Abstract C11: CD117 and Stro-1 identify osteosarcoma stem cells associated with metastasis and chemotherapy-drug resistance

Abstract

Osteosarcoma, the most common bone cancer, is the second highest cause of cancer-related death in children and adolescents. Approximately 90% of cases show micro-metastasis at diagnosis, making systematic chemotherapy the first choice of treatment. Despite intensive chemotherapy, the survival rate for high-grade osteosarcomas remains only 50-80%. The inadequacy of current treatments may result from the inability to effectively target cancer stem cells (CSCs) or tumor initiating cells (TI-Cs) of osteosarcoma. Thus, novel therapies targeting cancer stem cells (CSCs) in osteosarcoma is an urgent requirement for eradicating this dreadful disease. Here, we have identified mouse and human osteosarcoma CSCs using mesenchymal stem cell markers CD117 and Stro-1. These markers were preferentially expressed in spheres and doxorubicin-resistant cells. CD117+Stro-1+ cells efficiently formed serially transplantable tumors, whereas CD117-Stro-1-cells rarely initiated tumors. Upon orthotopic injections, CD117+Stro-1+-derived tumors metastasized at a high frequency. Further, CD117+Stro-1+ cells were capable of differentiating into adipogenic lineage, and were enriched for CXCR4 and ABCG2, respectively associated with metastasis and drug-resistance. Thus, CD117 and Stro-1 identify osteosarcoma CSCs with the most lethal characteristics of the disease—metastasis and drug-resistance—proposing these markers as potential candidates for CSC-targeted drug delivery towards eradication of osteosarcoma. Citation Information: Cancer Res 2009;69(23 Suppl):C11.

Metastatic potential of tumor-initiating cells in solid tumors

“…Recently, our group (40) showed in vitro as well as in vivo evidence of the high metastatic potential of osteosarcoma TICs (Table 1). Using murine primary and established cell lines, we demonstrated that mesenchymal stem cell markers CD117 and Stro-1, but not markers such as CD44, CD105, and CD49b, were preferentially expressed in spheres and doxorubicin-resistant cells.…”

“…CD117/c-kit is a 145 kDa transmembrane glycoprotein and is expressed in both haematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs). Recently, our group has shown that CD117 in combination with another MSC-specific marker Stro-1 can identify osteosarcoma TICs (40). Thus, TICs can be identified from various types of cancer using stem cell surface markers.…”

“…By culturing tumor cells in a sphere-specific condition, formed spheres have been shown to be enriched in TICs. These studies include glioblastoma (76), ovarian cancer (77), melanoma (78), cervical cancer (79), and osteosarcoma (40,80). However, sphere formation requires prolonged culture times, amounting to about two weeks, which could give rise to non-TICs after cell division.…”