Developmental counterpart of the Wilms Tumour cancer stem cell
Cartlidge, Christopher W. J.
Wilms tumour (WT; more correctly known as nephroblastoma) is an important childhood renal cancer. The WT cancer stem cell (CSC) has been identified as being a neural cell adhesion molecule-1+ (NCAM1) and aldefluor+ sub-population of tumour cells that can recapitulate the characteristic histology of WT when only 200 cells were used to seed the tumour in vivo. The aim was to explore the relationship between normal nephron progenitor cells and the WT cancer stem cell, with the hypothesis that the CSC has a normal developmental cell counterpart and when this is transformed by cancer-causing mutations it initiates WT. We show that ALDH1A2 is responsible for the aldefluor activity seen both in CSCs and normal embryonic kidneys, and that NCAM1 and ALDH1A2 are expressed in different cell lineages in the normal developing mouse kidney. Ncam1 expression is found in the Six2-positive nephrogenic progenitor cells, whereas Aldh1a2 is expressed in the Foxd1- positive stromal lineage. When we conditionally knock-out Wt1 in mice (the classical WT-causing mutation) we find that NCAM1 and ALDH1A2 become present in the same cells, as in the CSCs. Similar results are seen when using a Six2-Cre, suggesting that the origin of the CSC is the NCAM1+ nephrogenic lineage. We conclude that the Wilms tumour initiating mutation is directly responsible for the co-expression of the two WT CSC markers in the same cells. The construction of an mCherry fluorescence expressing vector with inducible Cre for insertion at the Ncam1 locus will allow future lineage tracing of the developmental equivalent of the CSC and conditional knock-out of other WT associated genes. In addition, pilot data is presented for the production of WT-like pseudo-tumours in NOD/SCID mice.