Dataset Information

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.

SUBMITTER: Young VJ

PROVIDER: S-EPMC4160207 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

The peritoneum is both a source and target of TGF-β in women with endometriosis.

Young Vicky J VJ Brown Jeremy K JK Saunders Philippa T K PT Duncan W Colin WC Horne Andrew W AW

PloS one 20140910 9

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 ...[more]

PMID: 25207642

Similar Datasets

Project description:The TGF-β signaling pathway governs key cellular processes under physiologic conditions and is deregulated in many pathologies, including cancer. TGF-β is a multifunctional cytokine that acts in a cell- and context-dependent manner as a tumor promoter or tumor suppressor. As a tumor promoter, the TGF-β pathway enhances cell proliferation, migratory invasion, metastatic spread within the tumor microenvironment and suppresses immunosurveillance. Collectively, the pleiotropic nature of TGF-β signaling contributes to drug resistance, tumor escape and undermines clinical response to therapy. Based upon a wealth of preclinical studies, the TGF-β pathway has been pharmacologically targeted using small molecule inhibitors, TGF-β-directed chimeric monoclonal antibodies, ligand traps, antisense oligonucleotides and vaccines that have been now evaluated in clinical trials. Here, we have assessed the safety and efficacy of TGF-β pathway antagonists from multiple drug classes that have been evaluated in completed and ongoing trials. We highlight Vactosertib, a highly potent small molecule TGF-β type 1 receptor kinase inhibitor that is well-tolerated with an acceptable safety profile that has shown efficacy against multiple types of cancer. The TGF-β ligand traps Bintrafusp alfa (a bifunctional conjugate that binds TGF-β and PD-L1), AVID200 (a computationally designed trap of TGF-β receptor ectodomains fused to an Fc domain) and Luspatercept (a recombinant fusion that links the activin receptor IIb to IgG) offer new ways to fight difficult-to-treat cancers. While TGF-β pathway antagonists are rapidly emerging as highly promising, safe and effective anticancer agents, significant challenges remain. Minimizing the unintentional inhibition of tumor-suppressing activity and inflammatory effects with the desired restraint on tumor-promoting activities has impeded the clinical development of TGF-β pathway antagonists. A better understanding of the mechanistic details of the TGF-β pathway should lead to more effective TGF-β antagonists and uncover biomarkers that better stratify patient selection, improve patient responses and further the clinical development of TGF-β antagonists.

Dataset Information

The peritoneum is both a source and target of TGF-β in women with endometriosis.

Publications

The peritoneum is both a source and target of TGF-β in women with endometriosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets