title: The differential effects of statins on the metastatic behaviour of prostate cancer.
abstract: BACKGROUND
  Although statins do not affect the incidence of prostate cancer (CaP), usage reduces the risk of clinical progression and mortality. Although statins are known to downregulate the mevalonate pathway, the mechanism by which statins reduce CaP progression is unknown.
  
  
  METHODS
  Bone marrow stroma (BMS) was isolated with ethical approval from consenting patients undergoing surgery for non-malignant disease. PC-3 binding, invasion and colony formation within BMS was assessed by standardised in vitro co-culture assays in the presence of different statins.
  
  
  RESULTS
  Statins act directly on PC-3 cells with atorvastatin, mevastatin, simvastatin (1 μM) and rosuvastatin (5 μM), but not pravastatin, significantly reducing invasion towards BMS by an average of 66.68% (range 53.93-77.04%; P<0.05) and significantly reducing both number (76.2±8.29 vs 122.9±2.48; P=0.0055) and size (0.2±0.0058 mm(2) vs 0.27±0.012 mm(2); P=0.0019) of colonies formed within BMS. Statin-treated colonies displayed a more compact morphology containing cells of a more epithelial phenotype, indicative of a reduction in the migrational ability of PC-3 cells. Normal PC-3 phenotype and invasive ability was recovered by the addition of geranylgeranyl pyrophosphate (GGPP).
  
  
  CONCLUSIONS
  Lipophilic statins reduce the migration and colony formation of PC-3 cells in human BMS by inhibiting GGPP production, reducing the formation and the spread of metastatic prostate colonies.
authors.affiliation: Genito Urinary Cancer Research Group, University of Manchester, Paterson Institute for Cancer Research, Manchester Academic Health Science Centre, The Christie NHS Foundation Trust, Wilmslow Road, Withington, Manchester M20 4BX, UK. mbrown@picr.man.ac.uk
authors.forename: M
authors.initials: M
authors.lastname: Brown
authors.forename: C
authors.initials: C
authors.lastname: Hart
authors.forename: T
authors.initials: T
authors.lastname: Tawadros
authors.forename: V
authors.initials: V
authors.lastname: Ramani
authors.forename: V
authors.initials: V
authors.lastname: Sangar
authors.forename: M
authors.initials: M
authors.lastname: Lau
authors.forename: N
authors.initials: N
authors.lastname: Clarke
mesh_terms: D001853:Bone Marrow / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008297:Male; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D011106:Polyisoprenyl Phosphates / Q000037:antagonists & inhibitors; D011471:Prostatic Neoplasms / Q000473:pathology*
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; C002963:geranylgeranyl pyrophosphate