(MRC DTP) Paracrine signalling pathways in endometriosis and related cancers

Background
Endometriosis affects 1 in 10 women of reproductive age and is the leading cause of chronic pelvic pain and infertility (1). The extent of disease is only fully characterised at laparoscopy when functional endometrial-like (endometriotic) tissue can be visualised beyond the lining of the uterus, primarily around the ovaries and on peritoneal surfaces. Adipocytes from the surrounding fat regulate energy homeostasis as well as express steroidogenic enzymes for disease pathogenesis. Paradoxically, endometriosis has been associated with low visceral fat accumulation at lesion sites and an overall decrease in pre-menopausal body mass index (2) in contrast to women with related neoplastic disease (3).

Aerobic glycolysis rather than oxidative phosphorylation is used preferentially as a main energy source by cancer cells. This promotes a malignant phenotype, increasing cell proliferation, apoptotic escape, tissue invasion and metastasis. Altered expression of glycolysis-related genes and metabolites has also been identified in endometriotic cells, which suggest mitochondrial dysfunction and glucose metabolism (4). However, the functional changes in redox homeostasis have not been investigated according to stage of menstrual cycle, severity of illness or medical treatment.

We hypothesise that omental adipose tissue provides differential endocrine support to endometriotic and cancer cells according to gynaecological disease type and severity.

Objectives
Our main aim is to investigate this paracrine relationship and exploit cell metabolism to improve therapeutic efficacy and patient outcome.

Methods
The project will involve a cell-based modelling approach using human endometrial and adipose tissues from consenting women undergoing routine laparoscopic surgery. Primary endometrial, endometriotic and cancer cells will be cultured alone and in co-culture with adipocytes from paired tissues and cross-matched individuals. The effect of novel therapeutic agents on cell metabolism, steroidogenesis and inflammation will be assessed using qRT-PCR, flow cytometry, immunoassay and a state-of-the-art redox system. Lipidomics will also be used to profile eicosanoids and other inflammatory mediators in cells, conditioned medium and biological fluids. Findings will be correlated with clinical history and patient-reported symptoms.

Potential outcomes/ impact
This preclinical approach will provide new insights into the paracrine pathways leading to disease pathogenesis, progression and the malignant transformation of cells. It will also indicate the therapeutic value of new treatment moieties for endometriosis and related gynaecological cancers.

https://www.research.manchester.ac.uk/portal/en/persons/kay-marshall(67840b9e-7d84-4f26-beb9-aa4cca141454).html
https://www.research.manchester.ac.uk/portal/Emma.Crosbie.html
https://www.research.manchester.ac.uk/portal/anna.nicolaou.html

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