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Transforming growth factor-β induced Warburg-like metabolic reprogramming may underpin the development of peritoneal endometriosis

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    Rights statement: This article has been published under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright for this article is retained by the author(s). Author(s) grant(s) the Endocrine Society the exclusive right to publish the article and identify itself as the original publisher.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207934/
Original languageEnglish
Pages (from-to)3450-3459
Number of pages10
JournalJournal of Clinical Endocrinology & Metabolism
Volume99
Issue number9
DOIs
Publication statusPublished - Sep 2014

Abstract

Context: Transforming growth factor-β (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: To determine whether TGF-β induces a 'Warburg-like' effect in peritoneal endometriosis. Design: Human tissue, cell culture. Setting: University Research Institute. Patients or Other Participants: Women undergoing surgical investigation for endometriosis. Interventions: 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 qRT-PCR and immunohistochemistry. The effect of TGF-β1 on primary human peritoneal (PMC) (n=6) and immortalized mesothelial (MeT-5A) cells (n=3) was assessed by qRT-PCR, Western blot and commercial assays. Main Outcome Measures: 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<0.05). Endometriosis lesions expressed increased 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<0.05 to P<0.001). Exposure of mesothelial cells to TGF-β1 increased production of lactate (P<0.05), increased HIF1A mRNA (P<0.05) and protein and concentrations of mRNAs encoded by glycolysis-associated genes (LDHA, PDK1, SLC2A1; P<0.05). Conclusions: A change in the metabolic phenotype of endometriosis lesions and peritoneal mesothelium in women with endometriosis may favor development of endometriosis.

    Research areas

  • CANCER-ASSOCIATED FIBROBLASTS, EUTOPIC ENDOMETRIUM, LACTATE PRODUCTION, GENE-EXPRESSION, STROMAL CELLS, MOUSE MODEL, HYPOXIA, WOMEN, ACTIVATION, PATHOGENESIS

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