The impact of the osteosarcoma cancer stem cell model on future treatment design. (A) The response of osteosarcoma to chemotherapy alone: Chemotherapy shrinks the bulk of the tumor. However, chemoresistant CSCs may survive this therapy and then can self-renew and differentiate to reform the bulk of the tumor. CSCs therefore are responsible for osteosarcoma chemoresistance and tumor recurrence. (B) The proposed response of osteosarcoma to a combination of chemotherapy and CSC-targeted therapy: Combinational treatment will not only kill the majority of tumor cells but also the CSCs. The remaining non-CSC tumor cells will eventually exhaust their growth ability, resulting in complete eradication of the tumor.