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Title: The proteoglycans of metastatic and non-metastatic B16 murine melanomas
Author: Hamilton, Mark
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1991
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Proteoglycans and glycosaminoglycans are implicated in a wide range of biological processes and phenomenom. Perhaps most importantly, the are attributed with a role in the modulation and maintenance of the physiochemical properties and integrity of the extracellular matrix, and in mediating cell adhesion and growth. Our understanding of the role of proteoglycans and glycosaminoglycans in tumorigenesis and metastatic spread is limited. Few proteoglycans have been determined to possess specific biological functions. Other studies have tried to correlate changes in the synthesis and properties of proteoglycans and glycosaminoglycans with metastatic potential and progression, but many of the observations have proved to be somewhat conflicting. Therefore the effects and relevance of changes in the properties of and alterations in the biosynthesis of these molecules have not been fully elucidated. In this study, the proteoglycans and glycosaminoglycans isolated from a series of B16 melanoma cell lines that differed in metastatic potential (as measured by lung colonization) were analyzed, and their chemical properties determined using ion exchange and size exclusion chromatography. In addition, the cell phenotypes of the cell lines were partially characterized, with cell adhesive and proteolytic responses being measured. Chemical agents, acknowledged as being capable of modifying glycosaminoglycan biosynthesis, were employed to modify the chemical properties of these molecules. The aim was to determine whether changes in the charge properties and the size of the GAG chains influence the ability of these cells to form lung metastases after intravenous inoculation, and whether a change or consistant alteration in the properties of the proteoglycans and glycosaminoglycans could be identified as being related with metastatic potential. Cell adhesion is a central process in many phases of the metastatic cascade. Many tumour cell types can be demonstrated as possessing adhesive preferences for extracellular matrices or isolated matrix proteins in vitro. The B16 cell lines were therefore assayed for such preferences and whether or not chemical modulation of the biochemical properties of the proteoglycans and glycosaminoglycans synthesized influenced their adhesive responses. No consistent adhesive preference could be identified that appeared to be related to metastatic potential for all of the cell lines tested. Modulation of the chemical properties of the glycosaminoglycans synthesized by the cell lines also appeared not to correlate with changes in metastatic potential. Differences in the composition and properties of the glycosaminoglycans synthesized did not appear to influence the level of cell adhesion either. In conclusion, preferential adhesion to complex matrices and individual matrix proteins did not appear to be related to the metastatic potentials of the B16 melanoma cell lines used in this study, and alterations in the chemical properties of the glycosaminoglycans synthesized also did not appear to influence lung colonization. Two consistant relationships were however identified. The ability to release 35S-isotope from metabolically labelled subendothelial matrix and an increased expression of cell surface glycosaminoglycans correlated with high levels of lung colonization. Increased cell surface glycosaminoglycans may be related to an increase in the number or size of the of the glycosaminoglycan chains polymerized onto proteoglycan core protein, whereas increased 35S-releasing activity may represent an increase in the ability of more metastatic cell lines to penetrate basement membrane-like structures, a rate regulating step in the process of metastasis. The relevence of these two parameters is discussed in more detail within the text.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available