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Cancer is one of the most important lethal diseases for dogs.
Nevertheless, most aspects of the cause and development of canine cancer are still unkown. Aim of the projects included in this thesis was therefore to obtain deeper insights into the molecular carcinogenesis of canine mammary tumors, mast cell tumors and canine cutaneous soft tissue sarcomas, which may allow for an improved diagnosis and new therapeutic approaches in the future. The prediction of metastatic disease of canine mammary carcinomas is difficult with the currently available diagnostic tools. Furthermore, carcinogenesis-associated signaling cascades and most aspects of their metastatic progress are unknown. In the present study, metastasis-associated, complex mRNA and protein expression patterns were identified using global transcriptome and proteome analysis. In addition, a stepwise change in the protein expression patterns during the different steps of malignant progression of canine mammary tumors was observed.
In an approach new to veterinary oncology, markers for circulating tumor cells in the peripheral blood of dogs with canine mammary tumors were identified and may serve as additional tools for an improved diagnosis of this tumor type.
Mutations of the stem cell receptor KIT are the only confirmed etiologic factor for the development of canine mast cell tumors. In the present study, expression of the interleukin 2 receptor was identified as a potential factor of mast cell tumor carcinogenesis. In another project, numerous target genes of KIT were identified in a cell culture model of tyrosine kinase inhibitor treatment of mast cell tumors.
These included several proproliferative signaling cascades with increased expression after inhibitor treatment. These cascades can now be considered potential targets for a more efficient combination therapy with tyrosine kinase inhibitors. Global proteome analysis also identified genes with influence on the stress resistance and cell motility of canine mast cell tumors. Some of these genes are already therapy targets for the treatment of human tumors and may possess similar potential for canine mast cell tumors.
Canine cutaneous soft tissue sarcomas are difficult to be differentiated into their subgroups by histology alone. cDNA-microarray analysis performed in this study, however, identified several genes with specific expression in peripheral nerve sheath tumors and fibrosarcomas. RT-PCR assays for these genes were able to sensitively and specifically separate peripheral nerve sheath tumors from fibrosarcomas.
In summary, application of modern molecular methods revealed new insights into factors of carcinogenesis and development of three of the most important canine tumor types. These finding were already used for the development of new diagnostic tools in this study and may facilitate the development of new therapeutic approaches in the future.
Similar work is well conceivable for other canine tumors or tumors of other species in subsequent projects.