Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569297
Title: Bladder carcinogenesis and the biological activity of sulforaphane and iberin
Author: Dunk, Melanie J.
Awarding Body: University of East Anglia
Current Institution: University of East Anglia
Date of Award: 2009
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Abstract:
In this thesis, I sought to explore the biological mechanisms that may underlie the chemoprotective effects of broccoli consumption towards bladder cancer. In particular, I was interested in the effects of diet on the transition from superficial bladder cancer to a more invasive form of this disease. Initially, I characterised global gene expression profiles of superficial and invasive bladder carcinomas through tissues obtained from the Norfolk and Norwich University Hospital Tissue Bank. Non hierarchical cluster analyses was used to identify a suite of genes that characterised these two tumour types. Of particular interest was variation in genes involved in the synthesis of the extra cellular matrix, such as COL6A1 that was upregulated in the more invasive tumour type. This was subsequently verified by RT PCR with independent tissue samples. I then explored how the broccoli isothiocyanates, sulforaphane and iberin and their N-acetylcysteine conjugates were able to perturb gene expression in two bladder cell lines that differed in their cancer phenotype. I showed that not only were these ITCs able to upregulate phase II detoxification genes, which has previously been reported in other cell lines, but they, and their conjugates, were able to down regulate the COL61A gene. Studies on the effects of ITCs on gene expression were complemented with studies on cell migration and invasiveness. I then sought to see if any of the changes in gene expression observed in the cell lines could be observed in tissues obtained as part of a human intervention study. I designed and executed a small pilot study that enabled bladder tissue biopsies to be obtained before and after a four day intervention with broccoli. Global gene expression analyses again suggested alterations in genes determining the extracellular matrix, such as Tenascin-C. This study demonstrated the proof-of-principle that these types of intervention studies are possible, but was of an insufficient size to draw definite conclusions. Finally, I investigated in more details the expression of splice variants of Tenascin-C in relationship to bladder cancer grade. In conclusion, this study has suggested that dietary ITCs may perturb genes involved in the extracellular matrix and this may be an important component of understanding their chemopreventive activities, and has demonstrated the feasibility of human intervention studies with the analyses of target tissues as opposed to peripheral biomarkers.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.569297  DOI: Not available
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