Nuclear accumulation of beta-catenin protein in Wilms' tumours.
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.
Koesters
Robert
R
Division of Molecular Pathology, Department of Pathology, University Hospital of Heidelberg, Heidelberg, Germany. r.koesters@dkfz.de
Niggli
Felix
F
von Knebel Doeberitz
Magnus
M
Stallmach
Thomas
T
D000293:Adolescent; D002462:Cell Membrane / Q000378:metabolism; D002467:Cell Nucleus; D002648:Child; D002675:Child, Preschool; D003593:Cytoplasm / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000032:analysis* / Q000235:genetics; D005260:Female; D016162:Genes, Wilms Tumor; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007223:Infant; D007668:Kidney / Q000378:metabolism*; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA / Q000379:methods; D015534:Trans-Activators / Q000032:analysis* / Q000235:genetics; D009396:Wilms Tumor / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin