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Androgen deprivation in LNCaP prostate tumour xenografts induces vascular changes and hypoxic stress, resulting in promotion of epithelial-to-mesenchymal transition

BACKGROUND: When single-agent androgen deprivation therapy (ADT) is administered for locally advanced prostate cancer, men usually relapse within 1–2 years with more malignant castrate-resistant disease. The reason for this is currently unknown. We now hypothesise that an initial treatment response...

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Autores principales: Byrne, N M, Nesbitt, H, Ming, L, McKeown, S R, Worthington, J, McKenna, D J
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800298/
https://www.ncbi.nlm.nih.gov/pubmed/26954717
http://dx.doi.org/10.1038/bjc.2016.29
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author Byrne, N M
Nesbitt, H
Ming, L
McKeown, S R
Worthington, J
McKenna, D J
author_facet Byrne, N M
Nesbitt, H
Ming, L
McKeown, S R
Worthington, J
McKenna, D J
author_sort Byrne, N M
collection PubMed
description BACKGROUND: When single-agent androgen deprivation therapy (ADT) is administered for locally advanced prostate cancer, men usually relapse within 1–2 years with more malignant castrate-resistant disease. The reason for this is currently unknown. We now hypothesise that an initial treatment response that increases tumour hypoxia drives selection of more malignant tumours. METHODS: The LNCaP prostate tumour xenografts were analysed for physiological (oxygen and vasculature) and genetic (PCR array) changes during longitudinal treatment with ADT (bicalutamide, 6 or 2 mg kg(−1) daily for 28 days). RESULTS: Bicalutamide caused an immediate (within 24 h) dose-dependent fall in oxygenation in LNCaP-luc prostate tumours with a nadir of ≤0.1% oxygen within 3–7 days; this was attributed to a significant loss of tumour microvessels (window chamber study). The hypoxic nadir persisted for 10–14 days. During the next 7 days, tumours regrew, oxygenation improved and the vasculature recovered; this was inhibited by the VEGF inhibitor B20.4.1.1. Gene expression over 28 days showed marked fluctuations consistent with the physiological changes. Accompanying the angiogenic burst (day 21) was a particularly striking increase in expression of genes associated with epithelial-to-mesenchymal transition (EMT). In particular, insulin-like growth factor 1 (IGF-1) showed increases in mRNA and protein expression. CONCLUSIONS: Hypoxic stress caused by ADT promotes EMT, providing a mechanism for the cause of malignant progression in prostate cancer.
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spelling pubmed-48002982017-03-15 Androgen deprivation in LNCaP prostate tumour xenografts induces vascular changes and hypoxic stress, resulting in promotion of epithelial-to-mesenchymal transition Byrne, N M Nesbitt, H Ming, L McKeown, S R Worthington, J McKenna, D J Br J Cancer Translational Therapeutics BACKGROUND: When single-agent androgen deprivation therapy (ADT) is administered for locally advanced prostate cancer, men usually relapse within 1–2 years with more malignant castrate-resistant disease. The reason for this is currently unknown. We now hypothesise that an initial treatment response that increases tumour hypoxia drives selection of more malignant tumours. METHODS: The LNCaP prostate tumour xenografts were analysed for physiological (oxygen and vasculature) and genetic (PCR array) changes during longitudinal treatment with ADT (bicalutamide, 6 or 2 mg kg(−1) daily for 28 days). RESULTS: Bicalutamide caused an immediate (within 24 h) dose-dependent fall in oxygenation in LNCaP-luc prostate tumours with a nadir of ≤0.1% oxygen within 3–7 days; this was attributed to a significant loss of tumour microvessels (window chamber study). The hypoxic nadir persisted for 10–14 days. During the next 7 days, tumours regrew, oxygenation improved and the vasculature recovered; this was inhibited by the VEGF inhibitor B20.4.1.1. Gene expression over 28 days showed marked fluctuations consistent with the physiological changes. Accompanying the angiogenic burst (day 21) was a particularly striking increase in expression of genes associated with epithelial-to-mesenchymal transition (EMT). In particular, insulin-like growth factor 1 (IGF-1) showed increases in mRNA and protein expression. CONCLUSIONS: Hypoxic stress caused by ADT promotes EMT, providing a mechanism for the cause of malignant progression in prostate cancer. Nature Publishing Group 2016-03-15 2016-03-08 /pmc/articles/PMC4800298/ /pubmed/26954717 http://dx.doi.org/10.1038/bjc.2016.29 Text en Copyright © 2016 Cancer Research UK http://creativecommons.org/licenses/by-nc-sa/4.0/ From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/
spellingShingle Translational Therapeutics
Byrne, N M
Nesbitt, H
Ming, L
McKeown, S R
Worthington, J
McKenna, D J
Androgen deprivation in LNCaP prostate tumour xenografts induces vascular changes and hypoxic stress, resulting in promotion of epithelial-to-mesenchymal transition
title Androgen deprivation in LNCaP prostate tumour xenografts induces vascular changes and hypoxic stress, resulting in promotion of epithelial-to-mesenchymal transition
title_full Androgen deprivation in LNCaP prostate tumour xenografts induces vascular changes and hypoxic stress, resulting in promotion of epithelial-to-mesenchymal transition
title_fullStr Androgen deprivation in LNCaP prostate tumour xenografts induces vascular changes and hypoxic stress, resulting in promotion of epithelial-to-mesenchymal transition
title_full_unstemmed Androgen deprivation in LNCaP prostate tumour xenografts induces vascular changes and hypoxic stress, resulting in promotion of epithelial-to-mesenchymal transition
title_short Androgen deprivation in LNCaP prostate tumour xenografts induces vascular changes and hypoxic stress, resulting in promotion of epithelial-to-mesenchymal transition
title_sort androgen deprivation in lncap prostate tumour xenografts induces vascular changes and hypoxic stress, resulting in promotion of epithelial-to-mesenchymal transition
topic Translational Therapeutics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4800298/
https://www.ncbi.nlm.nih.gov/pubmed/26954717
http://dx.doi.org/10.1038/bjc.2016.29
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