Genetic and Biochemical Factors Involved in the Progression of Mouse Skin Tumours

Liddell, Jennifer (1995) Genetic and Biochemical Factors Involved in the Progression of Mouse Skin Tumours. PhD thesis, University of Glasgow.

Abstract

A dramatic change in cell phenotype is sometimes seen in an advanced stage of mouse skin carcinogenesis when a relatively well-differentiated squamous cell carcinoma progresses to a less differentiated spindle cell carcinoma. This thesis describes a study of some genetic and epigenetic events that may be responsible for the squamous to spindle cell transition using a panel of fixed morphology and plastic morphology cell lines. The experimental approaches used include genetic and cell biology-based studies. An allelotype of clonally related but morphologically distinct cell lines, A5, B9 and D3 was compiled using 118 informative markers and genetic alterations distinguishing the differing cell types have been described. Alterations distinguishing the squamous and spindle cells were found on chromosomes 1, 4, 5, 6, 8, 12, 13, 16, 18 and 19. The most interesting of these with respect to tumorigenesis are on chromosomes 4 and 6; these have been shown to be involved in carcinogenesis in other studies. Although no specific allelic losses were shown to correlate with the squamous/spindle transition, this study has provided information on the lineage of clonally related cell lines from the same tumour and has provided some clues to the gross alterations that may be central to this process. A wide range of biochemical studies have also been used to characterise the fixed morphology cell lines plus additional cell lines which have more plastic morphologies i.e. the SN161 single cell clones. It has been possible to induce the transition from a squamous morphology to a more fibroblast-like phenotype in vitro and in vivo and some of the candidate effectors of this change have been analysed. When the SN161 cell lines are injected into nude mice, they all produce spindle tumours regardless of their morphology in vitro. Explants from tumours induced by squamous cell lines can regain their squamous morphology when grown in normal culture conditions. It seems that some factor present in vivo is encouraging the spindle phenotype; alternatively some factor present in vitro could be encouraging the squamous phenotype. Specific extracellular factors were shown to influence the morphology of SN161 derived cell lines. Growth on fibronectin coated plates made the spindle cells more fibroblast-like but had no effect on the squamous cells. The same was true for Matrigel coated plates. The most interesting result was found with TGF? treatment of the cells. This induced the squamous cell lines, EIN and E4, to become fibroblast-like and caused their E-cadherin to become delocalised and its expression reduced. This observation was consistent with the appearance of the spindle morphology. This system can now be used to study the immediate consequences of changes of morphology rather than secondary changes which can complicate results based on the study of spindle tumours.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Additional Information: Adviser: Allan Balmain
• Keywords: Biochemistry, Genetics, Oncology
• Date of Award: 1995
• Depositing User: Enlighten Team
• Unique ID: glathesis:1995-76317
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 19 Nov 2019 15:46
• Last Modified: 19 Nov 2019 15:46
• URI: https://theses.gla.ac.uk/id/eprint/76317