Delta-like 4/Notch signaling promotes ApcMin/+ tumor initiation through angiogenic and non-angiogenic related mechanisms View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2017-01-13

AUTHORS

Marina Badenes, Alexandre Trindade, Hugo Pissarra, Luís Lopes-da-Costa, António Duarte

ABSTRACT

BackgroundDelta like 4 (Dll4)/Notch signaling is a key regulator of tumor angiogenesis. Additionally, the role of Dll4 has been studied on tumor stem cells. However, as these cells are implicated in tumor angiogenesis, it is conceivable that the effect of Dll4 on these cells may be a consequence of its angiogenic function. Our aim was to evaluate the expression and dissect the functions of Dll4 in the ApcMin/+ model of colorectal cancer.MethodsWe evaluated the protein expression pattern of Dll4 and other Notch members in the ApcMin/+ tumors relatively to the normal gut and compared endothelial-specific with ubiquitous Dll4 knockout mice on an ApcMin/+ background.ResultsAll Notch pathway members were present in the normal small and large intestine and in the adenomas of the same regions. Dll4, all Notch receptors and Hes1 expression seemed upregulated in the tumors, with some regional differences. The same members and Hes5, instead of Hes1, presented ectopic expression in the tumor parenchyma. Dll4 expression was most pronounced in the tumor cells but it was also present in the tumor blood vessels and in other stromal cells. Ubiquitous and endothelial-specific Dll4 deletion led to an equivalent reduction of tumor growth because of a similarly marked tumoral angiogenic phenotype promoting non-productive vasculature and consequently hypoxia and apoptosis. The ubiquitous Dll4 inhibition led to a stronger decrease of tumor multiplicity than the endothelial-specific deletion by further reducing tumor proliferation and tumor stem cell density through upregulation of the cyclin-dependent kinase inhibitors 1C and 1B and downregulation of Myc, Cyclin D1 and D2 independently of β-catenin activation. This phenotype was associated to the observed increased epithelial differentiation deviated towards the secretory lineages by Atoh1 and Klf4 upregulation only in the ubiquitous Dll4 mutants.ConclusionsDll4 seems to promote ApcMin/+ tumorigenesis through both angiogenic and non-angiogenic related mechanisms. More... »

PAGES

50

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12885-016-3036-0

DOI

http://dx.doi.org/10.1186/s12885-016-3036-0

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1038537774

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/28086833


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56 MYC
57 MethodsWe
58 Notch members
59 Notch pathway members
60 Notch receptors
61 activation
62 adenomas
63 aim
64 angiogenesis
65 angiogenic function
66 angiogenic phenotype
67 apoptosis
68 background
69 blood vessels
70 cancer
71 cell density
72 cells
73 colorectal cancer
74 consequences
75 cyclin D1
76 cyclin-dependent kinase inhibitor 1C
77 decrease
78 deletion
79 density
80 differences
81 differentiation
82 downregulation
83 downregulation of MYC
84 ectopic expression
85 effect
86 endothelial-specific deletion
87 epithelial differentiation
88 equivalent reduction
89 expression
90 expression patterns
91 function
92 growth
93 gut
94 inhibition
95 initiation
96 intestine
97 key regulator
98 knockout mice
99 large intestine
100 lineages
101 mechanism
102 members
103 mice
104 model
105 multiplicity
106 mutants
107 normal gut
108 parenchyma
109 pathway members
110 patterns
111 phenotype
112 proliferation
113 promotes
114 protein expression patterns
115 receptors
116 reduction
117 region
118 regional differences
119 regulator
120 related mechanisms
121 role
122 role of Dll4
123 same members
124 same region
125 secretory lineages
126 signaling
127 signaling promotes
128 stem cell density
129 stem cells
130 stromal cells
131 strong decrease
132 tumor angiogenesis
133 tumor blood vessels
134 tumor cells
135 tumor growth
136 tumor initiation
137 tumor multiplicity
138 tumor parenchyma
139 tumor proliferation
140 tumor stem cells
141 tumorigenesis
142 tumors
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144 vasculature
145 vessels
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