Transforming Growth Factor-β Induced Warburg-Like Metabolic Reprogramming May Underpin the Development of Peritoneal Endometriosis

Context: TGF-beta is believed to play a major role in the etiology of peritoneal endometriosis. In tumors, TGF-beta 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-beta induces a Warburg-like effect in peritoneal endometriosis. Design: The study was informed by human tissue analysis and cel culture. Setting: The study was conducted at the university research institute. Patients or Other Participants: We studied women undergoing surgical investigation for endometriosis. Interventions: Concentrations of lactate and TGF-beta 1 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-beta 1 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. Main Outcome Measures: Lactate, TGF-beta 1, and markers of glycolysis were measured. Results: Concentrations of lactate in peritoneal fluid paralleled those of TGF-beta 1, 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-beta 1 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.