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Title: Investigation into key molecular pathways in the pathogenesis of cutaneous melanoma
Author: Brown, Ewan R. S.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2009
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The melanocortin-1 receptor (MC1R) is a major determinant of skin phototype and sensitivity to UV light. The postulated role of MC1R in protecting melanocytes from apoptosis in response to UV irradiation led to our hypothesis that manipulation of the MC1R may affect growth of melanoma cell lines and sensitivity to DNA damage. Melanoma cell lines were characterised with respect to MC1R sequence, MC1R mRNA expression, presence of BRAF mutations and sensitivity of cell lines to DNA damage-induced apoptosis. Manipulation of MC1R using MC1R ligand, MC1R antibody or MC1R siRNA had no major effect on proliferation or DNA damage-induced apoptosis. In order to compare the characteristics of melanoma cells in culture with the melanoma from which they were derived, a novel melanoma cell line was established from fresh human metastatic melanoma tissue fragments removed during surgery. The cell line (Edmel 3) was found to retain the morphological characteristics of the tumour from which it was derived (i.e. mixed spindle/epithelioid cells). Compared to established cell lines response to DNA damage was delayed and growth as xenografts was considerably slower. A series of tissue microarrays which included 51 benign naevi, 27 dysplastic naevi, 54 in-situ melanoma, 312 primary melanomas and 64 metastatic melanomas were constructed in order to provide an efficient method of evaluating the expression of proteins at various stages of melanoma progression. A significant fall in B-catenin, bcl-2 and galectin-3 expression between primary and metastatic melanomas and a rise in B-catenin and gelectin-3 expression between naevi and dysplastic naevi were found. Correlation of protein expression with clinicopathologic data confirmed that low nuclear galectin-3 expression was associated with poor survival. These findings suggest that nuclear galectin-3 is a novel prognostic marker in primary melanoma.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available