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

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.