The Peritoneum Is Both a Source and Target of TGF-β in Women with Endometriosis

Abstract

Transforming growth factor-β (TGF-β) is believed to play a major role in the aetiology of peritoneal endometriosis. We aimed to determine if the peritoneum is a source of TGF-β and if peritoneal TGF-β expression, reception or target genes are altered in women with endometriosis. Peritoneal fluid, peritoneal bushings and peritoneal biopsies were collected from women with and without endometriosis. TGF-β1, 2 and 3 protein concentrations were measured in the peritoneal fluid. TGF-β1 was measured in mesothelial cell conditioned media. Control peritoneum and peritoneum prone to endometriosis (within Pouch of Douglas) from women without disease (n = 16) and peritoneum distal and adjacent to endometriosis lesions in women with endometriosis (n = 15) and were analysed for TGF-β expression, reception and signalling by immunohistochemistry, qRT-PCR and a TGF-β signalling PCR array. TGF-β1 was increased in the peritoneal fluid of women with endometriosis compared to those without disease (P<0.05) and peritoneal mesothelial cells secrete TGF-β1 in-vitro. In women with endometriosis, peritoneum from sites adjacent to endometriosis lesions expressed higher levels of TGFB1 mRNA when compared to distal sites (P<0.05). The TGF-β-stimulated Smad 2/3 signalling pathway was active in the peritoneum and there were significant increases (P<0.05) in expression of genes associated with tumorigenesis (MAPK8, CDC6), epithelial-mesenchymal transition (NOTCH1), angiogenesis (ID1, ID3) and neurogenesis (CREB1) in the peritoneum of women with endometriosis. In conclusion, the peritoneum, and in particular, the peritoneal mesothelium, is a source of TGF-β1 and this is enhanced around endometriosis lesions. The expression of TGF-β-regulated genes is altered in the peritoneum of women with endometriosis and this may promote an environment favorable to lesion formation.

Genome-Wide Microarray Analysis of Long Non-Coding RNAs in Eutopic Secretory Endometrium with Endometriosis

“…We [46]. The expression of CREB1 was increased in the peritoneum of patients with endometriosis [34]. Therefore, the CNC network results further verify the reliability of the microarray analysis.…”

“…CDC6 also serves as an important driver for epithelial-mesenchymal transition and cancer development. The expression of CDC6 was increased in the peritoneum of patients with endometriosis [34]. Therefore, CDC6 might be one of the candidate genes of endometriosis and its action might be related to the theory of epithelial-mesenchymal transition.…”

Epithelial-to-Mesenchymal Transition in the Female Reproductive Tract: From Normal Functioning to Disease Pathology

“…The role of TGF-β in the etiology of peritoneal endometriosis has also been demonstrated in women affected by endometriosis (115). TGF-β1 level is high in the peritoneal fluid of women with endometriosis and in vitro peritoneal MC also secrete TGF-β1.…”

Cancer driver mutations in endometriosis: Variations on the major theme of fibrogenesis

“…In endometriosis, Musashi‐1, a positive regulator of NOTCH1 through suppression of NOTCH1 inhibitor NUMB, has been shown to be elevated . NOTCH1 expression has been reported to be increased in peritoneum adjacent to endometriotic lesions, although it is found to be decreased in eutopic endometrium in women with endometriosis, along with Jagged2 and Dll4 . The expression of c‐Myc, one NOTCH1 downstream gene, has been well‐documented to be increased in endometriosis .…”