| Lower urinary tract urothelial carcinomas are commonly diagnosed neoplasms in humans and dogs. Similarities between human and canine urothelial carcinomas have been well described in terms of histomorphology and clinical progression. Further due to strong breed predispositions for tumor development, there are likely heritable factors that regulate carcinogenesis in the lower urinary tract of subsets of dogs. This has led to the suggestion that canine urothelial carcinomas could be used as a naturally occurring animal model. However, it is unclear what features in canine urothelial carcinomas are associated with prognostic significance or treatment response. Further, while some similarities between human and canine urothelial carcinomas are known, what similarities or differences may exist in terms of molecular features that drive carcinogenesis are largely unknown. This dissertation first examines correlations of common urothelial carcinoma markers to histologic classification, grading, and degree of bladder wall invasion in dogs relative to the histologic classification scheme accepted for humans in order strengthen the stance that there are biologic differences between proliferative urothelial lesions and histologic grades. Then, specific carcinogenesis pathways that have been suggested to play roles in epithelial-to-mesenchymal transition and that have prognostic significance in human urinary bladder urothelial carcinomas were evaluated. These included pathways that govern prostaglandin E2 regulation, cadherin swithching, and Wnt signaling. Finally, the role of defective DNA mismatch repair (MMR) was examined. In urothelial carcinomas, evidence of MMR repair dysfunction was found and was correlated with genetic background of the dogs from which tumors originated. Additionally, canine lower urinary tract urothelial carcinoma cell lines were established which differential MMR proficiency and which had also had differential response to treatment similar to that described in humans. These studies combine to show that while there are many similarities between urothelial carcinomas in dogs and humans; there are also many differences suggesting that while further study of canine urothelial carcinoma is warranted, canine urothelial carcinoma do not perfectly recapitulate similar disease in humans. |
