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Analysing the role of Pten in the murine small intestine

Marsh, Victoria 2008. Analysing the role of Pten in the murine small intestine. PhD Thesis, Cardiff University.

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Colorectal cancer is a significant cause of mortality in the UK, being the third most common cancer type. Activating mutations within the Phosphoinositide 3-Kinase/Akt pathway have previously been reported in a significant proportion of sporadic colorectal cancers. Phosphatase and tensin homolog mutated on chromosome 10 (PTEN) is an antagonist of the PI3K/Akt pathway, and as such is a well characterised tumour suppressor. In this thesis I aimed to characterise the role of Pten within the murine intestine, with respect to homeostasis of otherwise normal epithelium, and also in the context of activated Wnt signalling and activation of the oncogene k-Ras. This has been achieved using a Cre-LoxP-based approach to conditionally delete Pten specifically from the adult murine intestinal epithelium. Deletion of Pten alone is reported here to have little immediate effect on normal homeostasis of the intestinal epithelium or the intestinal stem cell. At extended timepoints after Pten loss, delayed formation of hamartomas and adenomas within the intestine is reported. In the context of activated Wnt signalling, additional loss of Pten is found to accelerate tumourigenesis, resulting in adenocarcinoma formation. These lesions are characterised by strong activation and membrane localisation of Akt. Co-ordinate deletion of Pten and activation of k-Ras is reported here to show strong synergy in promoting the formation of both papillomatous lesions of biliary epithelia and widespread hyperplasia of the forestomach squamous epithelium. Lesions within the biliary epithelium are characterised by strong activation of Akt, with gall bladder lesions again showing membrane localisation of Akt. In the intestine, preliminary data reported here also indicates synergy between Pten loss and k-Ras activation in promoting hyperproliferation of the epithelium. Together, these data therefore indicate that, in normal intestinal epithelium, PTEN is a weak tumour suppressor, but is critical for suppressing neoplasia in the context of other mutations.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH301 Biology
ISBN: 9781303213830
Date of First Compliant Deposit: 30 March 2016
Last Modified: 01 Feb 2017 04:29

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