Tumour derived metabolic modulators : With particular reference to mouse hepatic citrate content

McNair, Anne W (1980) Tumour derived metabolic modulators : With particular reference to mouse hepatic citrate content. PhD thesis, University of Glasgow.

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Abstract

In recent years much interest has "been generated in the concept of tumour agents or "signal factors" (Toporek, 1973) affecting host metabolic processes. It has been shown that tumour growth markedly alters the metabolism, of and induces biochemical changes in various tissues and organs of the host (Theologides, 1972). These effects occur at sites remote from the site of tumour growth, therefore the possibility of the secretion of chemical modulators by the tumour cells must be considered. Previous work (Caiman and McAllister, 1975(a), 1975(b)) using a variety of experimental tumours has demonstrated metabolic abnormalities in the livers of tumour-bearing mice. Of the tumour systems studied the TLX-5 lymphoma is of particular interest, since a cell-free ascitic fluid preparation of this tumour, when injected into normal mice, will produce these same liver metabolic changes without subsequent tumour growth occurring (McAllister, Soukop and Caiman, 1976). The most significant of these liver metabolite changes produced were an increase in citrate content and a decrease in coenzyme-A levels. It was postulated, therefore, that a factor or factors present in this tumour cell-free preparation was responsible for producing these metabolic abnormalities, and the work described in this thesis demonstrates the presence of a factor in the ascitic fluid and serum of tumour-bearing mice responsible for increasing hepatic citrate levels. This work also demonstrates the presence of other factors in ascitic fluid responsible for spleen hypertrophy, thymic atrophy and increases in epididymal fat pad weight. Since ascitic fluid from mice bearing TLX-5 lymphoma contains a multiplicity of host and tumour derived factors which may be involved in producing the observed metabolic changes, it was necessary to determine whether the factor or factors involved in increasing hepatic citrate levels was of host or tumour origin. It was shown likely to be of tumour origin, since it was present in the cell-free growth medium of TLX-5 cells grown in vitro. This biologically active factor was also shown to be non-dialysable, heat labile and protein in nature, since treatment of cell-free ascitic fluid with trypsin destroyed its biological activity. High speed centrifugation of the cell-free ascitic fluid preparation did not affect its biological activity, and resulted in considerable purification of the preparation in terms of protein content, as well as removing any virus particles present. The problem of viral contamination of TLX-5 lymphoma was investigated, and in vivo grown tumour cells were shown to be contaminated with a virus. The factor involved in increasing hepatic citrate levels is, however, unlikely to be viral in nature since it' is present in virus free ascitic fluid preparations, and in a preparation of in vitro grown tumour cells which have been shown to be free of virus. The viral contaminant of the in vivo grown tumour cells may be the Riley virus or lactate dehydrogenase virus (LDV) since it has been shown to be a widespread contaminant of murine tumours. Electron microscope examination of the in vivo grown cells revealed a virus particle with a similar size and shape to LDV, but this particle could not be detected in the in vitro grown cells. Injection of the in vivo grown cells into normal mice did produce an elevation of serum lactate dehydrogenase activity in these animals, which is a characteristic effect of LDV. Injection of virus-free ascitic fluid (SN2) into normal animals also produced this effect, therefore it would appear that a factor or factors present in the tumour cell preparation and in the virus-free preparation are responsible for producing this effect. Gel filtration and gel. electrophoresis experiments using, SN2 indicate that the factor present in SN2 responsible for increasing hepatic citrate levels has a molecular weight between 6,800-7,600 daltons. Finally, this factor was shown not to be insulin, since injection of normal mice with insulin does not result in an elevation of hepatic citrate levels.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: K C Calman
Keywords: Physiology
Date of Award: 1980
Depositing User: Enlighten Team
Unique ID: glathesis:1980-72112
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 17 May 2019 12:57
Last Modified: 17 May 2019 12:57
URI: http://theses.gla.ac.uk/id/eprint/72112

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