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Title: Functional evaluation of human colorectal cancer modifiers in the ApcMin/+ genetic model
Author: Harper, James Alexander
ISNI:       0000 0001 3532 3625
Awarding Body: University of Bristol
Current Institution: University of Bristol
Date of Award: 2008
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Alterations in expression of a number of human genes have been identified as being essential in the transition of an adenoma to a carcinoma. The genes coding for Insulin-like growth factor 2 (IGF2) , E-cadherin (COH1) and IGF2I Mannose 6phosphate receptor (IGF2R) are imprinted, epigenetically silenced and mutated respectively in colorectal cancer. I evaluated the functional consequence of changes in Ig!2, Cdh1 and Igf2r allelic dosage on intestinal adenoma development in the Apd'inl+ intestinal adenoma model. Igf210ss of imprinting (L1H1gml+1j and Cdh1 haploinsufficiency (Cdh1+1 .) alone both resulted in the significant elongation of the intestinal crypt. In combination with Apcf1inl+ increased allelic Igf2 expression led to increased adenoma growth independent of systemic growth, and increased adenoma nuclear l3-catenin staining combined with a reduction in E-Cadherin levels. The introduction of a transgene expressing a soluble form' of the full length IGF-II/ Mannose 6phosphate receptor (sIGF2R) in the intestine, which acted as a specific inhibitor of IGF-II ligand bioavailability (ligand trap), rescued the Igf2 LOI dependent Apcf1inl+ intestinal and adenoma phenotype. Combination of Cdhrl . with Apcf1inl+ resulted in an increase in adenoma number independent of any change in adenoma progression. Increased Igf2r gene dosage' as a result of a targeted deletion within the imprinting mechanism present on the maternal allele in combination with Apcf1inl+ caused a significant reduction in intestinal and colonic adenoma number. The combinations of these modifications resulted in an additive phenotype within the crypts of .!J.H1gml+P, Cdh1+1 ., Apc+l+ mice and possible synergistic effects in the presence of Apcf1inl+ that resulted in a peri-natal lethality phenotype of .!J.H1gml+p , Cdh1+1 ', Apcf1iril+ mice. These data suggested that allelic dosage of Igf2, Cdh1 and Igf2r genes had modest modifier activity alone. However when either combined together, or with the Apcf1inl+ tumour initiating mutation, exerted potent additive and synergistic activity in vivo.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available