Endothelial Dll4 overexpression reduces vascular response and inhibits tumor growth and metastasization in vivo View Full Text


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Article Info

DATE

2017-03-14

AUTHORS

Alexandre Trindade, Dusan Djokovic, Joana Gigante, Liliana Mendonça, António Duarte

ABSTRACT

BackgroundThe inhibition of Delta-like 4 (Dll4)/Notch signaling has been shown to result in excessive, nonfunctional vessel proliferation and significant tumor growth suppression. However, safety concerns emerged with the identification of side effects resulting from chronic Dll4/Notch blockade. Alternatively, we explored the endothelial Dll4 overexpression using different mouse tumor models.MethodsWe used a transgenic mouse model of endothelial-specific Dll4 overexpression, previously produced. Growth kinetics and vascular histopathology of several types of solid tumors was evaluated, namely Lewis Lung Carcinoma xenografts, chemically-induced skin papillomas and RIP1-Tag2 insulinomas.ResultsWe found that increased Dll4/Notch signaling reduces tumor growth by reducing vascular endothelial growth factor (VEGF)-induced endothelial proliferation, tumor vessel density and overall tumor blood supply. In addition, Dll4 overexpression consistently improved tumor vascular maturation and functionality, as indicated by increased vessel calibers, enhanced mural cell recruitment and increased network perfusion. Importantly, the tumor vessel normalization is not more effective than restricted vessel proliferation, but was found to prevent metastasis formation and allow for increased delivery to the tumor of concomitant chemotherapy, improving its efficacy.ConclusionsBy reducing endothelial sensitivity to VEGF, these results imply that Dll4/Notch stimulation in tumor microenvironment could be beneficial to solid cancer patient treatment by reducing primary tumor size, improving tumor drug delivery and reducing metastization. Endothelial specific Dll4 overexpression thus appears as a promising anti-angiogenic modality that might improve cancer control. More... »

PAGES

189

References to SciGraph publications

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  • Identifiers

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    http://scigraph.springernature.com/pub.10.1186/s12885-017-3171-2

    DOI

    http://dx.doi.org/10.1186/s12885-017-3171-2

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/28288569


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    39 schema:description BackgroundThe inhibition of Delta-like 4 (Dll4)/Notch signaling has been shown to result in excessive, nonfunctional vessel proliferation and significant tumor growth suppression. However, safety concerns emerged with the identification of side effects resulting from chronic Dll4/Notch blockade. Alternatively, we explored the endothelial Dll4 overexpression using different mouse tumor models.MethodsWe used a transgenic mouse model of endothelial-specific Dll4 overexpression, previously produced. Growth kinetics and vascular histopathology of several types of solid tumors was evaluated, namely Lewis Lung Carcinoma xenografts, chemically-induced skin papillomas and RIP1-Tag2 insulinomas.ResultsWe found that increased Dll4/Notch signaling reduces tumor growth by reducing vascular endothelial growth factor (VEGF)-induced endothelial proliferation, tumor vessel density and overall tumor blood supply. In addition, Dll4 overexpression consistently improved tumor vascular maturation and functionality, as indicated by increased vessel calibers, enhanced mural cell recruitment and increased network perfusion. Importantly, the tumor vessel normalization is not more effective than restricted vessel proliferation, but was found to prevent metastasis formation and allow for increased delivery to the tumor of concomitant chemotherapy, improving its efficacy.ConclusionsBy reducing endothelial sensitivity to VEGF, these results imply that Dll4/Notch stimulation in tumor microenvironment could be beneficial to solid cancer patient treatment by reducing primary tumor size, improving tumor drug delivery and reducing metastization. Endothelial specific Dll4 overexpression thus appears as a promising anti-angiogenic modality that might improve cancer control.
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    47 DLL4 overexpression
    48 Dll4/Notch signaling
    49 Lewis lung carcinoma xenografts
    50 MethodsWe
    51 Notch blockade
    52 Notch signaling
    53 Notch stimulation
    54 ResultsWe
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    56 addition
    57 blockade
    58 blood supply
    59 caliber
    60 cancer control
    61 cancer patient treatment
    62 carcinoma xenografts
    63 cell recruitment
    64 chemotherapy
    65 concern
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    67 control
    68 delivery
    69 delta
    70 density
    71 different mouse tumor models
    72 drug delivery
    73 effect
    74 efficacy
    75 endothelial growth factor
    76 endothelial proliferation
    77 endothelial sensitivity
    78 factors
    79 formation
    80 functionality
    81 growth
    82 growth factor
    83 growth kinetics
    84 growth suppression
    85 histopathology
    86 identification
    87 inhibition
    88 inhibition of delta
    89 insulinoma
    90 kinetics
    91 lung carcinoma xenografts
    92 maturation
    93 metastasis formation
    94 metastasization
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    96 microenvironment
    97 modalities
    98 model
    99 mouse model
    100 mouse tumor models
    101 mural cell recruitment
    102 network perfusion
    103 normalization
    104 overexpression
    105 papillomas
    106 patient treatment
    107 perfusion
    108 primary tumor size
    109 proliferation
    110 recruitment
    111 response
    112 results
    113 safety concerns
    114 sensitivity
    115 side effects
    116 signaling
    117 significant tumor growth suppression
    118 size
    119 skin papillomas
    120 solid tumors
    121 stimulation
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