Nuclear accumulation of β‐catenin protein in Wilms' tumours†

Abstract

The wnt-signalling pathway plays an important role during both normal kidney development and Wilms' tumourigenesis. Activation of this pathway involves stabilization, intracellular accumulation, and nuclear translocation of the beta-catenin protein and may be caused by specific mutations in the beta-catenin gene itself. Such mutations have been found in about 15% of Wilms' tumours. This study has analysed the intracellular levels and subcellular distribution of beta-catenin protein in 36 primary Wilms' tumour specimens and has correlated these results with the mutational status of the beta-catenin gene. Immunohistochemistry detected faint cytoplasmic and strong membranous expression of beta-catenin protein in the epithelial compartment of all tumours examined. In contrast, nuclear immunoreactivity for beta-catenin was detected in 9 of 9 Wilms' tumours containing a mutation of the beta-catenin gene and in 15 of 27 Wilms' tumours without detectable beta-catenin mutation. Nuclear positivity, in each case, was found to be very strong, but was usually present only in a fraction of cells ranging from 5% to 10%. Among the different histological subcompartments, blastemal and mesenchymal cell nuclei preferentially stained positive, whereas cells of epithelial differentiation displayed nuclear localization of beta-catenin protein in only a single case. Furthermore, nuclear positive cells were found in Wilms' tumours of all stages and in tumours of both favourable and unfavourable histology. These data support the idea that activation of the wnt-signalling pathway is a key oncogenic step in Wilms' tumourigenesis and that it probably involves transcriptional activation of critical target genes, carried out by beta-catenin protein in the nucleus. The fact that nuclear immunoreactivity specific for beta-catenin was detected in a significant number of Wilms' tumours in the absence of beta-catenin mutations suggests that genetic defects affecting other members of the wnt-signalling pathway may contribute to the development of Wilms' tumours in those cases.

Canonical WNT signalling determines lineage specificity in Wilms tumour

“…We next examined 53 tumours by immunohistochemistry (IHC) for nuclear accumulation of b-catenin. The intensity and distribution of nuclear staining of b-catenin were variable both within and between tumours as we and other groups have previously reported (Koesters et al, 2003;Fukuzawa et al, 2004a;Li et al, 2004;Fukuzawa et al, 2007). Nuclear immunostaining of b-catenin was detected predominantly in the undifferentiated mesenchymal cells and sometimes in the blastemal cells in 17 tumours (T2-4, 6-14, 16-20) (Table 1a).…”

“…b-catenin is normally localized within the cytoplasm or the cell membrane in the epithelial component of WT (Koesters et al, 2003;Li et al, 2004;Fukuzawa et al, 2004a). The absence of canonical WNT signalling in the epithelial elements despite the presence of b-catenin mutations suggests a different role for b-catenin in the genesis of the epithelial component of WT.…”

“…WT1 mutations are strongly associated with ILNR (Beckwith, 1998) that often develop into WTs with ectopic mesenchymal elements (Beckwith et al, 1990;Beckwith, 1998). A series of immunohistochemical studies of b-catenin in WT have shown that nuclear accumulation of b-catenin is predominantly observed in mesenchymal cells irrespective of CTNNB1 mutations (Koesters et al, 2003;Li et al, 2004;Fukuzawa et al, 2004aFukuzawa et al, , 2008Zirn et al, 2006). These observations suggest a relationship between the mesenchymal lineage in WT and active WNT signalling.…”

“…The WNT-signalling pathway is known to be involved in a subset of WT (Koesters et al, 1999(Koesters et al, , 2003Maiti et al, 2000;Li et al 2004;Fukuzawa et al, 2004a). These tumours typically have WT1 mutations and/or CTNNB1 mutations (Koesters et al, 1999;Maiti et al, 2000;Li et al, 2004;Fukuzawa et al, 2004a).…”

Upregulation of c-MYC in WT1-mutant tumors: assessment of WT1 putative transcriptional targets using cDNA microarray expression profiling of genetically defined Wilms' tumors

“…This is of particular relevance for this study since b-catenin mutations occur in B10-15% of WTs (Koesters et al, 1999;Maiti et al, 2000), and a strong correlation (Po10 À13 ) exists between the presence of WT1 and b-catenin mutations such that tumors carrying b-catenin mutations almost invariably also carry WT1 mutations and half of the tumors carrying WT1 mutations also carry b-catenin mutations (Maiti et al, 2000). The b-catenin mutations observed in Wilmstumors, like those identified in other types of cancers, ablate phosphorylation sites and are expected to result in stabilization of b-catenin protein.…”