The long-term goal of this project is to develop a swine animal model of cancer. There is a pressing need to develop new models to study cancer in an animal that is genetically, anatomically, and physiologically more analogous to humans and that metabolizes drugs and undergoes tumorigenesis similar to humans. Differences between mice, the most commonly used cancer biology model, and humans limit their utility for the study of the underlying causes of specific cancers and in the development of preclinical therapeutics for the treatment of this disease, thereby preventing the transition from basic to clinical research. Towards this end, a genetically malleable, large animal solid tumor and T-cell lymphoma models utilizing the pig was developed. Primary porcine cells were genetically engineered to be tumorigenic through the altered expression of proteins known to disrupt pathways commonly affected in human cancers. The transformed porcine cells were returned to the isogenic host animal and produced solid tumors at the site of injection. To test the hypothesis that this approach could be used to induce tumorigenesis in cells derived from each of the three embryonic germ layers, isolated porcine ectodermic fibroblasts and endodermic keratinocytes were transformed using this method. This approach was then adapted to induce the transformation of T-cells, derived from the mesoderm, in vivo. The ability to transform various cell types derived from all three embryonic layers and rapidly generate genetically defined tumors similar to those treated clinically in humans may provide a robust model for preclinical studies of adjunct cancer therapies.
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