Abstract
Sarcomas are a heterogeneous group of cancers that arise from transformed connective tissue cells. Although rare, accounting for less than ten percent of all cancers, they cause a relatively high rate of morbidity and mortality, especially amongst children and adolescents. Many signaling pathways that normally regulate stem cell self-renewal and differentiation are also associated with a diverse range of cancers when they are dysregulated. Although the cell of origin of sarcomas is still widely debated, mesenchymal stem cells (MSCs), while having great therapeutic potential in regenerative medicine and tissue engineering have been implicated as the cell in which sarcomagenesis begins. As more endogenous sources of MSCs with links to cancer are identified and, since stem cell tumorigenicity represents a potential obstacle for the use of stem cell based regenerative medicine, it is critical to understand the links between stem cells and cancer cells. Therefore, in this study we have developed and characterized genetically defined MSC models using a combinatorial approach with various oncogenes. These models can be used for the investigation of the molecular etiology of human stem cell-related cancers (i.e. sarcomagenesis), as well as be used as a platform to identify novel tumor suppressor genes. We found that the morphology, proliferation rates, and differentiation capacity were variable among the different groups with several cell lines capable of anchorage independent growth, indicative of oncogenic transformation. This process may allow us to advance our attempts at creating more accurate MSC-based models of sarcomagenesis and help us to further elucidate the underlying mechanisms involved in the onset and progression of these cancers. Moreover, these models offer a powerful way to understand the combinatorial process that leads to cancer. This can help us to provide a better understanding of the specific genetic alterations involved in tumorigenesis as well as a deeper understanding of the molecular basis of sarcoma, thereby leading us to develop more specific therapies against these sarcoma initiating cells.