CD117 and Stro-1 Identify Osteosarcoma Tumor-Initiating Cells Associated with Metastasis and Drug Resistance

Abstract

Emerging evidence indicates the presence of tumor-initiating cells (TIC) or cancer stem cells in osteosarcoma. However, no study has shown specific markers to identify osteosarcoma TICs with in vivo tumor formation ability. Additionally, there has been a lack of investigations gauging the contribution of osteosarcoma TICs to metastatic and drug-resistant properties. In this study, we have identified mouse and human osteosarcoma TICs using mesenchymal stem cell markers CD117 and Stro-1. These markers were preferentially expressed in spheres and doxorubicin-resistant cells. Both mouse and human cells expressing these markers were sorted and analyzed for their abilities of tumor formation with as few as 200 cells, self-renewability, multipotency, drug resistance, metastatic potential, and enrichment of a metastasis-associated marker (CXCR4) and a drug resistance marker (ABCG2). CD117⁺Stro-1⁺ cells efficiently formed serially transplantable tumors, whereas CD117⁻Stro-1⁻ cells rarely initiated tumors. On orthotopic injections, CD117⁺Stro-1⁺ cell-derived tumors metastasized at a high frequency. Further, CD117⁺Stro-1⁺ cells showed high invasive and drug-resistant properties and were efficiently enriched for CXCR4 (20–90%) and ABCG2 (60–90%). These results suggest possible mechanisms for the high metastatic and drug-resistant properties of osteosarcoma TICs. In summary, CD117 and Stro-1 identify osteosarcoma TICs associated with the most lethal characteristics of the disease—metastasis and drug resistance—and these markers offer candidates for TIC-targeted drug delivery aimed at eradicating osteosarcoma. Cancer Res; 70(11); 4602–12. ©2010 AACR.