Abstract
Mesenchymal progenitor cells (MPCs) have been hypothesized as cells of origin for sarcomas, and c-Fos transcription factor has been showed to act as an oncogene in bone tumors. In this study, we show c-Fos is present in most sarcomas with chondral phenotype, while multiple other genes are related to c-Fos expression pattern. To further define the role of c-Fos in sarcomagenesis, we expressed it in primary human MPCs (hMPCs), immortalized hMPCs and transformed murine MPCs (mMPCs). In immortalized hMPCs, c-Fos expression generated morphological changes, reduced mobility capacity and impaired adipogenic- and osteogenic-differentiation potentials. Remarkably, immortalized hMPCs or mMPCs expressing c-Fos generated tumors harboring a chondrogenic phenotype and morphology. Thus, here we show that c-Fos protein has a key role in sarcomas and that c-Fos expression in immortalized MPCs yields cell transformation and chondrogenic tumor formation.
Highlights
In the case of CS, the cell of origin for peripheral chondrosarcoma seems to arise from differentiated chondrocytes
We examined c-Fos mRNA expression in human sarcoma samples and found c-Fos is expressed at mRNA level in different types of sarcomas with chondral phenotype (Fig. 1F,G), which is in consonance with the immunohistochemistry data
Discussion c-Fos is a known oncogene expressed in sarcoma tumors, whose deregulated expression is enough to transform a number of cell types, including cells of mesenchymal origin as fibroblasts[31]
Summary
In the case of CS, the cell of origin for peripheral chondrosarcoma seems to arise from differentiated chondrocytes. Cartilage progenitor cells of mouse mandibular condyles differentiate to osteoblasts, and generate temporal pattern of c-Fos expression in hypertrophic chondrocytes, which precedes the expression of bone cell characteristic genes[22]. The induction of c-Fos expression using ubiquitous promoter results in specific transformation of osteoblasts, leading to OS formation[5]; on the contrary, chimeric mice obtained from c-Fos-overexpressing embryonic stem cells develop chondrogenic tumors[25]. In other study c-Fos expression was detected in 50% human CS tumors[28], while inoculation of human CS HCS-2/8 cells in nude mice generates CS with high expression levels of c-Fos[29]. Most human CS expresses detectable levels of c-Fos protein in tested clinical samples
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