Browsing by Subject "Canine"
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Item Gene and protein expression in canine follicular thyroid carcinoma.(2011-08) Metivier, Kristy StacyThe major goal of this study was to investigate the molecular characteristics of canine follicular thyroid carcinoma (FTC). This is a rapidly growing and highly aggressive tumor in dogs, and many patients present with evidence of invasion or metastasis. Some smaller independent studies have attempted to evaluate the role of single molecules such as p53 and thyroid transcription factor-1 in tumor development, often with inconclusive results. In the present study, a genome-wide approach was employed to achieve the first objective of determining the gene expression profile of FTC compared to normal thyroid tissue. Microarray analysis was performed in a pilot study using five FTC tissues and four normal thyroid gland tissues, and this showed 489 transcripts as differentially expressed between the two groups; 242 were down-regulated and 247 were up-regulated. Some important biological functions that were affected include regulation of cell shape, cell adhesion, regulation of MAP kinase activity, angiogenesis, and regulation of cell migration. Osteopontin was a gene of interest as tumors consistently expressed it at high levels while it was expressed at low levels in all of the healthy samples. One of its up-stream regulators, VEGFA, was also differentially expressed but with a smaller fold change. The expression of osteopontin was validated by quantitative PCR using three groups: non-invasive FTC (tumors with capsular invasion only), invasive FTC (tumors with capsular and vascular invasion), and normal thyroid tissue. Both non-invasive FTC and invasive FTC had higher osteopontin gene expression than normal thyroid tissue but the two tumor groups were not different from each other. The second objective was to determine the protein expression of osteopontin and VEGFA in the same cases using semi-quantitative scoring of tissues stained by immunohistochemistry. The results were similar, with non-invasive and invasive FTC having higher osteopontin protein expression than normal thyroid tissue, but showing no difference from each other. With respect to VEGFA, there was no difference in gene or protein expression among the three groups. The final objective was to determine the plasma concentration of VEGFA and osteopontin in dogs diagnosed with FTC compared to clinically healthy dogs using a commercially available canine-specific ELISA. In this case, both VEGFA and osteopontin had higher plasma concentrations in dogs with FTC compared to healthy dogs. A small number of FTC cases were also measured two weeks after surgical removal of the tumor. Some cases showed a post-surgical decrease in VEGFA and osteopontin while others either remained the same or increased; however, the sample size for this comparison was small. The consistent expression of osteopontin in both tissues and blood suggest that it is a promising marker for identification of canine FTC. As in human studies of osteopontin in aggressive carcinomas, it is also possible to investigate it as a means of monitoring response to therapy, recurrence, and clinical outcome.Item Uncovering Mechanisms of Osteosarcoma Metastasis(2016-08) Marko, TracyOsteosarcoma (OS) is the most common primary malignant bone tumor, with metastatic disease responsible for most treatment failure and patient death. A better understanding of the metastatic disease state is needed to improve patient survival. The studies presented here explore a variety of questions surrounding metastatic OS. A literature search of the PubMed database was conducted to compare the prevalence of metastatic OS at diagnosis across countries. The average prevalence of metastasis at diagnosis increased as Human Development Index score (HDI) decreased, with an 18% global average. In countries with medium/low HDI, where more barriers to accessing healthcare exist, the higher prevalence of metastasis may result from treatment delay or an artificially inflated prevalence due to patients with less severe symptoms not presenting to clinic. Canine OS is a naturally occurring, spontaneous disease with more rapid disease progression and greater incidence than human OS. An understanding and utilization of studies on metastatic OS in dogs could help identify new treatment strategies to improve patient outcomes in humans and dogs. We evaluated the similarities of metastatic OS between the species by comparing risk factors for having metastatic OS at diagnosis between pet dogs from our veterinary clinic and pediatric patients in the Surveillance, Epidemiology, and End Results database. Here we build on current knowledge of canine OS by showing that primary tumors in similar anatomical locations metastasize at comparable rates in both species. A Sleeping Beauty mutagenesis screen previously conducted in our laboratory identified Slit-Robo GTPase- Activating Protein 2 (SRGAP2) as a potential suppressor of OS metastasis. SRGAP2 controls phenotypes in neurons supporting the hypothesis that it may suppress migration in the context of cancer. Although the effects of SRGAP2 in OS were not consistent across all cell lines, they tended to support this hypothesis. Additionally, expression levels of other genes in the Slit-Robo pathway were significantly altered in a subset of mouse and human OS, and SRGAP2 protein expression was lost in a subset of primary tumor samples. SRGAP2 and other axon guidance proteins likely play a role in OS metastasis, with loss of SRGAP2 contributing to a more aggressive phenotype.