Chondrosarcomas are malignant cartilage tumors that do not respond to traditional chemotherapy or radiation. The 5-year survival rate of histologic grade III chondrosarcoma is less than 30%. To achieve a greater understanding of chondrosarcoma tumorigenesis, a model for human chondrosarcoma has been established in a rat system. The model, known as the Swarm rat chondrosarcoma (SRC), resembles human chondrosarcoma and provides a system to study tumor growth and progression. Here we examined the influence of the tumor microenvironment and the impact of genome-wide hypomethylation on the behavior of SRC tumors, two factors known to contribute fundamentally to the development and progression of solid tumors.
Previous studies with SRC revealed that tumor microenvironment can significantly influence chondrosarcoma malignancy, but the underlying biologic mechanisms have not been defined. To address this issue we carried out epigenetic and gene expression studies on the SRC tumors that were initiated at different transplantation sites. The epigenetic analysis revealed that microenvironmental changes could promote global DNA hypomethylation in SRC cells. Subsequent gene expression analyses revealed that the transplantation site had a significant impact on the gene expression profiles of SRC tumors. These SRC tumors had unique gene expression profiles, and we were able to identify genes that were differentially expressed between SRC tumors originating from different transplantation sites. Functional analyses of two differentially expressed genes, thymosin-beta-4 and c-fos, provided insight into the role that these genes may play in the development and progression of chondrosarcoma.