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Title: Early events in tumour development : a study based on mouse models of human colorectal cancer
Author: Kongkanuntn, Rungtiva
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2000
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I have investigated the pattern of β-catenin staining in a spectrum of apparently normal epithelium from animals bearing mutations in Apc (the Min mouse), p53 and Msh2 and compared this with patterns of Apc and E-cadherin protein immunohistochemistry staining. In general, β-catenin and E-cadherin expression was found at the lateral intercellular membrane in all types of epithelium, whereas Apc staining was found in the cytoplasm of epithelial cells in each organ but also showed strong positivity at the apical surface in intestinal epithelium. In animals bearing heterozygous mutation of Apc, enhanced β-catenin expression was identified in intestinal and pancreatic lesions in ApcMin +/- and (Apc +/-, p53 -/-) mice and in a subset of intestinal lesions in Msh2-/- mice. This thesis characterised in detail the pattern of β-catenin expression in intestinal and pancreatic lesions arising in mice singly or multiple singly or multiply mutant for Apc, p53 and Msh2. These lesions were first graded on the basis of morphology. Overexpression of β-catenin was found in the majority of early intestinal lesions arising on an ApcMin +/- background. In all categories of lesion studied mosaic patterns of β-catenin expression were observed with the proportion of cells showing a decrease in staining intensity associated with increasing lesion size. p53 status did not have any effects on these patterns. Mice mutant for the mismatch repair gene, Msh2, also showed increased expression of β-catenin in intestinal adenomas and microadenomas. However, in contrast with ApcMin +/- mice, a subset of these lesions retained apparently normal expression. β-catenin upregulation was also found in the pancreas in foci of histologically abnormal cells in ApcMin +/- and (Apc +/-, p53 -/-) mice. PCR analysis of microdissected materials confirmed that β-catenin overexpression was consistently associated with loss of the remaining wild type Apc allele. Subsequently analysis and adenocarcinomas of the pancreas arose and were characterised by an increased staining intensity of β-catenin. Taken together, these findings demonstrated that increased expression of β-catenin is an efficient marker of early neoplasic change in both murine intestine and pancreas in Apc mutant mice.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available