title: Transforming growth factor-β induced Warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis.
abstract: BACKGROUND
  TGF-β is believed to play a major role in the etiology of peritoneal endometriosis. In tumors, TGF-β induces the metabolic conversion of glucose to lactate via glycolysis, a process referred to as the "Warburg effect." Lactate increases cell invasion, angiogenesis, and immune suppression, all crucial steps in the development of endometriosis.
  
  
  OBJECTIVE
  The aim of this study was to determine whether TGF-β induces a "Warburg-like" effect in peritoneal endometriosis.
  
  
  METHODS
  The study was informed by human tissue analysis and cel culture.
  
  
  METHODS
  The study was conducted at the university research institute.
  
  
  METHODS
  We studied women undergoing surgical investigation for endometriosis.
  
  
  METHODS
  Concentrations of lactate and TGF-β1 in peritoneal fluid (n = 16) were measured by commercial assay. Expression of genes implicated in glycolysis was measured in endometrial and peritoneal biopsies (n = 31) by quantitative RT-PCR and immunohistochemistry. The effect of TGF-β1 on primary human peritoneal mesothelial cells (n = 6) and immortalized mesothelial (MeT-5A) cells (n = 3) was assessed by quantitative RT-PCR, Western blot, and commercial assays.
  
  
  METHODS
  Lactate, TGF-β1, and markers of glycolysis were measured.
  
  
  RESULTS
  Concentrations of lactate in peritoneal fluid paralleled those of TGF-β1, being significantly higher in women with endometriosis compared to women without (P < .05). Endometriosis lesions expressed higher levels of glycolysis-associated genes HIF1A, PDK1, and LDHA than eutopic endometrium, and adjacent peritoneum had higher levels of HIF1A and SLC2A1 than peritoneum from women without disease (P < .05 to P < .001). Exposure of mesothelial cells to TGF-β1 increased production of lactate (P < .05), increased HIF1A mRNA (P < .05), and protein, and increased concentrations of mRNAs encoded by glycolysis-associated genes (LDHA, PDK1, SLC2A1; P < .05).
  
  
  CONCLUSIONS
  A change in the metabolic phenotype of endometriosis lesions and peritoneal mesothelium in women with endometriosis may favor development of endometriosis.
authors.affiliation: Medical Research Council Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh EH16 4TJ, United Kingdom.
authors.forename: Vicky J
authors.initials: VJ
authors.lastname: Young
authors.forename: Jeremy K
authors.initials: JK
authors.lastname: Brown
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Maybin
authors.forename: Philippa T K
authors.initials: PT
authors.lastname: Saunders
authors.forename: W Colin
authors.initials: WC
authors.lastname: Duncan
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Horne
mesh_terms: D001202:Ascitic Fluid / Q000378:metabolism; D002461:Cell Line, Transformed; D004715:Endometriosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004717:Endometrium / Q000378:metabolism / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006019:Glycolysis / Q000235:genetics / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000080864:Lactate Dehydrogenase 5; D019344:Lactic Acid / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010537:Peritoneum / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
chemical_list: D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007527:Isoenzymes; C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D012333:RNA, Messenger; C495677:SLC2A1 protein, human; D053773:Transforming Growth Factor beta1; D019344:Lactic Acid; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D017346:Protein Serine-Threonine Kinases