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Title: Metabolic biomarkers of colorectal cancer
Author: Alfa-Wali, Maryam
ISNI:       0000 0004 2736 8411
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2013
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Colorectal cancer (CRC) remains a major public health problem with advanced and recurrent disease being a management challenge due to the lack of efficacy of currently available monitoring tools. Carcinoembryonic antigen is used as a marker for recurrent disease but has limited sensitivity. Early sensitive markers of disease severity and recurrence are required. The aim of this thesis was to identify potential metabolic biomarkers of CRC patients using ‘Metabonomics’ based on proton nuclear magnetic resonance (1H NMR) spectroscopy. The breadth of 1H NMR metabonomics exploring different aspects of CRC pathogenesis was investigated. A global approach profiling a large number of metabolites was undertaken in cell line and chemoprevention studies with subsequent targeted profiling experiments using human polypoid tissue samples. The studies primarily exhibited changes in choline and lipids to be associated with CRC. Although these metabolites are well reported, this thesis presents contemporary metabolic profiling using systems not previously reported. Tumour extracts of CRC xenografts showed higher levels in the ratio of phosphocholine and glycerophosphocholine between poorly and well-differentiated cell lines. Human tissue and biofluids were used to define metabolic phenotypes. Normal and polypoid colorectal tissues were also metabolically characterised by changes in choline using magic angle spinning (MAS) 1 H NMR. Investigating chemoprevention strategies with bile acids in adenoma patients indicated alterations in short chain fatty acids, related to gut microflora metabolism. In clinical studies, higher levels of lactate and glycoproteins were identified in rectal cancer patients, as potential metabolic predictors of response to chemoradiotherapy. A metabolically translational feature of the thesis in a heterogeneous population confers a significant increase in the risk of CRC incidence with metabolic syndrome (MetS). Thus, inferring identification of MetS components as part of screening measures. In vivo studies provide a functional way of networking metabolic pathways to pathological states, thereby unifying perspectives post hoc.
Supervisor: Antoniou, Anthony ; Keun, Hector ; Darzi, Ara Sponsor: Bowel Disease Research Foundation ; Royal Marsden Hospital (London, England)
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral