p53 loss and Kras mutation in an invasive murine model of colorectal cancer

Cuesta Garcia, Nerea (2013) p53 loss and Kras mutation in an invasive murine model of colorectal cancer. MSc(R) thesis, University of Glasgow.

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Abstract

For many years there have been many excellent mouse models of benign intestinal adenoma though not of later stage invasive disease. In this study we have attempted to generate a number of murine models that closely recapitulate the human disease by manipulating mutations that occur during colorectal cancer (CRC) progression. The p53 tumour suppressor gene is commonly mutated in sporadic CRC, though loss alone does not drive intestinal tumorigenesis. When we targeted p53 deletion to the adult murine intestine in concert with a single mutation in the Adenomatous Polyposis Coli (Apc) tumour suppressor gene, this led to an acceleration of tumorigenesis and an increase in the number of invasive tumours and more rarely metastasis. These invasive tumours closely resemble human tumours and importantly had many features of Epithelial to Mesenchymal Transition (EMT). Tumours in this background still formed at relatively long latencies suggesting other genetic events were occurring to drive the progression in the absence of p53. Up to 50% of colon cancers have a mutation in KRAS. Targeting mutant KrasG12D to the intestinal epithelium promotes hyperplasia though not tumorigenesis. In combination with Apc mutation there is an acceleration of tumorigenesis and a greater propensity to develop colonic tumours. To test whether Kras mutation caused a more marked phenotype in the background of p53 deficiency we generated VillinCreER+ Apcfl/+ p53fl/fl KrasG12D/+ mice. Remarkably these mice develop invasive and rarely metastatic tumours in as little as 50 days. Moreover even small tumours (less than 1mm) could be invasive. We believe these mouse models of invasive and metastatic intestinal adenocarcinoma will be an excellent tool to study the invasive and metastatic process in vivo. Moreover they should allow us to test the efficacy of drugs aimed to inhibit the invasion process.

Item Type: Thesis (MSc(R))
Qualification Level: Masters
Keywords: colorectal cancer, p53, APC, Kras, mouse models
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Veterinary Medicine
Funder's Name: UNSPECIFIED
Supervisor's Name: Sansom, Prof. Owen
Date of Award: 2013
Depositing User: Miss Nerea/N Cuesta-Garcia
Unique ID: glathesis:2013-4595
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 07 Apr 2014 10:59
Last Modified: 07 Apr 2014 11:18
URI: http://theses.gla.ac.uk/id/eprint/4595

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