title: Localization of immunoreactive HIF-1alpha and HIF-2alpha in neuroendocrine cells of both benign and malignant prostate glands.
abstract: BACKGROUND
  Hypoxia induces increased tumor growth by promoting angiogenic and glycolytic pathways. Tumors expressing hypoxia-inducible factor-1alpha (HIF-1alpha), an important transcriptional activator of oxygen-regulated genes, are resistant to chemotherapy and radiotherapy. The major challenge in prostate cancer therapy today is to gain a better understanding of the development of hormone-refractory tumors, which is often characterized by neuroendocrine differentiation. Here we studied the expression of HIF-1alpha and HIF-2alpha in neuroendocrine cells of the benign prostate and in prostate cancer.
  
  
  METHODS
  Tissue sections from 30 patients who underwent radical prostatectomy and from 21 patients operated by transurethral resection of the prostate were selected for immunohistochemical analysis for expression of HIF-1alpha, HIF-2alpha, androgen receptor (AR), neuroendocrine markers (chromogranin A, synaptophysin), and two gene products downstream of HIF-1alpha: VEGF and GAPDH.
  
  
  RESULTS
  Immunoreactive HIF-1alpha was detected in a subpopulation of AR-negative neuroendocrine cells in benign and malignant prostate tissue. Analysis of serial sections showed that the levels of expression of GAPDH and VEGF proteins are increased in AR-negative malignant neuroendocrine cells expressing HIF-1alpha. In situ-hybridization indicated that HIF-1alpha mRNA levels are not higher in neuroendocrine prostate cancer cells relative to corresponding non-neuroendocrine tumor cells. We also demonstrated induced stabilization of nuclear HIF-1alpha in LNCaP cells by hypoxia and long-term stimulation with interleukin-6. Focal HIF-2 expression was detected in benign neuroendocrine-like cells and in malignant prostatic cells.
  
  
  CONCLUSIONS
  The expression of HIF-1alpha and HIF-2alpha in prostate cancer has been confirmed, but we also identified immunoreactive HIF-1alpha and downstream gene products in benign and malignant prostate neuroendocrine cells.
authors.affiliation: Department of Clinical Sciences, Division of Urological Cancer, Malmö University Hospital, Lund University, Sweden.
authors.forename: Nastaran
authors.initials: N
authors.lastname: Monsef
authors.forename: Leszek
authors.initials: L
authors.lastname: Helczynski
authors.forename: Ake
authors.initials: A
authors.lastname: Lundwall
authors.forename: Sven
authors.initials: S
authors.lastname: Påhlman
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D051792:Basic Helix-Loop-Helix Proteins / Q000032:analysis* / Q000235:genetics; D045744:Cell Line, Tumor; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000032:analysis* / Q000235:genetics; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D008875:Middle Aged; D009490:Neurosecretory Systems / Q000737:chemistry* / Q000473:pathology*; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000737:chemistry* / Q000473:pathology* / Q000601:surgery; D012333:RNA, Messenger / Q000032:analysis; D011944:Receptors, Androgen / Q000032:analysis; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger; D011944:Receptors, Androgen; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human