.E., Thornton G.E., Williams R.A., Prevo R., Jackson D.G., Nishikawa S., Kubo H., and Achen M.G. VEGF-D promotes the metastatic spread of tumor cells via the lymphatics. Nat Med 7 (2001) 186-191
68. Mandriota S.J., Jussila L., Jeltsch M., Compagni A., Baetens D., Prevo R., Banerji S., Huarte J., Montesano R., Jackson D.G., et al. Vascular endothelial growth factor-C-mediated lymphangiogenesis promotes tumour metastasis. EMBO J 20 (2001) 672-682
69. Enholm B., Karpanen T., Jeltsch M., Kubo H., Stenback F., Prevo R., Jackson D.G., Yla-Herttuala S., and Alitalo K. Adenoviral expression of vascular endothelial growth factor-C induces lymphangiogenesis in the skin. Circ Res 88 (2001) 623-629
70. Karpanen T., Egeblad M., Karkkainen M.J., Kubo H., Yla-Herttuala S., Jaattela M., and Alitalo K. Vascular endothelial growth factor C promotes tumor lymphangiogenesis and intralymphatic tumor growth. Cancer Res 61 (2001) 1786-1790
71. Byzova T.V., Goldman C.K., Jankau J., Chen J., Cabrera G., Achen M.G., Stacker S.A., Carnevale K.A., Siemionow M., Deitcher S.R., et al. Adenovirus encoding vascular endothelial growth factor-D induces tissue-specific vascular patterns in vivo. Blood 99 (2002) 4434-4442
72. Skobe M., Hawighorst T., Jackson D.G., Prevo R., Janes L., Velasco P., Riccardi L., Alitalo K., Claffey K., and Detmar M. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med 7 (2001) 192-198
73. Saaristo A., Tammela T., Timonen J., Yla-Herttuala S., Tukiainen E., Asko-Seljavaara S., and Alitalo K. Vascular endothelial growth factor-C gene therapy restores lymphatic flow across incision wounds. FASEB J 18 (2004) 1707-1709
74. Tammela T., Saaristo A., Holopainen T., Lyytikka J., Kotronen A., Pitkonen M., Abo-Ramadan U., Yla-Herttuala S., Petrova T.V., and Alitalo K. Therapeutic differentiation and maturation of lymphatic vessels after lymph node dissection and transplantation. Nat Med 13 (2007) 1458-1466. Here, an elegant mouse model of lymph node dissection and transplantation was used to demonstrate that VEGF-C therapy can be used to generate functional, mature lymph vessels in adult mice.
75. Lohela M., Helotera H., Haiko P., Dumont D.J., and Alitalo K. Transgenic induction of vascular endothelial growth factor-C is strongly angiogenic in mouse embryos but leads to persistent lymphatic hyperplasia in adult tissues. Am J Pathol 173 (2008) 1891-1901
76. Karpanen T., and Alitalo K. Molecular biology and pathology of lymphangiogenesis. Annu Rev Pathol 3 (2008) 367-397
77. Pajusola K., Aprelikova O., Korhonen J., Kaipainen A., Pertovaara L., Alitalo R., and Alitalo K. FLT4 receptor tyrosine kinase contains seven immunoglobulin-like loops and is expressed in multiple human tissues and cell lines. Cancer Res 52 (1992) 5738-5743
78. Kaipainen A., Korhonen J., Mustonen T., van Hinsbergh V.W., Fang G.H., Dumont D., Breitman M., and Alitalo K. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc Natl Acad Sci U S A 92 (1995) 3566-3570
79. Dumont D.J., Jussila L., Taipale J., Lymboussaki A., Mustonen T., Pajusola K., Breitman M., and Alitalo K. Cardiovascular failure in mouse embryos deficient in VEGF receptor-3. Science 282 (1998) 946-949
80. Partanen T.A., Arola J., Saaristo A., Jussila L., Ora A., Miettinen M., Stacker S.A., Achen M.G., and Alitalo K. VEGF-C and VEGF-D expression in neuroendocrine cells and their receptor, VEGFR-3, in fenestrated blood vessels in human tissues. FASEB J 14 (2000) 2087-2096
81. Joukov V., Kumar V., Sorsa T., Arighi E., Weich H., Saksela O., and Alitalo K. A recombinant mutant vascular endothelial growth factor-C that has lost vascular endothelial growth factor receptor-2 binding, activation, and vascular permeability activities. J Biol Chem 273 (1998) 6599-6602
82. Makinen T., Veikkola T., Mustjoki S., Karpanen T., Catimel B., Nice E.C., Wise L., Mercer A., Kowalski H., Kerjaschki D., et al. Isolated lymphatic endothelial cells transduce growth, survival and migratory signals via the VEGF-C/D receptor VEGFR-3. EMBO J 20 (2001) 4762-4773
83. Karpanen T., Wirzenius M., Makinen T., Veikkola T., Haisma H.J., Achen M.G., Stacker S.A., Pytowski B., Yla-Herttuala S., and Alitalo K. Lymphangiogenic growth factor responsiveness is modulated by postnatal lymphatic vessel maturation. Am J Pathol 169 (2006) 708-718
84. Makinen T., Jussila L., Veikkola T., Karpanen T., Kettunen M.I., Pulkkanen K.J., Kauppinen R., Jackson D.G., Kubo H., Nishikawa S., et al. Inhibition of lymphangiogenesis with resulting lymphedema in transgenic mice expressing soluble VEGF receptor-3. Nat Med 7 (2001) 199-205
85. Pytowski B., Goldman J., Persaud K., Wu Y., Witte L., Hicklin D.J., Skobe M., Boardman K.C., and Swartz M.A. Complete and specific inhibition of adult lymphatic regeneration by a novel VEGFR-3 neutralizing antibody. J Natl Cancer Inst 97 (2005) 14-21
86. Haiko P., Makinen T., Keskitalo S., Taipale J., Karkkainen M.J., Baldwin M.E., Stacker S.A., Achen M.G., and Alitalo K. Deletion of vascular endothelial growth factor C (VEGF-C) and VEGF-D is not equivalent to VEGF receptor 3 deletion in mouse embryos. Mol Cell Biol 28 (2008) 4843-4850. This study indicates that the angiogenic activities of VEGFR-3 during embryonic development are independent of its known ligands VEGF-C and VEGF-D.
87. Dixelius J., Makinen T., Wirzenius M., Karkkainen M.J., Wernstedt C., Alitalo K., and 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 278 (2003) 40973-40979
88. Dorrell M.I., Aguilar E., and Friedlander M. Retinal vascular development is mediated by endothelial filopodia, a preexisting astrocytic template and specific R-cadherin adhesion. Invest Ophthalmol Vis Sci 43 (2002) 3500-3510
89. Ruhrberg C., Gerhardt H., Golding M., Watson R., Ioannidou S., Fujisawa H., Betsholtz C., and Shima D.T. Spatially restricted patterning cues provided by heparin-binding VEGF-A control blood vessel branching morphogenesis. Genes Dev 16 (2002) 2684-2698
90. Gerhardt H., Golding M., Fruttiger M., Ruhrberg C., Lundkvist A., Abramsson A., Jeltsch M., Mitchell C., Alitalo K., Shima D., et al. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161 (2003) 1163-1177
91. Tammela T., Zarkada G., Wallgard E., Murtomaki A., Suchting S., Wirzenius M., Waltari M., Hellstrom M., Schomber T., Peltonen R., et al. Blocking VEGFR-3 suppresses angiogenic sprouting and vascular network formation. Nature 454 (2008) 656-660. This work links VEGFR-3 to the VEGFR-2 and Notch signalling pathways known to regulate angiogenic sprouting and vascular network formation, and demonstrates that blockage of VEGFR-3 can augment the effects of VEGFR-2 inhibition in anti-angiogenic targeting.
92. Augustin HG, Koh GY, Thurston G, Alitalo K: Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol, in press.
93. ••] were the first to describe Dll4/Notch-signalling as a determinant for tip cell versus stalk cell differentiation in sprouting angiogenesis, establishing yet another possible anti-tumour target.
94. ••]
95. ••]
96. ••]
97. ••]
98. ••]
99. Hainaud P., Contreres J.O., Villemain A., Liu L.X., Plouet J., Tobelem G., and Dupuy E. The role of the vascular endothelial growth factor-Delta-like 4 ligand/Notch4-ephrin B2 cascade in tumor vessel remodeling and endothelial cell functions. Cancer Res 66 (2006) 8501-8510
100. Williams C.K., Li J.L., Murga M., Harris A.L., and Tosato G. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 107 (2006) 931-939
101. Nagy J.A., Vasile E., Feng D., Sundberg C., Brown L.F., Detmar M.J., Lawitts J.A., Benjamin L., Tan X., Manseau E.J., et al. Vascular permeability factor/vascular endothelial growth factor induces lymphangiogenesis as well as angiogenesis. J Exp Med 196 (2002) 1497-1506
102. Wirzenius M., Tammela T., Uutela M., He Y., Odorisio T., Zambruno G., Nagy J.A., Dvorak H.F., Yla-Herttuala S., Shibuya M., et al. Distinct vascular endothelial growth factor signals for lymphatic vessel enlargement and sprouting. J Exp Med 204 (2007) 1431-1440
103. Hong Y.K., Lange-Asschenfeldt B., Velasco P., Hirakawa S., Kunstfeld R., Brown L.F., Bohlen P., Senger D.R., and Detmar M. VEGF-A promotes tissue repair-associated lymphatic vessel formation via VEGFR-2 and the alpha1beta1 and alpha2beta1 integrins. FASEB J 18 (2004) 1111-1113
104. Hirakawa S., Kodama S., Kunstfeld R., Kajiya K., Brown L.F., and Detmar M. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med 201 (2005) 1089-1099
105. Cursiefen C., Chen L., Borges L.P., Jackson D., Cao J., Radziejewski C., D'Amore P.A., Dana M.R., Wiegand S.J., and Streilein J.W. VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment. J Clin Invest 113 (2004) 1040-1050
106. Schoppmann S.F., Birner P., Stockl J., Kalt R., Ullrich R., Caucig C., Kriehuber E., Nagy K., Alitalo K., and Kerjaschki D. Tumor-associated macrophages express lymphatic endothelial growth factors and are related to peritumoral lymphangiogenesis. Am J Pathol 161 (2002) 947-956
107. Baluk P., Tammela T., Ator E., Lyubynska N., Achen M.G., Hicklin D.J., Jeltsch M., Petrova T.V., Pytowski B., Stacker S.A., et al. Pathogenesis of persistent lymphatic vessel hyperplasia in chronic airway inflammation. J Clin Invest 115 (2005) 247-257
108. Dvorak H.F. Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20 (2002) 4368-4380
109. Dvorak H.F., Harvey V.S., Estrella P., Brown L.F., McDonagh J., and Dvorak A.M. Fibrin containing gels induce angiogenesis: implications for tumor stroma generation and wound healing. Lab Invest 57 (1987) 673-686
110. Egeblad M., and Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2 (2002) 161-174
111. Ferrara N. VEGF as a therapeutic target in cancer. Oncology 69 Suppl. 3 (2005) 11-16
112. Hurwitz H., Fehrenbacher L., Novotny W., Cartwright T., Hainsworth J., Heim W., Berlin J., Baron A., Griffing S., Holmgren E., et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350 (2004) 2335-2342
113. Crawford Y., and Ferrara N. VEGF inhibition: insights from preclinical and clinical studies. Cell Tissue Res 335 (2009) 261-269
114. Avery R.L., Pieramici D.J., Rabena M.D., Castellarin A.A., Nasir M.A., and Giust M.J. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 113 (2006) 363-372 e365
115. Ferrara N., Damico L., Shams N., Lowman H., and Kim R. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 26 (2006) 859-870
116. Jain R.K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307 (2005) 58-62
117. Bergers G., and Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8 (2008) 592-603. A recent review of the mechanisms responsible for the increasingly evident problems of tumour resistance to anti-angiogenic therapy.
118. Fischer C., Jonckx B., Mazzone M., Zacchigna S., Loges S., Pattarini L., Chorianopoulos E., Liesenborghs L., Koch M., De Mol M., et al. Anti-PlGF inhibits growth of VEGF(R)-inhibitor-resistant tumors without affecting healthy vessels. Cell 131 (2007) 463-475. This study showed that neutralising PlGF can reduce the infiltration of angiogenic macrophages in tumours, a phenomenon that is increasingly recognised as crucially important for the growth and spread of some tumours, establishing PlGF as a promising target for cancer therapy.
119. Pan Q., Chanthery Y., Liang W.C., Stawicki S., Mak J., Rathore N., Tong R.K., Kowalski J., Yee S.F., Pacheco G., et al. Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11 (2007) 53-67
120. Laakkonen P., Waltari M., Holopainen T., Takahashi T., Pytowski B., Steiner P., Hicklin D., Persaud K., Tonra J.R., Witte L., et al. Vascular endothelial growth factor receptor 3 is involved in tumor angiogenesis and growth. Cancer Res 67 (2007) 593-599
121. Achen M.G., and Stacker S.A. Molecular control of lymphatic metastasis. Ann N Y Acad Sci 1131 (2008) 225-234
122. Alitalo K: VEGF Family and Lymphangiogenesis. In Conquering Lymphatic Disease: Setting the Research Agenda: 2001; Bethesda, Maryland, U.S.A. Edited by Witte MH: The University of Arizona; 2000:214-216.
123. He Y., Kozaki K., Karpanen T., Koshikawa K., Yla-Herttuala S., Takahashi T., and Alitalo K. Suppression of tumor lymphangiogenesis and lymph node metastasis by blocking vascular endothelial growth factor receptor 3 signaling. J Natl Cancer Inst 94 (2002) 819-825
124. Krishnan J., Kirkin V., Steffen A., Hegen M., Weih D., Tomarev S., Wilting J., and Sleeman J.P. Differential in vivo and in vitro expression of vascular endothelial growth factor (VEGF)-C and VEGF-D in tumors and its relationship to lymphatic metastasis in immunocompetent rats. Cancer Res 63 (2003) 713-722
125. Kopfstein L., Veikkola T., Djonov V.G., Baeriswyl V., Schomber T., Strittmatter K., Stacker S.A., Achen M.G., Alitalo K., and Christofori G. Distinct roles of vascular endothelial growth factor-D in lymphangiogenesis and metastasis. Am J Pathol 170 (2007) 1348-1361
126. Hirakawa S., Brown L.F., Kodama S., Paavonen K., Alitalo K., and Detmar M. VEGF-C-induced lymphangiogenesis in sentinel lymph nodes promotes tumor metastasis to distant sites. Blood 109 (2007) 1010-1017
127. 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., et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296 (2002) 1883-1886
128. He Y., Rajantie I., Pajusola K., Jeltsch M., Holopainen T., Yla-Herttuala S., Harding T., Jooss K., Takahashi T., and 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 65 (2005) 4739-4746
129. Padera T.P., Stoll B.R., Tooredman J.B., Capen D., di Tomaso E., and Jain R.K. Pathology: cancer cells compress intratumour vessels. Nature 427 (2004) 695
130. Heckman C.A., Holopainen T., Wirzenius M., Keskitalo S., Jeltsch M., Yla-Herttuala S., Wedge S.R., Jurgensmeier J.M., and Alitalo K. The tyrosine kinase inhibitor cediranib blocks ligand-induced vascular endothelial growth factor receptor-3 activity and lymphangiogenesis. Cancer Res 68 (2008) 4754-4762
131. Matsui J., Funahashi Y., Uenaka T., Watanabe T., Tsuruoka A., and 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 14 (2008) 5459-5465
132. Burton J.B., Priceman S.J., Sung J.L., Brakenhielm E., An D.S., Pytowski B., Alitalo K., and Wu L. Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res 68 (2008) 7828-7837
133. Roberts N., Kloos B., Cassella M., Podgrabinska S., Persaud K., Wu Y., Pytowski B., and Skobe M. Inhibition of VEGFR-3 activation with the antagonistic antibody more potently suppresses lymph node and distant metastases than inactivation of VEGFR-2. Cancer Res 66 (2006) 2650-2657
134. Shimizu K., Kubo H., Yamaguchi K., Kawashima K., Ueda Y., Matsuo K., Awane M., Shimahara Y., Takabayashi A., Yamaoka Y., et al. Suppression of VEGFR-3 signaling inhibits lymph node metastasis in gastric cancer. Cancer Sci 95 (2004) 328-333
135. Caunt M., Mak J., Liang W.C., Stawicki S., Pan Q., Tong R.K., Kowalski J., Ho C., Reslan H.B., Ross J., et al. Blocking neuropilin-2 function inhibits tumor cell metastasis. Cancer Cell 13 (2008) 331-342
136. Saharinen P., Eklund L., Miettinen J., Wirkkala R., Anisimov A., Winderlich M., Nottebaum A., Vestweber D., Deutsch U., Koh G.Y., et al. Angiopoietins assemble distinct Tie2 signalling complexes in endothelial cell-cell and cell-matrix contacts. Nat Cell Biol 10 (2008) 527-537
137. Fukuhara S., Sako K., Minami T., Noda K., Kim H.Z., Kodama T., Shibuya M., Takakura N., Koh G.Y., and Mochizuki N. Differential function of Tie2 at cell-cell contacts and cell-substratum contacts regulated by angiopoietin-1. Nat Cell Biol 10 (2008) 513-526