Use this URL to cite or link to this record in EThOS: https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.724419
Title: Chemopreventive effect of resveratrol in preclinical colorectal cancer models with different genetic drivers
Author: Jawad, Dhafer Sahib
ISNI:       0000 0004 6424 8232
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2017
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Abstract:
Previous reports indicate resveratrol can modulate many processes and targets in colorectal cancer (CRC) cells and rodent models but it is uncertain whether these effects translate to humans in vivo. The lack of relevant experimental models, particularly premalignant colorectal cells, the major targets for prevention, is a significant obstacle to translation of effective preventive agents to the clinic. Development of improved 3-dimensional organoid models with discrete mutational drivers (Apc, Apc+Kras and Braf) representing different subtypes of early CRC is an aim of this thesis. A further aim is to evaluate resveratrol across these models and examine in greater detail the ability of resveratrol to interfere with the development of cancers driven by mutant BrafV600E. Organoid cultures using intestinal cells isolated from genetically engineered mice and human cancer/adenoma tissue were successfully established and conditions optimised to allow long-term maintenance. Notably, the organoids derived from adenomas arising in Villin-Cre/BrafV600E mice constitute a novel preclinical model of CRC. After first demonstrating that resveratrol had anti-proliferative activity across a panel of human CRC cell lines with different mutation profiles it was tested in the organoids at clinically-achievable concentrations for effects on autophagy, senescence, apoptosis and stem cells. Administration of a high-fat diet to Villin-Cre/BrafV600E mice enhanced Braf-induced cryptal hyperplasia in a short-term study and this was significantly reduced by resveratrol. In a follow-up survival study, high dose resveratrol greatly prolonged the lifespan of Villin-Cre/BrafV600E mice on high-fat diet. However, resveratrol had no effect on the survival of mice given standard diet. Overall, these findings suggest a specific interaction between mutant Braf expressed in mouse intestine and high-fat, and that the effects are blocked by high dose resveratrol. Future studies are needed to investigate underlying mechanisms. Results suggest resveratrol may have value in the prevention of colorectal adenomas/cancers with different genetic alterations, including mutant BrafV600E.
Supervisor: Brown, Karen ; Rufini, Alessandro Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.724419  DOI: Not available
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