Investigating the impact of intestinal stem cell dynamics on tumour initiation

Hodder, Michael C. (2019) Investigating the impact of intestinal stem cell dynamics on tumour initiation. PhD thesis, University of Glasgow.

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In the intestines of mammals, crypt structures are known to house the intestinal Stem Cells (SCs). These intestinal SCs compete with each other at the base of each crypt, and consequently the parameters of SC competition determine the accumulation of mutations within the intestinal tract. I used genetically engineered mouse models to investigate the functional impact of SC competition on tumour formation and propose that SC competition can be targeted as a tumour preventative strategy.
Hyper-activated Wnt signalling is a common occurrence in Colorectal Cancer (CRC) with mutations in Adenomatous Polyposis Coli (APC), a negative regulator of the Wnt signalling pathway, occurring in 60-70% of CRC patients. In chapter III of this thesis I discuss the robustness of current methods to quantify intestinal SC dynamics, and propose a new method to trace Apc mutant SCs. Additionally, I functionally demonstrate that intestinal SC dynamics influences the efficiency of tumour formation in the Intestinal Epithelium (IE).
In chapter IV I propose that SC competition represents a bottleneck in the tumourigenesis process, and that this initial stage of tumourigenesis could be targeted therapeutically. I describe the effect of multiple drug treatments upon Apc mutant SC competition and the ability of these cells to form tumours in the IE. Furthermore, I define the window of opportunity for targeting of Apc mutant intestinal SCs.
Chapter V discusses the role of the anti-apoptotic protein MCL1 in intestinal SC survival and tumour formation. I discuss how MCL1 is vital for a number of intestinal cell lineages and demonstrate a lineage specific dependency upon MCL1.
Overall, I demonstrate that the parameters of intestinal SC dynamics are essential for dictating the efficacy of tumour formation from intestinal SCs. I provide proof of concept data that demonstrate mutant intestinal SCs can be targeted by xenobiotics. Finally I demonstrate that different intestinal cell lineages are differentially dependent upon MCL1.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Colorectal cancer, Wnt, intestine, stem cells, tumourigenesis, APC, MCL1, apoptosis, tumour prevention.
Subjects: Q Science > Q Science (General)
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences > Beatson Institute of Cancer Research
Supervisor's Name: Sansom, Prof. Owen J.
Date of Award: 2019
Embargo Date: 21 January 2022
Depositing User: Mr Michael C. Hodder
Unique ID: glathesis:2019-40952
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 29 Jan 2019 11:52
Last Modified: 05 Mar 2020 22:09
Thesis DOI: 10.5525/gla.thesis.40952

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