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
