title: Tumour-derived alkaline phosphatase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer.
abstract: BACKGROUND
  Recent evidence suggests that bone-related parameters are the main prognostic factors for overall survival in advanced prostate cancer (PCa), with elevated circulating levels of alkaline phosphatase (ALP) thought to reflect the dysregulated bone formation accompanying distant metastases. We have identified that PCa cells express ALPL, the gene that encodes for tissue nonspecific ALP, and hypothesised that tumour-derived ALPL may contribute to disease progression.
  
  
  METHODS
  Functional effects of ALPL inhibition were investigated in metastatic PCa cell lines. ALPL gene expression was analysed from published PCa data sets, and correlated with disease-free survival and metastasis.
  
  
  RESULTS
  ALPL expression was increased in PCa cells from metastatic sites. A reduction in tumour-derived ALPL expression or ALP activity increased cell death, mesenchymal-to-epithelial transition and reduced migration. Alkaline phosphatase activity was decreased by the EMT repressor Snail. In men with PCa, tumour-derived ALPL correlated with EMT markers, and high ALPL expression was associated with a significant reduction in disease-free survival.
  
  
  CONCLUSIONS
  Our studies reveal the function of tumour-derived ALPL in regulating cell death and epithelial plasticity, and demonstrate a strong association between ALPL expression in PCa cells and metastasis or disease-free survival, thus identifying tumour-derived ALPL as a major contributor to the pathogenesis of PCa progression.
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: S R
authors.initials: SR
authors.lastname: Rao
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Snaith
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: D
authors.initials: D
authors.lastname: Marino
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: X
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK.|Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: S T
authors.initials: ST
authors.lastname: Lwin
authors.affiliation: Royal Veterinary College, University of London, London NW1 0TU, UK.
authors.forename: I R
authors.initials: IR
authors.lastname: Orriss
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: F C
authors.initials: FC
authors.lastname: Hamdy
authors.affiliation: Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 7LD, UK.|Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford OX3 7LD, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Edwards
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000502:physiology*; D000818:Animals; D016923:Cell Death / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics*; D002478:Cells, Cultured; D018450:Disease Progression; D018572:Disease-Free Survival; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology* / Q000628:therapy*
chemical_list: D000469:Alkaline Phosphatase