Burkitt, Michael (2011) Investigation of the importance of individual members of the Nuclear Factor-κB family during Helicobacter felis induced gastric carcinogenesis. Doctoral thesis, University of Liverpool.
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Gastric cancer is the final outcome of a well-defined process of inflammation, remodelling of the gastric mucosal architecture and finally carcinogenesis. In humans, the trigger to develop gastric epithelial inflammation is infection with Helicobacter pylori. Whilst the pathological progression following Helicobacter infection has been well described, the reasons why some individuals progress towards gastric carcinogenesis, whilst others do not, remain relatively poorly understood. Previous studies in transgenic mice have demonstrated an association between classical pathway NF-κB signalling and Helicobacter induced gastric pathology. However the roles of specific NF-κB family members and of alternative pathway NF-κB signalling have not previously been investigated. We hypothesised that individual NF-κB proteins would play specific roles in determining the onset of Helicobacter induced gastric pathology, and that these pathways may influence the eventual outcome of Helicobacter infection. To address these hypotheses we used transgenic mice with constitutive deletions of NF-κB1, NF-κB2 and c-Rel, along with the established H. felis model of murine gastric cancer. Animals were studied at 6 and 48 weeks post infection. NF-κB1 null mice developed gastric inflammation and atrophy even without infection when aged to 1 year. These animals also developed more advanced gastric atrophy and metaplasia when infected with Helicobacter felis for 1 year. c-Rel null mice demonstrated similar epithelial pathology to wild-type mice, but following long-term infections developed significant atypia in infiltrating lymphoid cells, in keeping with c-Rel playing a role in gastric lymphomagenesis. In contrast NF-κB2 null mice developed minimal pathology at both 6 and 48 weeks following infection, and hence appear to be resistant to gastric corpus atrophy in response to Helicobacter felis infection. These findings confirm the previously known role for classical pathway NF-κB signalling in epithelial cancers, and suggest that this is an NF-κB1 specific effect, rather than being mediated by c-Rel. We provide the first description of c-Rel null mice showing enhanced gastric lymphomagenesis, and also describe profound resistance to Helicobacter induced gastric pathology in mice with abrogated alternative pathway NF-κB signalling, a pathway that has not previously been investigated in studies of epithelial carcinogenesis.
|Item Type:||Thesis (Doctoral)|
|Uncontrolled Keywords:||Helicobacter, NF-kappaB, stomach, cancer, atrophy|
|Subjects:||R Medicine > R Medicine (General)|
R Medicine > RC Internal medicine
|Departments, Research Centres and Related Units:||Academic Faculties, Institutes and Research Centres > Faculty of Medicine > School of Clinical Sciences|
|Deposited On:||16 Jan 2012 16:52|
|Last Modified:||16 Jan 2012 16:52|
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