Le Belle, Janel Ethel; (2000) Studies of metabolism in human astrocytes and astrocytomas using NMR spectroscopy and other analytical techniques. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The object of this research was to investigate profiles of human astrocyte and astrocytoma metabolism using NMR spectroscopy and other analytical techniques such as high performance liquid chromatography (HPLC), mass spectrometry and radiation scintillation counting. Using these techniques species differences and transformation-related differences in metabolism were assessed in the human and rodent astrocytic lineage. In vitro and in vivo comparisons of astrocytomas with normal human astrocytes and normal brain revealed that certain characteristic aspects of the transformed cells' metabolism may be related to the normal metabolic features of their lineage. However, several transformation-specific changes were also observed in the astrocytomas both in culture and in vivo which implicate the metabolic pathways involved in glutaminolysis and the hydrolysis of the membrane phospholipid, phosphatidylcholine, for generating the unique 1H-NMR profile for astrocytomas which may distinguish them from other CNS tumours. Furthermore, the conservation in vivo of the 1H-NMR astrocytoma profile seen in cell culture serves as a strong validation for the development of tumour-specific profiles based on cell culture extracts, where conditions can be carefully controlled and a large number of metabolites simultaneously investigated. Based on the similarities between the astrocytomas and their normal cell lineage, and the theory that the progression of transformation in malignant cells involves a de-differentiation to an earlier developmental state, the ability of astrocytomas to metabolise fatty acid in a similar manner known to occur in normal astrocytes from the developing brain was investigated. The astrocytomas were found to β-oxidise fatty acids at rates comparable to those reported in the literature for normal astrocytes. This metabolic pathway was capable of producing 37-50% of cellular ATP under different conditions. Exogenously supplied oleic acid was also shown to be readily incorporated into cell membrane phospholipids and possibly into intracellular lipid droplets where they may serve as an energy-reserve. This has led to the proposal that astrocytomas only partially utilise several metabolic pathways (glycolysis, glutaminolysis, and partial fatty acid β-oxidation) which may be advantageous to adapt to variable energy substrate supplies and energy demands.

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