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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

Abstract

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.

Type Journal
ISBN 1532-1827 (Electronic) 0007-0920 (Linking)
Authors Byrne, N. M.; Nesbitt, H.; Ming, L.; McKeown, S. R.; Worthington, J.; McKenna, D. J.;
Responsible Garvan Author Dr Niall Byrne
Publisher Name BRITISH JOURNAL OF CANCER
Published Date 2016-01-01
Published Volume 114
Published Issue 6
Published Pages 659-68
Status Published in-print
URL link to publisher's version http://www.ncbi.nlm.nih.gov/pubmed/26954717
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/13763