title: Regional differences in prostaglandin E₂ metabolism in human colorectal cancer liver metastases.
abstract: BACKGROUND
  Prostaglandin (PG) E2 plays a critical role in colorectal cancer (CRC) progression, including epithelial-mesenchymal transition (EMT). Activity of the rate-limiting enzyme for PGE2 catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) is dependent on availability of NAD+. We tested the hypothesis that there is intra-tumoral variability in PGE2 content, as well as in levels and activity of 15-PGDH, in human CRC liver metastases (CRCLM). To understand possible underlying mechanisms, we investigated the relationship between hypoxia, 15-PGDH and PGE2 in human CRC cells in vitro.
  
  
  METHODS
  Tissue from the periphery and centre of 20 human CRCLM was analysed for PGE2 levels, 15-PGDH and cyclooxygenase (COX)-2 expression, 15-PGDH activity, and NAD+/NADH levels. EMT of LIM1863 human CRC cells was induced by transforming growth factor (TGF) β.
  
  
  RESULTS
  PGE2 levels were significantly higher in the centre of CRCLM compared with peripheral tissue (P = 0.04). There were increased levels of 15-PGDH protein in the centre of CRCLM associated with reduced 15-PGDH activity and low NAD+/NADH levels. There was no significant heterogeneity in COX-2 protein expression. NAD+ availability controlled 15-PGDH activity in human CRC cells in vitro. Hypoxia induced 15-PGDH expression in human CRC cells and promoted EMT, in a similar manner to PGE2. Combined 15-PGDH expression and loss of membranous E-cadherin (EMT biomarker) were present in the centre of human CRCLM in vivo.
  
  
  CONCLUSIONS
  There is significant intra-tumoral heterogeneity in PGE2 content, 15-PGDH activity and NAD+ availability in human CRCLM. Tumour micro-environment (including hypoxia)-driven differences in PGE2 metabolism should be targeted for novel treatment of advanced CRC.
authors: Section of Molecular Gastroenterology, Leeds Institute of Molecular Medicine, University of Leeds, St James's University Hospital, Leeds LS9 7TF, UK.
authors: Alastair L
authors: AL
authors: Young
authors: Claire R
authors: CR
authors: Chalmers
authors: Gillian
authors: G
authors: Hawcroft
authors: Sarah L
authors: SL
authors: Perry
authors: Darren
authors: D
authors: Treanor
authors: Giles J
authors: GJ
authors: Toogood
authors: Pamela F
authors: PF
authors: Jones
authors: Mark A
authors: MA
authors: Hull
mesh_terms: D015687:Cell Hypoxia; D015179:Colorectal Neoplasms / Q000473:pathology*; D015232:Dinoprostone / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D006801:Humans; D006911:Hydroxyprostaglandin Dehydrogenases / Q000378:metabolism; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism* / Q000556:secondary*; D046228:Microarray Analysis; D009363:Neoplasm Proteins / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment
chemical_list: D009363:Neoplasm Proteins; D016212:Transforming Growth Factor beta; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase; D015232:Dinoprostone