title: Osteoblast-derived factors induce androgen-independent proliferation and expression of prostate-specific antigen in human prostate cancer cells.
abstract: OBJECTIVE
  Prostate cancer metastasizes to the skeleton to form osteoblastic lesions. Androgen ablation is the current treatment for metastatic prostate cancer. This therapy is palliative, and the disease will return in an androgen-independent form that is preceded by a rising titer of prostate-specific antigen (PSA). Here, we investigated the possibility that human osteoblasts might secrete factors that contribute to the emergence of androgen-independent prostate cancer.
  
  
  METHODS
  Primary cultures of human osteoblasts were used as a source of conditioned medium (OCM). Proliferation, expression of androgen-regulated genes, and transactivation of the androgen receptor (AR) were monitored in LNCaP human prostate cancer cells in response to OCM using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, Northern blot analysis, and reporter gene constructs. Levels of interleukin-6 (IL-6) present in OCM were measured, and its contribution to proliferation and expression of PSA were investigated by neutralization studies with anti IL-6 antibodies.
  
  
  RESULTS
  OCM increased the proliferation and expression of PSA at both the protein and RNA levels in LNCaP cells. Synergistic increases in the activities of PSA (6.1 kb)- and pARR(3)-tk-luciferase reporters were measured in cells cotreated with both OCM and androgen. OCM targeted the NH(2)-terminal domain of the AR. The effect of OCM on transcriptional activity of the AR was inhibited by an antiandrogen. Neutralizing antibodies to IL-6 blocked proliferation and expression of PSA by OCM.
  
  
  CONCLUSIONS
  Osteoblasts secrete factors, such as IL-6, that cause androgen-independent induction of PSA gene expression and proliferation of prostate cancer cells by a mechanism that partially relies on the AR. Identifying such molecular mechanisms may lead to improved clinical management of metastatic prostate cancer.
authors.affiliation: Department of Cancer Endocrinology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Natalie
authors.initials: N
authors.lastname: Blaszczyk
authors.forename: Bassam A
authors.initials: BA
authors.lastname: Masri
authors.forename: Nasrin R
authors.initials: NR
authors.lastname: Mawji
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ueda
authors.forename: Gavan
authors.initials: G
authors.lastname: McAlinden
authors.forename: Clive P
authors.initials: CP
authors.lastname: Duncan
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bruchovsky
authors.forename: Hans-Udo
authors.initials: HU
authors.lastname: Schweikert
authors.forename: Doris
authors.initials: D
authors.lastname: Schnabel
authors.forename: Edward C
authors.initials: EC
authors.lastname: Jones
authors.forename: Marianne D
authors.initials: MD
authors.lastname: Sadar
mesh_terms: D000728:Androgens / Q000502:physiology*; D002455:Cell Division; D045744:Cell Line, Tumor; D017930:Genes, Reporter; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008297:Male; D010006:Osteoblasts / Q000502:physiology*; D017430:Prostate-Specific Antigen / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000473:pathology*; D011944:Receptors, Androgen / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D014162:Transfection
chemical_list: D000728:Androgens; D015850:Interleukin-6; D011944:Receptors, Androgen; D011994:Recombinant Proteins; D008156:Luciferases; D017430:Prostate-Specific Antigen