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The epithelial–mesenchymal transition (EMT) plays a central role in morphogenesis during embryonic development as well as in the malignant progression of cancer including acquisition of the metastatic phenotype. Although the underlying molecular mechanisms are complex, the EMT is regulated by three major groups of transcription factors belonging to the Zeb, Snail and Twist families. Upregulation of the expression of these EMT‐inducing transcription factors (EMT‐TF) promotes tumor invasiveness and correlates with disease relapse and poor prognosis in individuals with various types of epithelial tumor. In addition, EMT‐TF are associated with resistance to chemotherapy and stem‐like characteristics in cancer cells. The EMT‐TF are implicated in the malignant progression of epithelial tumors, but their role in mesenchymal tumors remains unclear.
Osteosarcoma is the most frequent type of malignant bone tumor and primarily affects children and adolescents. Although the prognosis of individuals with osteosarcoma has improved with chemotherapy, a significant proportion of patients remains incurable as a result of the development of metastatic lesions. While EMT‐TF are thought to contribute to the maintenance of mesenchymal features of osteosarcoma, it remains largely unknown whether they might promote metastasis and malignant behavior in this tumor type as they do in epithelial tumors. Amplification or deletion of the TWIST1 locus has been detected in pediatric osteosarcoma, with such deletion being associated with a poor clinical outcome. Twist1 and Twist2 are highly conserved basic helix–loop–helix transcription factors that play essential roles during embryogenesis. Twist proteins inhibit skeletal development through direct and indirect inhibition of Runx2, a key regulator of osteogenic differentiation. Expression of Twist1 and Twist2 in mesenchymal cells has been suggested to promote adipogenesis. Together, these various observations suggest that Twist proteins might play an important role in normal bone marrow stromal cells (BMSC) as well as in malignant mesenchymal tumors.
We recently established osteosarcoma‐initiating cells by introducing the c‐Myc gene into BMSC of Ink4a/Arf knockout (Ink4a KO) mice. Mice injected with these cells develop osteosarcoma with pathological features similar to those of human osteosarcoma, including the production of osteoid and highly metastatic behavior. In addition, we established two distinct types of cell lines from the c‐Myc‐overexpressing Ink4a KO BMSC: low‐tumorigenic cells, which can differentiate into osteogenic, chondrogenic and adipogenic lineages; and high‐tumorigenic cells, which can differentiate into osteogenic and...