Given the considerable differences in tumor biology between adult and pediatric cancers, the existence of cancer initiating cells/cancer stem cells (CIC/CSC) in pediatric solid tumors is questionable. Herein, we have propagated primary human Wilms' tumor (WT), a common pediatric renal malignancy, in immunodeficient mice, demonstrating the presence of a population of highly proliferative CIC/CSCs capable of serial xenograft initiation. Cell sorting and limiting dilution transplantation analysis of xenograft cells, identified WT CSCs that harbor a primitive undifferentiated - NCAM1 expressing- "blastema" phenotype, including a capacity to expand and differentiate into the mature renal-like cell types observed in the primary tumor. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal 'stemness' and additional genes linked to poor patient prognosis, showed preferential protein expression of phosphorylated PKB/Akt and strong reduction of the miR-200 family. Complete eradication of WT in multiple xenograft models was achieved with a human NCAM antibody drug conjugate. We go on to show the presence of CIC/CSCs that are able to propagate other human renal malignancies such as rhabdoid tumors and angiomyolipoma, identify and target specific pathways relevant to the function of these cells.
Altogether, the existence of CIC/CSCs in pediatric renal tumors affords novel therapeutic targets.
