title: [Mechanisms of castration resistance: Intratumoral hypoxia stimulates the androgen receptor expression].
abstract: OBJECTIVE
  Tumor hypoxia and its biological consequence lead to microenvironment adaptation of tumor initiation, promotion and progression. The aim of the study was to observe the influence of hypoxia on the expression of the androgen receptor (AR), using an original model of multicellular spheroids obtained from castration-resistant prostate tumor cells.
  
  
  METHODS
  Two human castration-resistant prostate cancer cell lines have been used to generate multicellular tumor spheroids (MTS). The conditions and duration of incubation modulated the final size of the MTS and the intrinsic hypoxia gradient. The expression of AR was studied by immunohistochemistry (IHC) and secretion of PSA measured in the culture medium.
  
  
  RESULTS
  The IHC expression of AR was characterized by a decreasing gradient from the periphery to the center of MTS (less intense in central hypoxic zone), corresponding to a nuclear translocation of activated AR. This result was proportionally correlated with the duration of hypoxic incubation period. Hypoxia caused significant increase in AR expression at 6h of oxygen deprivation. This activation of AR was correlated with transcriptional activity increase of target genes, including increased secretion of PSA.
  
  
  CONCLUSIONS
  This demonstration of activation, increased expression and increased transcriptional activity of AR by hypoxia is the first to have been made with an original model of hypoxia, closer to reality than previous models, i.e. close to tissue hypoxia observed in primary prostate cancer.
  
  
  METHODS
  4.
authors.affiliation: Département d'urologie, d'andrologie et de transplantation rénale, 1, avenue J.-Pouilhès, 31059 Toulouse, France. Electronic address: lunardi.p@chu-toulouse.fr.
authors.forename: P
authors.initials: P
authors.lastname: Lunardi
authors.affiliation: Département d'urologie, d'andrologie et de transplantation rénale, 1, avenue J.-Pouilhès, 31059 Toulouse, France.
authors.forename: J-B
authors.initials: JB
authors.lastname: Beauval
authors.affiliation: Département d'urologie, d'andrologie et de transplantation rénale, 1, avenue J.-Pouilhès, 31059 Toulouse, France.
authors.forename: M
authors.initials: M
authors.lastname: Roumiguié
authors.affiliation: Département d'urologie, d'andrologie et de transplantation rénale, 1, avenue J.-Pouilhès, 31059 Toulouse, France.
authors.forename: M
authors.initials: M
authors.lastname: Soulié
authors.affiliation: Inserm, institut de pharmacologie et de biologie structurale, 205, route de Narbonne, 31077 Toulouse, France.
authors.forename: O
authors.initials: O
authors.lastname: Cuvillier
authors.affiliation: Département d'urologie, d'andrologie et de transplantation rénale, 1, avenue J.-Pouilhès, 31059 Toulouse, France.
authors.forename: B
authors.initials: B
authors.lastname: Malavaud
mesh_terms: D006801:Humans; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology*; D011944:Receptors, Androgen / Q000096:biosynthesis*; D018874:Spheroids, Cellular; D014407:Tumor Cells, Cultured; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment
chemical_list: D011944:Receptors, Androgen
keywords: Androgen receptor; Cancer de la prostate; Hypoxia; Hypoxie; Prostate cancer; Récepteur aux androgènes; Sphéroïdes tumoraux; Tumor spheroids