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Title: Understanding the role of obesity and complex metabolic dysregulation in the development of endometrial cancer
Author: Raglan, Olivia Eva
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2019
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A rapidly increasing major public health problem is the continuum of obesity, metabolic disorders and development of cancer. Obesity is associated with an up to 5-fold increase in endometrial cancer. I hypothesised that complex metabolic dysregulation, including insulin resistance and increased local inflammation may contribute to the multi-factorial aetiology of endometrial cancer. This thesis examined the strength and validity of evidence for associations between risk factors and endometrial cancer with an umbrella review of the literature. Key components of the insulin signalling (IGF-R/mTOR/Akt) pathway in benign and endometrial cancer tissues were investigated, assessing whether protein expression correlated with obesity and insulin resistance status. Phospholipid expression according to metabolic status was investigated using mass spectrometry imaging, and vaginal microbiota composition and local cytokine expression is described in obese women, with assessment of temporal changes after partial correction of metabolic dysregulation by bariatric surgery. Body mass index and waist-to-hip ratio were risk factors strongly associated with increased endometrial cancer risk. Proteomic analysis found upregulation of proteins involved in insulin and oncogenic signalling pathways in obese and insulin resistant women with normal endometrial tissue, suggesting an ‘at-risk’ metabolic profile for endometrial carcinogenesis. Lipidomic analysis of endometrial tissue found increased expression of distinct phosphatidylinositol and phosphatidylethanolamine lipid species among cancer tissues, and benign endometrium had higher relative abundance of phosphatidylglycerol species. These findings have added to our understanding of upregulated lipid-associated metabolic pathways in endometrial cancer. Characterisation of the vaginal microbiota in obesity found increased bacterial species diversity, which transitioned towards dominance of reproductive health-promoting low-diversity bacteria after surgically-induced weight loss. The multi-factorial aetiology of endometrial cancer is complex and the signalling pathways that are activated leading to endometrial cancer development need further investigation. Understanding the impact on these pathways by metabolic changes brought about by obesity and insulin resistance may lead to identifying biomarkers with preventative and treatment potential.
Supervisor: Kyrgiou, Maria ; Nautiyal, Jaya ; Gunter, Marc ; Gabra, Hani Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral