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Molecular and functional characterisation of the chemopreventative effects of dietary polyphenols in intestinal cancer

May, Stephanie 2017. Molecular and functional characterisation of the chemopreventative effects of dietary polyphenols in intestinal cancer. PhD Thesis, Cardiff University.
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Abstract

It is estimated that over half of colorectal cancer (CRC) cases in the UK are preventable through lifestyle changes. Perhaps unsurprisingly, bowel cancer is strongly linked to dietary choices. Diets that are high in fat and low in fibre are associated with increased risk of cancer while diets rich in fruit, vegetables and fibre have a reduced risk. Several studies have investigated the effect of certain dietary components in CRC initiation and development. Previous work, in humans and animals, has demonstrated that the polyphenols found in black raspberries (BRBs) have chemopreventative and therapeutic effects. However, the exact mechanism for these effects remain unknown. As CRC can originate from an intestinal stem cell (ISC) it is possible that the chemopreventative role is due to the impact BRBs have on the normal and/or malignant ISCs. This thesis aimed to investigate the chemopreventative effect of BRBS on normal intestinal tissue and on the initial and later stages of intestinal tumourigenesis, in the context of ISC dynamics and activated Wnt signalling. This was achieved using a Cre-loxP based approach to conditionally delete Apc (the negative regulator of the Wnt signalling pathway) within different compartments of the adult murine intestinal epithelium and also utilised the 3D intestinal organoid system. Exposure to a BRB enriched diet is reported here to be well tolerated in mice and have no major detrimental effects on normal intestinal homeostasis and health. Feeding of BRB diet 2 weeks prior to Apc gene ablation is shown to partially attenuate the ‘crypt-progenitor’ phenotype typical of acute Apc loss. In this context of activated Wnt signalling, BRBs altered ISC dynamics in vivo and reduced the self-renewal capacity of Apc deficient cells ex vivo. Additionally, long-term feeding of BRB diet was shown to significantly improve survival of mice which developed macroscopic stem-cell derived Wnt-driven adenomas. Together, these data are the first evidence that BRBs play a role in CRC chemoprevention by protectively regulating the ISC compartment. These findings further support the use of BRB intervention in cancer prevention in the context of Wnt-driven tumourigenesis.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Funders: Tenovus Cancer Care
Date of First Compliant Deposit: 24 May 2017
Last Modified: 04 Jun 2017 09:50
URI: http://orca.cf.ac.uk/id/eprint/100833

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