Differences in Plasticity and Expression of Developmental Genes in Canine Mammary Carcinomas and Sarcomas

Mammary tumors are the most common type of tumors affecting female dogs. There is a remarkable heterogeneity among mammary tumors and the underlying cause is poorly understood. The aims of this thesis were, firstly, to investigate whether tumor cells show plasticity and thereby get insight into how heterogeneity arises and, secondly, to identify embryonic developmental genes expressed in the tumors. A comparison between sarcomas and carcinomas in these respects was of central importance for this investigation Primary tumors, an osteosarcoma, a spindle-cell tumor, and a simple carcinoma were cloned and resulting clones were subcutaneously injected in mice, to form experimental tumors. By following the expression of lineage markers in the primary tumors, the clones in vitro, and in the experimental tumors, it was found that the sarcoma clones showed distinct signs of plasticity, and that the carcinoma clones transformed in line with an epithelial to mesenchymal transition. The expression of genes coding for the developmentally important bone morphogenetic proteins was studied in the clones from the tumors described above. Further, three groups of tumors, i.e., osteosarcomas, fibrosarcomas and simple carcinomas were studied using gene expression profiling technology. Thereby, extensive expression of homeobox genes, a group of important developmental genes, was identified. Sarcomas displayed the most prominent expression of developmental genes, both for the number of genes expressed and the levels of expression for the respective genes. Interestingly, many homeobox genes expressed in the sarcomas have been linked to craniofacial development, a process dependent on neural crest contribution. In line with this, cell markers for neural crest derived tissues were also expressed in the sarcomas, including tooth, nerve and glial markers. The results show that sarcomas are more plastic and have a more diverse gene expression than carcinomas. Heterogeneity seen in sarcomas of the mammary gland may be related to the expression of homeobox genes.