Fig. 5

A schematic representation of the HO in the present case. Although the primary tumor did not produce BMP-2 nor show HO, the metastasized tumor cells acquired the ability to express BMP-2 and TGF-β1. TGF-β1 stimulated the expression of BMP-2 and Gli2, and Gli2 stimulated the expression of BMP-2. BMP-2 induced the production of bone material, such as osteonectin or osteocalcin. BMP-2 and TGF-β1 were secreted outside the tumor cells and transformed fibroblasts and, probably, pluripotent stem cells into osteocytes. In addition, Gli2 stimulated the Smad pathway in the nucleus and induced bone formation through the RUNX2 pathway. Chemotherapy might contribute to Gli2 overexpression by activating the Hedgehog pathway. These findings provide evidence that HO can occur independently, without the transformation of pluripotent stem cells into osteoblast-like cells, and that the present case resulted from osteogenesis via the EMT. In contrast, most previously reported cases resulted from the metaplasia of stromal cells into osteoblasts