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Title: Modelling intestinal cancer development and progression in the mouse
Author: Davies, Emma Jane
ISNI:       0000 0004 2752 0700
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2011
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Colorectal cancer is the second most common cause of death from cancer in the UK. One of the reasons for this high mortality rate is the late presentation of patients to the clinic, i.e. when they have late stage invasive or metastatic tumours. The development of new therapeutic compounds for late stage disease is therefore paramount to tackling the disease. Better models of colorectal cancer are also needed to test new therapeutic compounds, and to try to improve understanding of the processes underlying tumour progression and metastasis. Currently, most mouse models of colorectal cancer only recapitulate the early stages of the disease and rarely progress to an invasive late-stage tumour. The tumour suppressor PTEN, the oncogene KRAS and the cell adhesion component E-cadherin have all been implicated in the progression, or poor prognosis of colorectal cancer. I have used the cre-loxP recombination system to alter the expression of these genes in the mouse intestine, and to further define their role in tumourigenesis. I have shown that mutations in Pten and Kras synergise in the context of Wnt initiated intestinal tumours to promote progression from adenoma to invasive adenocarcinoma. It is also reported here that mutations in Pten and Kras alone, predispose to non-Wnt initiated tumours that progress to metastatic carcinoma in the intestine. In addition to the synergy of Pten and Kras mutations in tumourigenesis, I have shown that they synergise to disrupt normal intestinal homeostasis resulting in increased cell number and villus bifurcation. These phenotypes are potentially driven through hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway. Investigation of the role of E-cadherin in the small intestine revealed that E-cadherin is indispensable for the structural maintenance of the epithelial layer. However, heterozygous loss of E-cadherin is viable, and mice do not develop any tumourigenic phenotype. Further, despite loss of E-cadherin correlating with invasion in human tumours, heterozygous loss of E-cadherin in the context of intestinal tumourigenesis does not promote tumour progression in the mouse. I also investigated the role of Pten in the small intestinal stroma. PTEN is a major tumour suppressor in humans. Constitutive heterozygous loss of Pten in the mouse gives rise to intestinal tumours, as does intestinal specific, conditional deletion of Pten in the epithelium and the underlying supporting stroma and smooth muscle. However, epithelial specific loss of Pten does not give rise to rapid tumourigenesis. I therefore, used the cre-loxP system to conditionally delete Pten from the stromal fibroblasts and smooth muscle of the intestine. These mice developed benign tumours along the length of the intestine, in particular the caecum and colon. These findings demonstrate the role of Pten in stromal-epithelial interactions in the intestine. Taken together, my data demonstrate that appropriate regulation of Pten and Kras together, contribute to the maintenance of homeostasis in the small intestinal epithelium, and alteration of the expression of these genes concomitantly in intestinal epithelial cells leads to the formation of intestinal metastatic carcinoma. My findings also indicate that the tumour suppressor function of Pten is not confined to epithelial cells, as deficiency of Pten exclusively in the supporting stroma and smooth muscle of the intestine results in tumourigenesis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available