Metastatic Progression of Osteosarcomas: A Review of Current Knowledge of Environmental versus Oncogenic Drivers.

Metastases of osteosarcomas are heterogeneous. They may grow simultaneously with the primary tumor, during treatment or shortly after, or a long time after the end of the treatment. They occur mainly in lungs but also in bone and various soft tissues. They can have the same histology as the primary tumor or show a shift towards a different differentiation path. However, the metastatic capacities of osteosarcoma cells can be predicted by gene and microRNA signatures. Despite the identification of numerous metastasis-promoting/predicting factors, there is no efficient therapeutic strategy to reduce the number of patients developing a metastatic disease or to cure these metastatic patients, except surgery. Indeed, these patients are generally resistant to the classical chemo- and to immuno-therapy. Hence, the knowledge of specific mechanisms should be extended to reveal novel therapeutic approaches. Recent studies that used DNA and RNA sequencing technologies highlighted complex relations between primary and secondary tumors. The reported results also supported a hierarchical organization of the tumor cell clones, suggesting that cancer stem cells are involved. Because of their chemoresistance, their plasticity, and their ability to modulate the immune environment, the osteosarcoma stem cells could be important players in the metastatic process.