Identification of cancer stem cells in Ewing's sarcoma.
Cancer stem cells that display tumor-initiating properties have recently been identified in several distinct types of malignancies, holding promise for more effective therapeutic strategies. However, evidence of such cells in sarcomas, which include some of the most aggressive and therapy-resistant tumors, has not been shown to date. Here, we identify and characterize cancer stem cells in Ewing's sarcoma family tumors (ESFT), a highly aggressive pediatric malignancy believed to be of mesenchymal stem cell (MSC) origin. Using magnetic bead cell separation of primary ESFT, we have isolated a subpopulation of CD133+ tumor cells that display the capacity to initiate and sustain tumor growth through serial transplantation in nonobese diabetic/severe combined immunodeficiency mice, re-establishing at each in vivo passage the parental tumor phenotype and hierarchical cell organization. Consistent with the plasticity of MSCs, in vitro differentiation assays showed that the CD133+ cell population retained the ability to differentiate along adipogenic, osteogenic, and chondrogenic lineages. Quantitative real-time PCR analysis of genes implicated in stem cell maintenance revealed that CD133+ ESFT cells express significantly higher levels of OCT4 and NANOG than their CD133- counterparts. Taken together, our observations provide the first identification of ESFT cancer stem cells and demonstration of their MSC properties, a critical step towards a better biological understanding and rational therapeutic targeting of these tumors.
Suvà
Mario-Luca
ML
Division of Experimental Pathology and Division of Clinical Pathology, Institute of Pathology, University of Lausanne, Lausanne, Switzerland.
Riggi
Nicolò
N
Stehle
Jean-Christophe
JC
Baumer
Karine
K
Tercier
Stéphane
S
Joseph
Jean-Marc
JM
Suvà
Domizio
D
Clément
Virginie
V
Provero
Paolo
P
Cironi
Luisa
L
Osterheld
Maria-Chiara
MC
Guillou
Louis
L
Stamenkovic
Ivan
I
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D001859:Bone Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D006023:Glycoproteins / Q000032:analysis; D006801:Humans; D018189:Immunomagnetic Separation / Q000379:methods*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology*; D010455:Peptides / Q000032:analysis; D012512:Sarcoma, Ewing / Q000473:pathology*
D000071916:AC133 Antigen; D015703:Antigens, CD; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse