Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.755033
Title: The relationship between docohexanoic acid (DHA) and L-serine, providing an insight into the biochemistry of meningioma
Author: Hatchell, Hayley
ISNI:       0000 0004 7428 0463
Awarding Body: University of Central Lancashire
Current Institution: University of Central Lancashire
Date of Award: 2017
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Abstract:
As far back as the 1920s, Otto Warburg observed that cancerous cells display an altered state of metabolism surrounding lipid biosynthesis. However, only until recently has metabolic reprogramming been a recognised hallmark of the disease. The number of cancer cases diagnosed is set to triple by 2030, demonstrating the need for disease prevention, improved diagnostic testing and personalised treatment therapies. However, with some cancers occurring in the brain and spinal cord, the type of treatment available can become challenging due to their locality. Such cancer types include meningioma and glioma which are the most common brain tumours diagnosed. An initial study involving human meningioma tissue revealed unusually high levels of the phosphatidylserine enriched with docosahexaenoic acid (DHA). In this study, the metabolism surrounding lipid biosynthesis was examined to establish if such alterations in lipid profiles were related to an altered state of metabolism. From the results gained, it can be suggested that meningioma does have an altered state of metabolism, evolving around serine as opposed to DHA. From the grade I and grade II meningioma tissues immunochemically examined, positive expressions of pyruvate kinase isoform 2 (PKM2) and phosphoglycerate dehydrogenase (PHGDH) were shown. Therefore, the results demonstrated that within meningioma tissues, serine can allosterically regulate the flux through glycolysis. The association that serine presence alone can alter the metabolic flux was demonstrated in the model organism, Lipomyces starkeyi. Those L. starkeyi cells supplemented with serine, displayed a 50% reduction in the amount of radiolabelled acetate taken up during exponential and stationary growth phases. The radiolabelled study also highlighted that with serine presence, de novo lipid biosynthesis was altered. Once synthesised, these neutral lipids go on to be 4 stored in membrane bound organelles. Within the phenotype of cancerous cells, such storage of neutral lipids into lipid droplets prevent lipotoxicity. The light microscopy study of L. starkeyi cells supplemented with serine demonstrated that the formation of such lipid droplets was enhanced during lipid accumulation. These findings suggest that the production, storage and mobilisation of lipids within serine supplemented cells are adapted to cellular requirements, promoting a cancerous phenotype. In order to gain an insight into the potential impact that an altered metabolic state may give to meningioma, a liposomal study was developed. Supplementation of both phosphatidylserine-consisting liposomes, as well as tumour-derived liposomes, enhanced the cellular viability of the non-cancerous cell line, SVG, during exponential phase. The supplementation of meningioma-derived liposomes also increased the viability of the non-cancerous human fetal glial SVG cell line, similar to that observed with phosphatidylserine containing liposomal preparations. Therefore, the data suggest that in fact, the phospholipid (phosphatidylserine), rather than the fatty acid (DHA) plays a role in cellular viability. It is concluded that the results gained from this study can be used clinically in the diagnosis and management of meningioma as well as other diseased cells displaying ectopic lipid accumulation. The observation that meningioma has an altered biochemistry may provide guidance when histologically grading meningioma tumours. For those tumours expressing the enzymes involved in serine biosynthesis, such as PKM2 and PHGDH, a targeted treatment therapy surrounding enzyme inhibitors can be examined. By targeting serine biosynthesis, the resources needed to enable a cancerous phenotype are depleted. Future research can examine such targeted therapies utilizing either the developed model organism, L. starkeyi or the conventional SVG and U87 cell lines.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.755033  DOI: Not available
Keywords: C790 - Molecular biology, biophysics & biochemistry not elsewhere classified
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