Dll4-Notch signaling in regulation of tumor angiogenesis
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- 作者：Zhaoguo Liu (1)
Fangtian Fan (1)
Aiyun Wang (2)
Shizhong Zheng (1) (2)
Yin Lu (1) (2) - 关键词：Dll4 ; Notch signaling ; Tumor angiogenesis ; Endothelial cell ; Jagged1 ; Notch1 ; Wnt/尾 ; catenin
- 刊名：Journal of Cancer Research and Clinical Oncology
- 出版年：2014
- 出版时间：April 2014
- 年：2014
- 卷：140
- 期：4
- 页码：525-536
- 全文大小：369 KB
- 参考文献：1. Aster JC, Blacklow SC, Pear WS (2011) Notch signalling in T-cell lymphoblastic leukaemia/lymphoma and other haematological malignancies. J Pathol 223:262鈥?73
2. Beel AJ, Sanders CR (2008) Substrate specificity of gamma-secretase and other intramembrane proteases. Cell Mol Life Sci 65:1311鈥?334
3. Benedito R, Trindade A, Hirashima M, Henrique D, Da CL, Rossant J, Gill PS, Duarte A (2008) Loss of Notch signalling induced by Dll4 causes arterial calibre reduction by increasing endothelial cell response to angiogenic stimuli. BMC Dev Biol 8:117
4. Benedito R, Roca C, Sorensen I, Adams S, Gossler A, Fruttiger M, Adams RH (2009) The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell 137:1124鈥?135
5. Bentley K, Mariggi G, Gerhardt H, Bates PA (2009) Tipping the balance: robustness of tip cell selection, migration and fusion in angiogenesis. PLoS Comput Biol 5:e1000549
6. Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8:592鈥?03
7. Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678鈥?89
8. Bridges E, Oon CE, Harris A (2011) Notch regulation of tumor angiogenesis. Future Oncol 7:569鈥?88
9. Carlson TR, Yan Y, Wu X, Lam MT, Tang GL, Beverly LJ, Messina LM, Capobianco AJ, Werb Z, Wang R (2005) Endothelial expression of constitutively active Notch4 elicits reversible arteriovenous malformations in adult mice. Proc Natl Acad Sci USA 102:9884鈥?889
10. Claxton S, Fruttiger M (2004) Periodic Delta-like 4 expression in developing retinal arteries. Gene Expr Patterns 5:123鈥?27
11. Corada M, Nyqvist D, Orsenigo F, Caprini A, Giampietro C, Taketo MM, Iruela-Arispe ML, Adams RH, Dejana E (2010) The Wnt/beta-catenin pathway modulates vascular remodeling and specification by upregulating Dll4/Notch signaling. Dev Cell 18:938鈥?49
12. Djokovic D, Trindade A, Gigante J, Badenes M, Silva L, Liu R, Li X, Gong M, Krasnoperov V, Gill PS, Duarte A (2010) Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis. BMC Cancer 10:641
13. Domenga V, Fardoux P, Lacombe P, Monet M, Maciazek J, Krebs LT, Klonjkowski B, Berrou E, Mericskay M, Li Z, Tournier-Lasserve E, Gridley T, Joutel A (2004) Notch3 is required for arterial identity and maturation of vascular smooth muscle cells. Genes Dev 18:2730鈥?735
14. Dou GR, Wang L, Wang YS, Han H (2012) Notch signaling in ocular vasculature development and diseases. Mol Med 18:47鈥?5
15. D鈥橲ouza B, Miyamoto A, Weinmaster G (2008) The many facets of Notch ligands. Oncogene 27:5148鈥?167
16. Duarte A, Hirashima M, Benedito R, Trindade A, Diniz P, Bekman E, Costa L, Henrique D, Rossant J (2004) Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev 18:2474鈥?478
17. Dufraine J, Funahashi Y, Kitajewski J (2008) Notch signaling regulates tumor angiogenesis by diverse mechanisms. Oncogene 27:5132鈥?137
18. Ebos JM, Lee CR, Kerbel RS (2009) Tumor and host-mediated pathways of resistance and disease progression in response to antiangiogenic therapy. Clin Cancer Res 15:5020鈥?025
19. Eilken HM, Adams RH (2010) Dynamics of endothelial cell behavior in sprouting angiogenesis. Curr Opin Cell Biol 22:617鈥?25
20. Fan X, Mikolaenko I, Elhassan I, Ni X, Wang Y, Ball D, Brat DJ, Perry A, Eberhart CG (2004) Notch1 and notch2 have opposite effects on embryonal brain tumor growth. Cancer Res 64:7787鈥?793
21. Filipazzi P, Burdek M, Villa A, Rivoltini L, Huber V (2012) Recent advances on the role of tumor exosomes in immunosuppression and disease progression. Semin Cancer Biol 22:342鈥?49
22. Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M (2004) The Notch target genes Hey1 and Hey2 are required for embryonic vascular development. Genes Dev 18:901鈥?11
23. Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285:1182鈥?186
24. Funahashi Y, Hernandez SL, Das I, Ahn A, Huang J, Vorontchikhina M, Sharma A, Kanamaru E, Borisenko V, Desilva DM, Suzuki A, Wang X, Shawber CJ, Kandel JJ, Yamashiro DJ, Kitajewski J (2008) A notch1 ectodomain construct inhibits endothelial notch signaling, tumor growth, and angiogenesis. Cancer Res 68:4727鈥?735
25. Gale NW, Dominguez MG, Noguera I, Pan L, Hughes V, Valenzuela DM, Murphy AJ, Adams NC, Lin HC, Holash J, Thurston G, Yancopoulos GD (2004) Haploinsufficiency of delta-like 4 ligand results in embryonic lethality due to major defects in arterial and vascular development. Proc Natl Acad Sci USA 101:15949鈥?5954
26. Garcia A, Kandel JJ (2012) Notch: a key regulator of tumor angiogenesis and metastasis. Histol Histopathol 27:151鈥?56
27. Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C (2003) VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol 161:1163鈥?177
28. Gridley T (2007) Notch signaling in vascular development and physiology. Development 134:2709鈥?718
29. Gurney A, Hoey T (2011) Anti-DLL4, a cancer therapeutic with multiple mechanisms of action. Vasc Cell 3:18
30. Hainaud P, Contreres JO, Villemain A, Liu LX, Plouet J, Tobelem G, Dupuy E (2006) 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 66:8501鈥?510
31. Haller BK, Brave A, Wallgard E, Roswall P, Sunkari VG, Mattson U, Hallengard D, Catrina SB, Hellstrom M, Pietras K (2010) Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma. Oncogene 29:4276鈥?286
32. Hanahan D, Coussens LM (2012) Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21:309鈥?22
33. Harrington LS, Sainson RC, Williams CK, Taylor JM, Shi W, Li JL, Harris AL (2008) Regulation of multiple angiogenic pathways by Dll4 and Notch in human umbilical vein endothelial cells. Microvasc Res 75:144鈥?54
34. Hellstrom M, Phng LK, Hofmann JJ, Wallgard E, Coultas L, Lindblom P, Alva J, Nilsson AK, Karlsson L, Gaiano N, Yoon K, Rossant J, Iruela-Arispe ML, Kalen M, Gerhardt H, Betsholtz C (2007) Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis. Nature 445:776鈥?80
35. Hemming ML, Elias JE, Gygi SP, Selkoe DJ (2008) Proteomic profiling of gamma-secretase substrates and mapping of substrate requirements. PLoS Biol 6:e257
36. High FA, Lu MM, Pear WS, Loomes KM, Kaestner KH, Epstein JA (2008) Endothelial expression of the Notch ligand Jagged1 is required for vascular smooth muscle development. Proc Natl Acad Sci USA 105:1955鈥?959
37. Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S, Fitch-Bruhns M, Lazetic S, Park IK, Sato A, Satyal S, Wang X, Clarke MF, Lewicki J, Gurney A (2009) DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 5:168鈥?77
38. Hofmann JJ, Iruela-Arispe ML (2007) Notch signaling in blood vessels: who is talking to whom about what? Circ Res 100:1556鈥?568
39. Imbimbo BP (2008) Therapeutic potential of gamma-secretase inhibitors and modulators. Curr Top Med Chem 8:54鈥?1
40. Jakobsson L, Franco CA, Bentley K, Collins RT, Ponsioen B, Aspalter IM, Rosewell I, Busse M, Thurston G, Medvinsky A, Schulte-Merker S, Gerhardt H (2010) Endothelial cells dynamically compete for the tip cell position during angiogenic sprouting. Nat Cell Biol 12:943鈥?53
41. Kamath BM, Spinner NB, Emerick KM, Chudley AE, Booth C, Piccoli DA, Krantz ID (2004) Vascular anomalies in Alagille syndrome: a significant cause of morbidity and mortality. Circulation 109:1354鈥?358
42. Karsan A (2005) The role of notch in modeling and maintaining the vasculature. Can J Physiol Pharmacol 83:14鈥?3
43. Kopan R, Ilagan MX (2009) The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137:216鈥?33
44. Krebs LT, Xue Y, Norton CR, Shutter JR, Maguire M, Sundberg JP, Gallahan D, Closson V, Kitajewski J, Callahan R, Smith GH, Stark KL, Gridley T (2000) Notch signaling is essential for vascular morphogenesis in mice. Genes Dev 14:1343鈥?352
45. Kuhnert F, Kirshner JR, Thurston G (2011) Dll4-Notch signaling as a therapeutic target in tumor angiogenesis. Vasc Cell 3:20
46. Kwon SM, Eguchi M, Wada M, Iwami Y, Hozumi K, Iwaguro H, Masuda H, Kawamoto A, Asahara T (2008) Specific Jagged-1 signal from bone marrow microenvironment is required for endothelial progenitor cell development for neovascularization. Circulation 118:157鈥?65
47. Laranjeiro R, Alcobia I, Neves H, Gomes AC, Saavedra P, Carvalho CC, Duarte A, Cidadao A, Parreira L (2012) The notch ligand delta-like 4 regulates multiple stages of early hemato-vascular development. PLoS ONE 7:e34553
48. Lee JH, Chun T, Park SY, Rho SB (2008) Interferon regulatory factor-1 (IRF-1) regulates VEGF-induced angiogenesis in HUVECs. Biochim Biophys Acta 1783:1654鈥?662
49. 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鈥?44
50. Li JL, Harris AL (2005) Notch signaling from tumor cells: a new mechanism of angiogenesis. Cancer Cell 8:1鈥?
51. Li JL, Sainson RC, Shi W, Leek R, Harrington LS, Preusser M, Biswas S, Turley H, Heikamp E, Hainfellner JA, Harris AL (2007) Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res 67:11244鈥?1253
52. Limbourg FP, Takeshita K, Radtke F, Bronson RT, Chin MT, Liao JK (2005) Essential role of endothelial Notch1 in angiogenesis. Circulation 111:1826鈥?832
53. Lin JT, Chen MK, Yeh KT, Chang CS, Chang TH, Lin CY, Wu YC, Su BW, Lee KD, Chang PJ (2010) Association of high levels of Jagged-1 and Notch-1 expression with poor prognosis in head and neck cancer. Ann Surg Oncol 17:2976鈥?983
54. Liu H, Kennard S, Lilly B (2009) NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1. Circ Res 104:466鈥?75
55. Lobov IB, Renard RA, Papadopoulos N, Gale NW, Thurston G, Yancopoulos GD, Wiegand SJ (2007) Delta-like ligand 4 (Dll4) is induced by VEGF as a negative regulator of angiogenic sprouting. Proc Natl Acad Sci USA 104:3219鈥?224
56. Loges S, Roncal C, Carmeliet P (2009) Development of targeted angiogenic medicine. J Thromb Haemost 7:21鈥?3
57. Louvi A, Arboleda-Velasquez JF, Artavanis-Tsakonas S (2006) CADASIL: a critical look at a Notch disease. Dev Neurosci 28:5鈥?2
58. Mailhos C, Modlich U, Lewis J, Harris A, Bicknell R, Ish-Horowicz D (2001) Delta4, an endothelial specific notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation 69:135鈥?44
59. Martinez AA, Zecchini V, Brennan K (2002) CSL-independent Notch signalling: a checkpoint in cell fate decisions during development? Curr Opin Genet Dev 12:524鈥?33
60. Mazzone M, Selfors LM, Albeck J, Overholtzer M, Sale S, Carroll DL, Pandya D, Lu Y, Mills GB, Aster JC, Artavanis-Tsakonas S, Brugge JS (2010) Dose-dependent induction of distinct phenotypic responses to Notch pathway activation in mammary epithelial cells. Proc Natl Acad Sci USA 107:5012鈥?017
61. Moserle L, Amadori A, Indraccolo S (2009) The angiogenic switch: implications in the regulation of tumor dormancy. Curr Mol Med 9:935鈥?41
62. Naumov GN, Akslen LA, Folkman J (2006) Role of angiogenesis in human tumor dormancy: animal models of the angiogenic switch. Cell Cycle 5:1779鈥?787
63. Noguera-Troise I, Daly C, Papadopoulos NJ, Coetzee S, Boland P, Gale NW, Lin HC, Yancopoulos GD, Thurston G (2006) Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444:1032鈥?037
64. Oon CE, Harris AL (2011) New pathways and mechanisms regulating and responding to Delta-like ligand 4-Notch signalling in tumour angiogenesis. Biochem Soc Trans 39:1612鈥?618
65. Patel NS, Li JL, Generali D, Poulsom R, Cranston DW, Harris AL (2005) Up-regulation of delta-like 4 ligand in human tumor vasculature and the role of basal expression in endothelial cell function. Cancer Res 65:8690鈥?697
66. Phng LK, Gerhardt H (2009) Angiogenesis: a team effort coordinated by notch. Dev Cell 16:196鈥?08
67. Potente M, Gerhardt H, Carmeliet P (2011) Basic and therapeutic aspects of angiogenesis. Cell 146:873鈥?87
68. Qiao L, Wong BC (2009) Role of Notch signaling in colorectal cancer. Carcinogenesis 30:1979鈥?986
69. Ramdass B, Maliekal TT, Lakshmi S, Rehman M, Rema P, Nair P, Mukherjee G, Reddy BK, Krishna S, Radhakrishna PM (2007) Coexpression of Notch1 and NF-kappaB signaling pathway components in human cervical cancer progression. Gynecol Oncol 104:352鈥?61
70. Real PJ, Ferrando AA (2009) NOTCH inhibition and glucocorticoid therapy in T-cell acute lymphoblastic leukemia. Leukemia 23:1374鈥?377
71. Ribatti D, Nico B, Crivellato E, Roccaro AM, Vacca A (2007) The history of the angiogenic switch concept. Leukemia 21:44鈥?2
72. Ridgway J, Zhang G, Wu Y, Stawicki S, Liang WC, Chanthery Y, Kowalski J, Watts RJ, Callahan C, Kasman I, Singh M, Chien M, Tan C, Hongo JA, de Sauvage F, Plowman G, Yan M (2006) Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444:1083鈥?087
73. Rizzo P, Osipo C, Foreman K, Golde T, Osborne B, Miele L (2008) Rational targeting of Notch signaling in cancer. Oncogene 27:5124鈥?131
74. Robert-Moreno A, Guiu J, Ruiz-Herguido C, Lopez ME, Ingles-Esteve J, Riera L, Tipping A, Enver T, Dzierzak E, Gridley T, Espinosa L, Bigas A (2008) Impaired embryonic haematopoiesis yet normal arterial development in the absence of the Notch ligand Jagged1. EMBO J 27:1886鈥?895
75. Roca C, Adams RH (2007) Regulation of vascular morphogenesis by Notch signaling. Genes Dev 21:2511鈥?524
76. Sainson RC, Harris AL (2007) Anti-Dll4 therapy: can we block tumour growth by increasing angiogenesis? Trends Mol Med 13:389鈥?95
77. Sainson RC, Aoto J, Nakatsu MN, Holderfield M, Conn E, Koller E, Hughes CC (2005) Cell-autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis. FASEB J 19:1027鈥?029
78. Sakata T, Sakaguchi H, Tsuda L, Higashitani A, Aigaki T, Matsuno K, Hayashi S (2004) Drosophila Nedd4 regulates endocytosis of notch and suppresses its ligand-independent activation. Curr Biol 14:2228鈥?236
79. Sandy AR, Maillard I (2009) Notch signaling in the hematopoietic system. Expert Opin Biol Ther 9:1383鈥?398
80. Scehnet JS, Jiang W, Kumar SR, Krasnoperov V, Trindade A, Benedito R, Djokovic D, Borges C, Ley EJ, Duarte A, Gill PS (2007) Inhibition of Dll4-mediated signaling induces proliferation of immature vessels and results in poor tissue perfusion. Blood 109:4753鈥?760
81. Schadler KL, Zweidler-McKay PA, Guan H, Kleinerman ES (2010) Delta-like ligand 4 plays a critical role in pericyte/vascular smooth muscle cell formation during vasculogenesis and tumor vessel expansion in Ewing鈥檚 sarcoma. Clin Cancer Res 16:848鈥?56
82. Sethi N, Dai X, Winter CG, Kang Y (2011) Tumor-derived JAGGED1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 19:192鈥?05
83. Shao H, Cai L, Grichnik JM, Livingstone AS, Velazquez OC, Liu ZJ (2011) Activation of Notch1 signaling in stromal fibroblasts inhibits melanoma growth by upregulating WISP-1. Oncogene 30:4316鈥?326
84. Shawber CJ, Funahashi Y, Francisco E, Vorontchikhina M, Kitamura Y, Stowell SA, Borisenko V, Feirt N, Podgrabinska S, Shiraishi K, Chawengsaksophak K, Rossant J, Accili D, Skobe M, Kitajewski J (2007) Notch alters VEGF responsiveness in human and murine endothelial cells by direct regulation of VEGFR-3 expression. J Clin Invest 117:3369鈥?382
85. Siekmann AF, Lawson ND (2007) Notch signalling limits angiogenic cell behaviour in developing zebrafish arteries. Nature 445:781鈥?84
86. Stenzel D, Franco CA, Estrach S, Mettouchi A, Sauvaget D, Rosewell I, Schertel A, Armer H, Domogatskaya A, Rodin S, Tryggvason K, Collinson L, Sorokin L, Gerhardt H (2011) Endothelial basement membrane limits tip cell formation by inducing Dll4/Notch signalling in vivo. EMBO Rep 12:1135鈥?143
87. Suchting S, Eichmann A (2009) Jagged gives endothelial tip cells an edge. Cell 137:988鈥?90
88. Suchting S, Freitas C, le Noble F, Benedito R, Breant C, Duarte A, Eichmann A (2007) The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc Natl Acad Sci USA 104:3225鈥?230
89. Takeshita K, Satoh M, Ii M, Silver M, Limbourg FP, Mukai Y, Rikitake Y, Radtke F, Gridley T, Losordo DW, Liao JK (2007) Critical role of endothelial Notch1 signaling in postnatal angiogenesis. Circ Res 100:70鈥?8
90. Takeuchi H, Haltiwanger RS (2010) Role of glycosylation of Notch in development. Semin Cell Dev Biol 21:638鈥?45
91. 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鈥?83
92. Thurston G, Kitajewski J (2008) VEGF and Delta-Notch: interacting signalling pathways in tumour angiogenesis. Br J Cancer 99:1204鈥?209
93. 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鈥?31
94. Trindade A, Kumar SR, Scehnet JS, Lopes-da-Costa L, Becker J, Jiang W, Liu R, Gill PS, Duarte A (2008) Overexpression of delta-like 4 induces arterialization and attenuates vessel formation in developing mouse embryos. Blood 112:1720鈥?729
95. Uyttendaele H, Ho J, Rossant J, Kitajewski J (2001) Vascular patterning defects associated with expression of activated Notch4 in embryonic endothelium. Proc Natl Acad Sci USA 98:5643鈥?648
96. Wang MM (2011) Notch signaling and Notch signaling modifiers. Int J Biochem Cell Biol 43:1550鈥?562
97. Wang Z, Li Y, Banerjee S, Sarkar FH (2009) Emerging role of Notch in stem cells and cancer. Cancer Lett 279:8鈥?2
98. Wang Z, Li Y, Kong D, Ahmad A, Banerjee S, Sarkar FH (2010) Cross-talk between miRNA and Notch signaling pathways in tumor development and progression. Cancer Lett 292:141鈥?48
99. 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鈥?39
100. Wu Y, Cain-Hom C, Choy L, Hagenbeek TJ, de Leon GP, Chen Y, Finkle D, Venook R, Wu X, Ridgway J, Schahin-Reed D, Dow GJ, Shelton A, Stawicki S, Watts RJ, Zhang J, Choy R, Howard P, Kadyk L, Yan M, Zha J, Callahan CA, Hymowitz SG, Siebel CW (2010) Therapeutic antibody targeting of individual Notch receptors. Nature 464:1052鈥?057
101. Yan M, Callahan CA, Beyer JC, Allamneni KP, Zhang G, Ridgway JB, Niessen K, Plowman GD (2010) Chronic DLL4 blockade induces vascular neoplasms. Nature 463:E6鈥揈7
102. Yin L, Velazquez OC, Liu ZJ (2010) Notch signaling: emerging molecular targets for cancer therapy. Biochem Pharmacol 80:690鈥?01 - 作者单位：Zhaoguo Liu (1)
Fangtian Fan (1)
Aiyun Wang (2)
Shizhong Zheng (1) (2)
Yin Lu (1) (2)
1. Department of Clinical Pharmacy, College of Pharmacy, Nanjing University of Chinese Medicine, 282 Hanzhong Road, Nanjing, 210029, Jiangsu, People鈥檚 Republic of China
2. Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210029, China - ISSN：1432-1335
文摘
Tumor angiogenesis is a complex process and involves the tight interplay of tumor cells, endothelial cells, phagocytes and their secreted factors, which may act as promoters or inhibitors of angiogenesis. Many signaling pathways involved in these processes such as vascular endothelial growth factor (VEGF), fibroblast growth factors, Wnt and mTOR signaling pathway. Though research has confirmed that VEGF can play an important role in tumor angiogenesis, and has designed a lot of drugs that target VEGF, both experimental and clinical studies showed that these pathways mentioned above including VEGF did not play key roles in tumor angiogenesis. With the deepening of the research, people find that of all the signaling pathways involved in tumor angiogenesis, Notch signaling is the most notable one and plays crucial role in tumor angiogenesis. It was previously recognized that the Notch signaling plays a key role only in physiological angiogenesis such as development, wound healing and pregnancy. However, an increasing number of studies have proved that Notch signaling is also involved in pathological angiogenesis such as tumor angiogenesis and plays a critical role in these processes. More importantly, compared to resistance caused by anti-VEGF or other signaling pathways, experimental evidence revealed that Notch was involved in anticancer drug resistance, indicating that targeting Notch could be a novel therapeutic approach to the treatment for cancer by overcoming drug resistance of cancer cells. More recently, research has demonstrated that Notch ligands Delta-like 4 (Dll4) plays a key role in tumor angiogenesis. Data show that Dll4 functions as a negative regulator of tumor angiogenesis and is upregulated in tumor vasculature. This review focus on recent insights into Dll4-Notch signaling in tumor angiogenesis and its mechanisms, which may be utilized for a potential pharmacological use as a target for anti-angiogenic cancer therapy.