Modulation of VEGF signalling output by the Notch pathway

BioEssays

Volumn 30, Issue 4, 2008, Pages 303-313

  Siekmann, Arndt F ^a   Covassin, Laurence ^a   Lawson, Nathan D ^a  

^a UNIVERSITY OF MASSACHUSETTS MEDICAL SCHOOL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

NOTCH RECEPTOR; VASCULOTROPIN;

ANGIOGENESIS; CELL DIFFERENTIATION; CELL INTERACTION; CELL MIGRATION; ENDOTHELIUM CELL; GENE INTERACTION; GOLGI COMPLEX; NONHUMAN; PROTEIN BINDING; PROTEIN DOMAIN; PROTEIN PHOSPHORYLATION; PROTEIN SYNTHESIS; RECEPTOR OCCUPANCY; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; CELL LINEAGE; CELL PHYSIOLOGY; ENDOTHELIAL CELLS; HUMANS; LIGANDS; MODELS, BIOLOGICAL; MUTATION; NEOVASCULARIZATION, PATHOLOGIC; RECEPTORS, NOTCH; RECEPTORS, VASCULAR ENDOTHELIAL GROWTH FACTOR; SIGNAL TRANSDUCTION; VASCULAR ENDOTHELIAL GROWTH FACTOR A; ZEBRAFISH;

EID: 41649088181     PISSN: 02659247     EISSN: None     Source Type: Journal    
DOI: 10.1002/bies.20736     Document Type: Review

References (110)

1. Cleaver O, Krieg PA. 1999. Molecular mechanisms of vascular development. In: Harvey RP, Rosenthal N, editors. Heart Development. San Diego: Academic Press; p 221-252.
2. Fouquet B, Weinstein BM, Serluca FC, Fishman MC. 1997. Vessel patterning in the embryo of the zebrafish: guidance by notochord. Dev Biol 183:37-48.
3. Gering M, Rodaway AR, Gottgens B, Patient RK, Green AR. 1998. The SCL gene specifies haemangioblast development from early mesoderm, Embo J 17:4029-4045.
4. Zhong TP, Childs S, Leu JP, Fishman MC. 2001. Gridlock signalling pathway fashions the first embryonic artery. Nature 414:216-220.
5. Lawson ND, Scheer N, Pham VN, Kim CH, Chitnis AB, et al. 2001. Notch signaling is required for arterial-venous differentiation during embryonic vascular development. Development 128:3675-3683.
6. Childs S, Chen JN, Garrity DM, Fishman MC. 2002. Patterning of angiogenesis in the zebrafish embryo. Development 129:973-982.
7. Isogai S, Lawson ND, Torrealday S, Horiguchi M, Weinstein BM. 2003. Angiogenic network formation in the developing vertebrate trunk. Development 130:5281-5290.
8. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, et al. 2003. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161:1163-1177.
9. Siekmann AF, Lawson ND. 2007. Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445:781-784.
10. Torres-Vazquez J, Gitler AD, Fraser SD, Berk JD, Van NP, et al. 2004. Semaphorin-plexin signaling guides patterning of the developing vasculature. Dev Cell 7:117-123.
11. Covassin LD, Villefranc JA, Kacergis MC, Weinstein BM, Lawson ND. 2006. Distinct genetic interactions between multiple Vegf receptors are required for development of different blood vessel types in zebrafish. Proc Natl Acad Sci USA.
12. Nasevicius A, Larson J, Ekker SC. 2000. Distinct requirements for zebrafish angiogenesis revealed by a VEGF-A morphant. Yeast 17:294-2301.
13. Martyn U, Schulte-Merker S. 2004. Zebrafish neuropilins are differentially expressed and interact with vascular endothelial growth factor during embryonic vascular development. Dev Dyn 231:33-42.
14. Lawson ND, Mugford JW, Diamond BA, Weinstein BM. 2003. Phospholipase C gamma-1 is required downstream of vascular endothelial growth factor during arterial development. Genes Dev 17: 1346-1351.
15. Cebe-Suarez S, Zehnder-Fjallman A, Ballmer-Hofer K. 2006. The role of VEGF receptors in angiogenesis; complex partnerships. Cell Mol Life Sci 63:601-615.
16. Matsumoto T, Mugishima H. 2006. Signal transduction via vascular endothelial growth factor (VEGF) receptors and their roles in atherogenesis. J Atheroscler Thromb 13:130-135.
17. Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. 2006. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7:359-371.
18. Shibuya M, Claesson-Welsh L. 2006. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp Cell Res 312:549-560.
19. Yamazaki Y, Morita T. 2006. Molecular and functional diversity of vascular endothelial growth factors. Mol Divers 10:515-527.
20. Cross MJ, Dixelius J, Matsumoto T, Claesson-Welsh L. 2003. VEGF-receptor signal transduction. Trends Biochem Sci 28:488-494.
21. Matsumoto T, Bohman S, Dixelius J, Berge T, Dimberg A, et al. 2005. VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. Embo J 24:2342-2353.
22. Sakurai Y, Ohgimoto K, Kataoka Y, Yoshida N, Shibuya M. 2005. Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc Natl Acad Sci USA 102:1076-1081.
23. Takahashi T, Shibuya M. 1997. The 230 kDa mature form of KDR/Flk-1 (VEGF receptor-2) activates the PLC-gamma pathway and partially induces mitotic signals in NIH3T3 fibroblasts. Oncogene 14:2079-2089.
24. Takahashi T, Yamaguchi S, Chida K, Shibuya M. 2001. 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 20:2768-2778.
25. Dayanir V, Meyer RD, Lashkari K, Rahimi N. 2001. 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 276:17686-17692.
26. Holmqvist K, Cross MJ, Rolny C, Hagerkvist R, Rahimi N. 2004. 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 279:22267-22275.
27. Meyer RD, Latz C, Rahimi N. 2003. Recruitment and activation of phospholipase Cgamma1 by vascular endothelial growth factor receptor-2 are required for tubulogenesis and differentiation of endothelial cells. J Biol Chem 278:16347-16355.
28. Datta SR, Brunet A, Greenberg ME. 1999. Cellular survival: a play in three Akts. Genes Dev 13:2905-2927.
29. Hong CC, Peterson QP, Hong JY, Peterson RT. 2006. Artery/vein specification is governed by opposing phosphatidylinositol-3 kinase and MAP kinase/ERK signaling. Curr Biol 16:1366-1372.
30. Phung TL, Ziv K, Dabydeen D, Eyiah-Mensah G, Riveras M, et al. 2006. Pathological angiogenesis is induced by sustained Akt signaling and inhibited by rapamycin. Cancer Cell 10:159-170.
31. Larcher F, Murillas R, Bolontrade M, Conti CJ, Jorcano JL. 1998. VEGF/VPF overexpression in skin of transgenic mice induces angiogenesis, vascular hyperpermeability and accelerated tumor development. Oncogene 17:303-311.
32. Kendall RL, Wang G, Thomas KA. 1996. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun 226:324-328.
33. Autiero M, Waltenberger J, Communi D, Kranz A, Moons L, et al. 2003. Role of PIGF in the intra- and intermolecular cross talk between the VEGF receptors Flt1 and Flk1. Nat Med 9:936-943.
34. Rahimi N, Dayanir V, Lashkari K. 2000. Receptor chimeras indicate that the vascular endothelial growth factor receptor-1 (VEGFR-1) modulates mitogenic activity of VEGFR-2 in endothelial cells. J Biol Chem 275:16986-16992.
35. Huang HY, Ho CC, Huang PH, Hsu SM. 2001. Co-expression of VEGF-C and its receptors, VEGFR-2 and VEGFR-3, in endothelial cells of lymphangioma. Implication in autocrine or paracrine regulation of lymphangioma. Lab Invest 81:1729-1734.
36. Dixelius J, Makinen T, Wirzenius M, Karkkainen MJ, Wernstedt C, et al. 2003. 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 278:40973-40979.
37. Liao W, Bisgrove BW, Sawyer H, Hug B, Bell B, et al. 1997. The zebrafish gene cloche acts upstream of a flk-1 homologue to regulate endothelial cell differentiation. Development 124:381-389.
38. Thompson MA, Ransom DG, Pratt SJ, MacLennan H, Kieran MW, et al. 1998. The cloche and spadetail genes differentially affect hematopoiesis and vasculogenesis. Dev Biol 197:248-269.
39. Habeck H, Odenthal J, Walderich B, Maischein H, Schulte-Merker S. 2002. Analysis of a zebrafish VEGF receptor mutant reveals specific disruption of angiogenesis. Curr Biol 12:1405-1412.
40. Staton CA, Kumar I, Reed MW, Brown NJ. 2007. Neuropilins in physiological and pathological angiogenesis. J Pathol 212:237-248.
41. Kawasaki T, Kitsukawa T, Bekku Y, Matsuda Y, Sanbo M, et al. 1999. A requirement for neuropilin-1 in embryonic vessel formation. Development 126:4895-4902.
42. Takashima S, Kitakaze M, Asakura M, Asanuma H, Sanada S, et al. 2002. Targeting of both mouse neuropilin-1 and neuropilin-2 genes severely impairs developmental yolk sac and embryonic angiogenesis. Proc Natl Acad Sci USA 99:3657-3662.
43. Lee P, Goishi K, Davidson AJ, Mannix R, Zon L, Klagsbrun M. 2002. Neuropilin-1 is required for vascular development and is a mediator of VEGF-dependent angiogenesis in zebrafish. Proc Natl Acad Sci USA 99: 10470-10475.
44. Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M. 1998. Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92:735-745.
45. Grazia Lampugnani M, Zanetti A, Corada M, Takahashi T, Balconi G, et al. 2003. Contact inhibition of VEGF-induced proliferation requires vascular endothelial Cadherin, beta-catenin, and the phosphatase DEP-1/ CD148. J Cell Biol 161:793-804.
46. Weis SM, Lindquist JN, Barnes LA, Lutu-Fuga KM, Cui J, et al. 2007. Cooperation between VEGF and beta3 integrin during cardiac vascular development. Blood 109:1962-1970.
47. Artavanis-Tsakonas S, Rand MD, Lake RJ. 1999. Notch signaling: cell fate control and signal integration in development. Science 284:770-776.
48. Bettenhausen B, Hrabe de Angelis M, Simon D, Guenet JL, Gossler A. 1995. Transient and restricted expression during mouse embryogenesis of DIM, a murine gene closely related to Drosophila Delta. Development 121:2407-2418.
49. Dunwoodie SL, Henrique D, Harrison SM, Beddington RS. 1997. Mouse DII3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development 124:3065-3076.
50. Lindsell CE, Shawber CJ, Boulter J, Weinmaster G. 1995. Jagged: a mammalian ligand that activates Notch1. Cell 80:909-917.
51. Shawber C, Boulter J, Lindsell CE, Weinmaster G. 1996. Jagged2: a serrate-like gene expressed during rat embryogenesis. Dev Biol 180: 370-376.
52. Shutter JR, Scully S, Fan W, Richards WG, Kitajewski J, et al. 2000. DII4, a novel Notch ligand expressed in arterial endothelium. Genes Dev 14:1313-1318.
53. del Arno FF, Gendron-Maguire M, Swiatek PJ, Jenkins NA, Copeland NG, Gridley T. 1993. Cloning, analysis, and chromosomal localization of Notch-1, a mouse homolog of Drosophila Notch. Genomics 15:259-264.
54. Lardelli M, Dahlstrand J, Lendahl U. 1994. The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium. Mech Dev 46:123-136.
55. Lardelli M, Lendahl U. 1993. Motch A and motch B - two mouse Notch homologues coexpressed in a wide variety of tissues. Exp Cell Res 204:364-372.
56. Uyttendaele H, Marazzi G, Wu G, Yan Q, Sassoon D, Kitajewski J. 1996. Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene. Development 122:2251-2259.
57. Weinmaster G, Roberts VJ, Lemke G. 1992. Notch2: a second mammalian Notch gene. Development 116:931-941.
58. Rebay I, Fleming RJ, Fehon RG, Cherbas L, Cherbas P, Artavanis-Tsakonas S. 1991. Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor. Cell 67:687-699.
59. Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, et al. 1998. The Notch1 receptor is cleaved constitutively by a furin-like convertase. Proc Natl Acad Sci USA 95:8108-8112.
60. Brou C, Logeat F, Gupta N, Bessia C, LeBail O, et al. 2000. A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. Mol Cell 5:207-216.
61. Mumm JS, Schroeter EH, Saxena MT, Griesemer A, Tian X, et al. 2000. A ligand-induced extracellular cleavage regulates gamma-secretase-like proteolytic activation of Notch1. Mol Cell 5:197-206.
62. Kato H, Taniguchi Y, Kurooka H, Minoguchi S, Sakai T. 1997. Involvement of RBP-J in biological functions of mouse Notch1 and its derivatives. Development 124:4133-4141.
63. Kurooka H, Kuroda K, Honjo T. 1998. Roles of the ankyrin repeats and C-terminal region of the mouse notch1 intracellular region. Nucleic Acids Res 26:5448-5455.
64. Roehl H, Kimble J. 1993. Control of cell fate in C. elegans by a GLP-1 peptide consisting primarily of ankyrin repeats. Nature 364:632-635.
65. Kurooka H, Honjo T. 2000. Functional interaction between the mouse notchl intracellular region and histone acetyltransferases PCAF and G CN5. J Biol Chem 275:17211-17220.
66. Leong GM, Subramaniam N, Issa LL, Barry JB, Kino T, et al. 2004. Ski-interacting protein, a bifunctional nuclear receptor coregulator that interacts with N-CoR/SMRT and p300. Biochem Biophys Res Commun 315:1070-1076.
67. Wallberg AE, Pedersen K, Lendahl U, Roeder RG. 2002. p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro. Mol Cell Biol 22:7812-7819.
68. Wu L, Griffin JD. 2004. Modulation of Notch signaling by mastermind-like (MAML) transcriptional co-activators and their involvement in tumori-genesis. Semin Cancer Biol 14:348-356.
69. Kageyama R, Ohtsuka T, Kobayashi T. 2007. The Hes gene family: repressors and oscillators that orchestrate embryogenesis. Development 134:1243-1251.
70. Simpson P. 1990. Lateral inhibition and the development of the sensory bristles of the adult peripheral nervous system of Drosophila. Development 109:509-519.
71. Lewis J. 1996. Neurogenic genes and vertebrate neurogenesis. Curr Opin Neurobiol 6:3-10.
72. de Celis JF, Bray S. 1997. Feed-back mechanisms affecting Notch activation at the dorsoventral boundary in the Drosophila wing. Development 124:3241-3251.
73. Radtke F, Raj K. 2003. The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3:756-767.
74. Rangarajan A, Talora C, Okuyama R, Nicolas M, Mammucari C, et al. 2001. Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation. Embo J 20:3427-3436.
75. Ghabrial AS, Krasnow MA. 2006. Social interactions among epithelial cells during tracheal branching morphogenesis. Nature 441:746-749.
76. Nagaraj R, Banerjee U. 2004. The little R cell that could. Int J Dev Biol 48:755-760.
77. Villa N, Walker L, Lindsell CE, Gasson J, Iruela-Arispe ML, Weinmaster G. 2001. Vascular expression of Notch pathway receptors and ligands is restricted to arterial vessels. Mech Dev 108:161-164.
78. Lawson ND, Vogel AM, Weinstein BM. 2002. Sonic hedgehog and vascular endothelial growth factor act upstream of the Notch pathway during arterial endothelial differentiation. Dev Cell 3:127-136.
79. Krebs LT, Shutter JR, Tanigaki K, Honjo T, Stark KL, Gridley T. 2004. Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants. Genes Dev 18:2469-2473.
80. Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, et al. 2000. Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14:1343-1352.
81. Stalmans I, Ng YS, Rohan R, Fruttiger M, Bouche A, et al. 2002. Arteriolar and venular patterning in retinas of mice selectively expressing VEGF isoforms. J Clin Invest 109:327-336.
82. Visconti RP, Richardson CD, Sato TN. 2002. Orchestration of angiogenesis and arteriovenous contribution by angiopoietins and vascular endothelial growth factor (VEGF). Proc Natl Acad Sci USA 99:8219-8224.
83. Grego-Bessa J, Luna-Zurita L, del Monte G, Bolos V, Melgar P, et al. 2007. Notch signaling is essential for ventricular chamber development. Dev Cell 12:415-429.
84. Whelan JT, Forbes SL, Bertrand FE. 2007. CBF-1 (RBP-J kappa) binds to the PTEN promoter and regulates PTEN gene expression. Cell Cycle 6:80-84.
85. Maehama T, Dixon JE. 1998. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem 273:13375-13378.
86. Gericke A, Munson M, Ross AH. 2006. Regulation of the PTEN phosphatase. Gene 374:1-9.
87. Taylor V, Wong M, Brandts C, Reilly L, Dean NM, et al. 2000. 5′ phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells. Mol Cell Biol 20:6860-6871.
88. Leslie JD, Ariza-McNaughton L, Bermange AL, McAdow R, Johnson SL, Lewis J. 2007. Endothelial signalling by the Notch ligand Delta-like 4 restricts angiogenesis. Development 134:839-844.
89. Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, et al. 2007. DII4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445:776-780.
90. Suchting S, Freitas C, Ie Noble F, Benedito R, Breant C, et al. 2007. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA 104:3225-3230.
91. Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, et al. 2007. Delta-like ligand 4 (DII4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA 104:3219-3224.
92. Liu ZJ, Shirakawa T, Li Y, Soma A, Oka M, et al. 2003. Regulation of Notch1 and DII4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis. Mol Cell Biol 23:14-25.
93. Williams CK, Li JL, Murga M, Harris AL, Tosato G. 2006. Up-regulation of the Notch ligand Delta-like 4 inhibits VEGF-induced endothelial cell function. Blood 107:931-939.
94. Harrington LS, Sainson RC, Williams CK, Taylor JM, Shi W, et al. 2007. Regulation of multiple angiogenic pathways by DII4 and Notch in human umbilical vein endothelial cells. Microvasc Res.
95. Taylor KL, Henderson AM, Hughes CC. 2002. Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression. Microvasc Res 64:372-383.
96. Shawber CJ, Funahashi Y, Francisco E, Vorontchikhina M, Kitamura Y, et al. 2007. Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J Clin Invest 117:3369-3382.
97. Henderson AM, Wang SJ, Taylor AC, Aitkenhead M, Hughes CC. 2001. The basic helix-loop-helix transcription factor HESR1 regulates endothelial cell tube formation. J Biol Chem 276:6169-6176.
98. Bray SJ. 2006. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678-689.
99. Gessler M, Knobeloch KP, Helisch A, Amann K, Schumacher N, et al. 2002. Mouse gridlock: no aortic coarctation or deficiency, but fatal cardiac defects in Hey2 -/- mice. Curr Biol 12:1601-1604.
100. Lefort K, Dotto GP. 2004. Notch signaling in the integrated control of keratinocyte growth/differentiation and tumor suppression. Semin Cancer Biol 14:374-386.
101. el-Deiry WS, Tokino T, Veloulescu VE, Levy DB, Parsons R, et al. 1993. WAF1, a potential mediator of p53 tumor suppression. Cell 75:817-825.
102. Hamada K, Sasaki T, Koni PA, Natsui M, Kishimoto H, et al. 2005. The PTEN/PI3K pathway governs normal vascular development and tumor angiogenesis. Genes Dev 19:2054-2065.
103. Martin-Belmonte F, Gassama A, Datta A, Yu W, Rescher U, et al. 2007. PTEN-mediated apical segregation of phosphoinositides controls epithelial morphogenesis through Cdc42. Cell 128:383-397.
104. Lawson ND, Weinstein BM. 2002. Arteries and veins: making a difference with zebrafish. Nat Rev Genet 3:674-682.
105. Hofmann JJ, Luisa Iruela-Arispe M. 2007. Notch expression patterns in the retina: An eye on receptor-ligand distribution during angiogenesis. Gene Expr Patterns 7:461-470.
106. Scehnet JS, Jiang W, Kumar SR, Krasnoperov V, Trindade A, et al. 2007. Inhibition of DII4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 109: 4753-4760.
107. Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, et al. 2006. Blockade of DII4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444:1032-1037.
108. Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, et al. 2006. Inhibition of DII4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444:1083-1087.
109. Sainson RC, Harris AL. 2007. Anti-DII4 therapy: can we block tumour growth by increasing angiogenesis? Trends Mol Med 13:389-395.
110. Thurston G, Noguera-Troise I, Yancopoulos GD. 2007. The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev Cancer 7:327-331.