title: 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.
authors.affiliation: Departments of Genetics, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: Amit S
authors.initials: AS
authors.lastname: Adhikari
authors.forename: Neeraj
authors.initials: N
authors.lastname: Agarwal
authors.forename: Byron M
authors.initials: BM
authors.lastname: Wood
authors.forename: Constance
authors.initials: C
authors.lastname: Porretta
authors.forename: Bernardo
authors.initials: B
authors.lastname: Ruiz
authors.forename: Radhika R
authors.initials: RR
authors.lastname: Pochampally
authors.forename: Tomoo
authors.initials: T
authors.lastname: Iwakuma
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000328:Adult; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000954:Antigens, Surface / Q000378:metabolism*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008297:Male; D051379:Mice; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism; D012516:Osteosarcoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C501412:Abcg2 protein, mouse; D000903:Antibiotics, Antineoplastic; D000954:Antigens, Surface; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; D009363:Neoplasm Proteins; D019718:Receptors, CXCR4; C525591:STRO-1 antigen, human; C525590:STRO-1 antigen, mouse; D004317:Doxorubicin; D019009:Proto-Oncogene Proteins c-kit
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