Journal
EMBO MOLECULAR MEDICINE
Volume 5, Issue 1, Pages 18-37Publisher
WILEY
DOI: 10.1002/emmm.201201516
Keywords
cancer initiating cells; cancer stem cells; kidney stem cells; renal progenitor cells; targeted therapy
Categories
Funding
- ICRF [PG-11-3072]
- ICRF Clinical Career Development Award [CRCDA 08-403]
- Israel Cancer Association
- Israel Ministry of Health [5107]
- ISF [1139/07]
- TAU Cancer Biology Research Center
- Brettler Foundation
- Sackler School of Medicine
- Tel Aviv University
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There are considerable differences in tumour biology between adult and paediatric cancers. The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear. Here, we show the successful propagation of primary human Wilms' tumour (WT), a common paediatric 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 harbour 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 tumour. WT CSCs, which can be further enriched by aldehyde dehydrogenase activity, overexpressed renal stemness and 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. The existence of CIC/CSCs in WT provides new therapeutic targets.
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