Comparison of gene expression profiling in sarcomas and mesenchymal stem cells identifies tumorigenic pathways in chemically induced rat sarcoma model

Abstract

Mesenchymal stem cells (MSCs) are believed to be the cell of origin for most sarcomas including osteosarcoma and malignant fibrous histiocytoma (MFH/UPS). To identify the signaling pathways involved in sarcoma pathogenesis, we compared gene expression profiles in rat osteosarcoma and MFH cells with those in syngeneic rat MSCs. Analysis of genes that characterize MSCs such as CD44, CD105, CD73, and CD90 showed higher expression in MSCs compared to sarcomas. Pathways involved in focal and cell adhesion, cytokine-cytokine receptors, extracellular matrix receptors, chemokines, and Wnt signaling were down-regulated in both sarcomas. Meanwhile, DNA replication, cell cycle, mismatch repair, Hedgehog signaling, and metabolic pathways were upregulated in both sarcomas. Downregulation of p21(Cip1) and higher expression of CDK4-cyclinD1 and CDK2-cyclinE could accelerate cell cycle in sarcomas. The current study indicated that these rat sarcomas could be a good model for their human counterparts and will provide the further insights into the molecular pathways and mechanisms involved in sarcoma pathogenesis.

Figure 1

The hierarchical clustering analysis of expression profiling data clearly shows separate clusters among osteosarcoma, MFH, and MSCs.

Figure 2

The ratio of g scale signal intensity of mesenchymal stem cell markers and other stem cell markers. The graph indicates the fold changes in rat sarcomas in comparison to rat MSCs.

Figure 3

The ratio of g scale signal intensity of cell adhesion and extracellular matrix interaction molecules in both sarcomas compared to MSCs are shown. Integrins and their ligands CAMS were strongly expressed in MSCs, especially differential expression of CAMs between sarcomas and MSCs was significant. Matrix metalloproteinase 2 and 9 also showed higher expression in MSCs.

Figure 4

Interleukins and their receptors showed higher expression in MSCs compared to both sarcomas, except for IL6 and its receptor IL6Ra in osteosarcoma.

Figure 5

The ratio of most chemokines and their receptors also showed predominant expression in MSCs compared to both sarcomas, except for CXCR 3 and 7.

Figure 6

The expression of genes involved in Wnt signaling and those in Hedgehog signaling suggests the downregulation of Wnt signaling and upregulation of Hedgehog signaling pathways might be involved in rat sarcomagenesis.

Figure 7

CDK inhibitor p21 showed significantly lower expression and cell cycle accelerators including CDK2 and 4, cyclinD1 and E1 were highly expressed in both sarcomas compared to MSCs.

Figure 8

A summary of pathways with differentially expressed genes comparing sarcomas to MSC in the current study. Disruption of p53 and activation of Hedgehog signaling may lead to cell cycle acceleration through downregulation of p21 and upregulation of CDK and cyclins. The inactivation of the Wnt signaling pathway may lead to the deregulation of differentiation as well as focal adhesion function in MSC, which might be required for normal stem cell maintenance.