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Title: Tumour suppression mediated through DPC4, P53 and APC
Author: Cullingworth, J.
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 2002
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Mutations in the tumour suppressor genes SMAD4 (or DPC4, deleted in pancreatic cancer locus 4), APC (adenomatous polyposis coli) and p53 have been implicated in pancreatic cancer in humans. This thesis firstly documents the in vivo effects of mutations in these genes singly and in combination through spontaneous and carcinogen-induced murine models of pancreatic tumourigenesis. Second, it examines the in vitro effects of TGF-β signalling, of which Smad4 is the central mediator, on murine primary cultured pancreatic acinar cells. Previously p53-/- ApcMin/+ mice have been shown to develop pancreatic tumours. To examine the effect of Smad4 heterozygous mutation on the development of these tumours, Smad4+/- mutation was introduced into p53-/- and p53-/- ApcMin/+ mice. No pancreatic phenotype was found in p53-/-Smad4+/- animals. p53-/- ApcMin/+ Smad4+/- animals did not exhibit promotion of tumourigenesis in any tissue compared to the p53-/-ApcMin/+ mice. Immunohistochemical studies revealed loss of Smad4 protein within the majority of the lesions arising in p53-/-ApcMin/+Smad4+/- animals. Furthermore microdissection and mutational analysis revealed LOH for Apc and Smad4. Treatment of wild-type (WT) Smad4+/-, ApcMin/+ or ApcMin/+ Smad4+/- mice with N-Nitroso-N-Methyl Urea (NMU) resulted in abnormal foci in pancreatic acinar cells characterised by β-catenin stabilisation. Previously these foci have been shown to be the precursors of pancreatic neoplasia. Interestingly, only NMU-treated ApcMin/+Smad4+/- mice exhibit a significant increase in abnormal pancreas, which was found to be due to increased number of abnormal foci rather than increased focus size. A range of foci sizes were analysed, but only smaller abnormal foci were characterised by morphological nuclear atypia. These studies suggest functional co-operation between TGF-β and Wnt signalling pathways in the suppression of pancreatic tumourigenesis in the mouse.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available