The isolation and characterization of renal cancer initiating cells from human Wilms' tumour xenografts unveils new therapeutic targets.
Bottom Line: The existence of cancer initiating cells/cancer stem cells (CIC/CSC) in paediatric solid tumours is currently unclear.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.The existence of CIC/CSCs in WT provides new therapeutic targets.
Affiliation: Pediatric Stem Cell Research Institute, Edmond and LiliSafra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel.Show MeSH
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Mentions: We next determined that biological properties of the NCAM+ALDH1+ CIC/CSCs in WT. Since Xn tumours initiated from NCAM+ cells differentially expressed specific proteins such as AKTpSer473 (Fig 2E and Supporting Information Table S4), the protein profile of tumour Xn early after initiation by NCAM+ALDH1+ cells might provide insights into CIC/CSCs biology. Nondenaturing PAGE and immunoblot analysis for the expression of proteasomal subunits 19s and 20s revealed overexpression of the subunits in comparison to both tumour xenografts generated from unsorted p-WT Xn cells and parental WT (Fig 4A). Moreover, Western blot analysis demonstrated differential protein expression in the NCAM+ALDH1+ tumour, specifically AKTpSer473 but not p-ERK and c-FOS, which have been recently implicated in WT and were strongly expressed in the primary parental WT (Fig 4B). c-Jun seemed to be activated in WT in general while β-catenin was similarly observed in NCAM+ALDH1+ tumour and hFK and therefore does not necessarily specify CIC pathways. c-MYC, SRC and YAP1 were expressed in most samples (WT and control rhabdoid tumours) with c-MYC elevated in NCAM+ALDH1+ tumour. Other proteins, such as NQO1, and to a lesser extent P53, were increased in control paediatric rhabdoid tumour, further indicating the specificity of the pathways active in WT and importantly in the NCAM+ALDH1+ CIC derived tumour xenografts. Thus, highly enriched WT CIC/CSCs are likely to feature signaling molecules and oncogenes distinct from those generally observed in WT and other closely related paediatric tumours.
Affiliation: Pediatric Stem Cell Research Institute, Edmond and LiliSafra Children's Hospital, Sheba Medical Center, Ramat-Gan, Israel.