Canine Mast Cell Tumours: Characterization of Subcutaneous Tumours and Receptor Tyrosine Kinase Profiling

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Canine Mast Cell Tumours: Characterization of Subcutaneous Tumours and Receptor Tyrosine Kinase Profiling

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dc.contributor.advisor Foster, Robert A
dc.contributor.advisor Coomber, Brenda L
dc.contributor.author Thompson, Jennifer Jane
dc.date 2012-04-25
dc.date.accessioned 2012-05-16T19:03:04Z
dc.date.available 2012-05-16T19:03:04Z
dc.date.issued 2012-05-16
dc.identifier.uri http://hdl.handle.net/10214/3652
dc.description.abstract This work explored features of canine mast cell tumours (MCT) to improve prognosis and to discover potential therapeutic targets. Subcutaneous MCT - a subset of these tumours arising in the subcutis - are usually grouped with cutaneous MCT, but there is evidence that they may be clinically different. The first objective was to develop a grading scheme for subcutaneous MCT. Over 300 canine subcutaneous MCT were evaluated retrospectively and parameters were correlated with clinical outcomes, making this the largest retrospective survival study of these tumours to date. The results of the study showed that the majority of subcutaneous MCT had excellent outcomes and key prognostic markers were identified (mitotic index, surgical margins and degree of infiltration). A subset of the subcutaneous MCT from the retrospective study was further evaluated to assess the cellular localization of KIT - a receptor tyrosine kinase (RTK) which is dysregulated and constitutively activated in some cutaneous MCT - as well as Ki67, a proliferation marker. In addition, evaluation of mutations of c-KIT, the gene for KIT, was determined for each MCT. Cytoplasmic KIT localization and high Ki67 values were predictive of decreased survival time and time to local reoccurrence, but no c-KIT mutations were detected. The majority of canine MCT do not appear to depend solely upon KIT for tumour progression and few other RTK targets have been studied in canine MCT. Based on evidence that vascular endothelial growth factor receptors (VEGFR) and platelet-derived growth factor receptors (PDGFR) - may play a role in the progression of canine MCT; the expression and distribution of these RTK were evaluated. The results showed that canine MCT have unique expression profiles and activity of KIT, VEGFR2 and PDGFR. Two novel mast cell tumour cell lines were generated and used to assess signalling of KIT and VEGFR2 in vitro. Stimulatory and inhibitory responses were assessed and found to be different in both cell lines. Both had autophosphorylated VEGFR2 and an autocrine VEGF/VEGFR2 signalling pathway existed for both cell lines. These findings are unique and the first that identify autocrine VEGF signalling as a possible survival mechanism for canine MCT. en_US
dc.description.sponsorship Pet Trust Foundation, Ontario Veterinary College en_US
dc.language.iso en en_US
dc.subject canine en_US
dc.subject mast cell tumour en_US
dc.subject KIT en_US
dc.subject survival en_US
dc.subject c-KIT en_US
dc.subject VEGFR en_US
dc.subject PDGFR en_US
dc.title Canine Mast Cell Tumours: Characterization of Subcutaneous Tumours and Receptor Tyrosine Kinase Profiling en_US
dc.type Thesis en_US
dc.degree.programme Pathobiology en_US
dc.degree.name Doctor of Philosophy en_US
dc.degree.department Department of Pathobiology en_US


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