title: 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.
authors.affiliation: Biomedical Science Research Institute, University of Ulster, Cromore Road, Coleraine, BT52 1SA Northern Ireland, UK.|Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia.
authors.forename: N M
authors.initials: NM
authors.lastname: Byrne
authors.affiliation: Biomedical Science Research Institute, University of Ulster, Cromore Road, Coleraine, BT52 1SA Northern Ireland, UK.
authors.forename: H
authors.initials: H
authors.lastname: Nesbitt
authors.affiliation: Biomedical Science Research Institute, University of Ulster, Cromore Road, Coleraine, BT52 1SA Northern Ireland, UK.
authors.forename: L
authors.initials: L
authors.lastname: Ming
authors.affiliation: Biomedical Science Research Institute, University of Ulster, Cromore Road, Coleraine, BT52 1SA Northern Ireland, UK.
authors.forename: S R
authors.initials: SR
authors.lastname: McKeown
authors.affiliation: Axis Bioservices Ltd, Research Laboratory, Castleroe Road, Coleraine BT51 3RP, Northern Ireland, UK.
authors.forename: J
authors.initials: J
authors.lastname: Worthington
authors.affiliation: Biomedical Science Research Institute, University of Ulster, Cromore Road, Coleraine, BT52 1SA Northern Ireland, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: McKenna
mesh_terms: D000726:Androgen Antagonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D048708:Cell Growth Processes; D015687:Cell Hypoxia / Q000187:drug effects*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014105:Tosyl Compounds / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D014105:Tosyl Compounds; C053541:bicalutamide; D010100:Oxygen