Combination of Dll4/Notch and Ephrin-B2/EphB4 targeted therapy is highly effective in disrupting tumor angiogenesis View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2010-11-23

AUTHORS

Dusan Djokovic, Alexandre Trindade, Joana Gigante, Marina Badenes, Lilliana Silva, Ren Liu, Xiuqing Li, Ming Gong, Valery Krasnoperov, Parkash S Gill, Antonio Duarte

ABSTRACT

BackgroundDll4/Notch and Ephrin-B2/EphB4 pathways play critical roles in tumor vessel development and maturation. This study evaluates the efficacy of the inhibition of both signaling pathways, alone and in combination, in reducing the growth of an autochthonous mouse tumor and assesses potential adverse effects.MethodsWe used the transgenic RIP1-Tag2 tumor model to study the effects of 1) inhibition of Dll4/Notch by either Dll4 allelic deletion or use of a soluble extracellular Dll4 (sDll4), 2) inhibition of Ephrin-B2/EphB4 signaling by a soluble extracellular EphB4 fused to albumin (sEphB4-Alb), and 3) inhibition of both pathways by sEphB4-Alb combined with either Dll4 allelic deletion or sDll4. To investigate adverse effects, we used inducible endothelial-specific Dll4 knock-out mice, treated with sEphB4-Alb, and carried out histopathological analysis.ResultsDll4 allele deletion or soluble Dll4 treatment resulted in increased tumor vessel density, reduced mural cell recruitment and vessel perfusion which resulted in reduced tumor size. The soluble EphB4 instead reduced vessel density and vessel perfusion, leading to reduction of tumor size. Greater efficacy was observed when sEphB4-Alb was combined with either Dll4 allele deletion or sDll4 in regards to tumor size, vessel perfusion and mural cell recruitment. Induced endothelial specific Dll4 loss-of-function caused hepatic vascular alterations, which were prevented by concomitant sEphB4-Alb treatment.ConclusionCombination targeting of Dll4/Notch and Ephrin-B2/EphB4 has potential for clinical investigation, providing cumulative efficacy and increased safety over Dll4/Notch inhibition alone. More... »

PAGES

641

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1471-2407-10-641

DOI

http://dx.doi.org/10.1186/1471-2407-10-641

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1051361524

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/21092311


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38 schema:description BackgroundDll4/Notch and Ephrin-B2/EphB4 pathways play critical roles in tumor vessel development and maturation. This study evaluates the efficacy of the inhibition of both signaling pathways, alone and in combination, in reducing the growth of an autochthonous mouse tumor and assesses potential adverse effects.MethodsWe used the transgenic RIP1-Tag2 tumor model to study the effects of 1) inhibition of Dll4/Notch by either Dll4 allelic deletion or use of a soluble extracellular Dll4 (sDll4), 2) inhibition of Ephrin-B2/EphB4 signaling by a soluble extracellular EphB4 fused to albumin (sEphB4-Alb), and 3) inhibition of both pathways by sEphB4-Alb combined with either Dll4 allelic deletion or sDll4. To investigate adverse effects, we used inducible endothelial-specific Dll4 knock-out mice, treated with sEphB4-Alb, and carried out histopathological analysis.ResultsDll4 allele deletion or soluble Dll4 treatment resulted in increased tumor vessel density, reduced mural cell recruitment and vessel perfusion which resulted in reduced tumor size. The soluble EphB4 instead reduced vessel density and vessel perfusion, leading to reduction of tumor size. Greater efficacy was observed when sEphB4-Alb was combined with either Dll4 allele deletion or sDll4 in regards to tumor size, vessel perfusion and mural cell recruitment. Induced endothelial specific Dll4 loss-of-function caused hepatic vascular alterations, which were prevented by concomitant sEphB4-Alb treatment.ConclusionCombination targeting of Dll4/Notch and Ephrin-B2/EphB4 has potential for clinical investigation, providing cumulative efficacy and increased safety over Dll4/Notch inhibition alone.
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45 schema:keywords ConclusionCombination
46 Dll4
47 Dll4/Notch
48 Dll4/Notch inhibition
49 EphB4
50 Ephrin-B2/EphB4
51 MethodsWe
52 Notch
53 Notch inhibition
54 adverse effects
55 allele deletion
56 allelic deletions
57 alterations
58 analysis
59 angiogenesis
60 cell recruitment
61 clinical investigation
62 combination
63 critical role
64 cumulative efficacy
65 deletion
66 density
67 development
68 effect
69 efficacy
70 function
71 greater efficacy
72 growth
73 histopathological analysis
74 inhibition
75 investigation
76 knock
77 loss
78 maturation
79 mice
80 model
81 mouse tumors
82 mural cell recruitment
83 pathway
84 perfusion
85 potential adverse effects
86 recruitment
87 reduced tumor size
88 reduction
89 regard
90 role
91 safety
92 size
93 soluble EphB4
94 study
95 therapy
96 treatment
97 tumor angiogenesis
98 tumor model
99 tumor size
100 tumor vessel density
101 tumor vessel development
102 tumors
103 use
104 vascular alterations
105 vessel density
106 vessel development
107 vessel perfusion
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