title: The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets.
abstract: 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.
authors.affiliation: Pediatric Stem Cell Research Institute, Edmond and LiliSafra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel.
authors.forename: Naomi
authors.initials: N
authors.lastname: Pode-Shakked
authors.forename: Rachel
authors.initials: R
authors.lastname: Shukrun
authors.forename: Michal
authors.initials: M
authors.lastname: Mark-Danieli
authors.forename: Peter
authors.initials: P
authors.lastname: Tsvetkov
authors.forename: Sarit
authors.initials: S
authors.lastname: Bahar
authors.forename: Sara
authors.initials: S
authors.lastname: Pri-Chen
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Goldstein
authors.forename: Eithan
authors.initials: E
authors.lastname: Rom-Gross
authors.forename: Yoram
authors.initials: Y
authors.lastname: Mor
authors.forename: Edward
authors.initials: E
authors.lastname: Fridman
authors.forename: Karen
authors.initials: K
authors.lastname: Meir
authors.forename: Amos
authors.initials: A
authors.lastname: Simon
authors.forename: Marcus
authors.initials: M
authors.lastname: Magister
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Victor S
authors.initials: VS
authors.lastname: Goldmacher
authors.forename: Orit
authors.initials: O
authors.lastname: Harari-Steinberg
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dekel
mesh_terms: D000071916:AC133 Antigen; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000080924:Aldehyde Dehydrogenase 1 Family; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D015703:Antigens, CD / Q000378:metabolism; D019002:CD56 Antigen / Q000378:metabolism; D002454:Cell Differentiation; D049109:Cell Proliferation; D002469:Cell Separation / Q000379:methods; D015870:Gene Expression; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D008453:Maytansine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010455:Peptides / Q000378:metabolism; D050697:Retinal Dehydrogenase; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D009396:Wilms Tumor / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D019002:CD56 Antigen; D006023:Glycoproteins; C522918:NCAM1 protein, human; D010455:Peptides; C579429:lorvotuzumab mertansine; D008453:Maytansine; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase