Wilms tumor cells with WT1 mutations have characteristic features of mesenchymal stem cells and express molecular markers of paraxial mesoderm.
Wilms tumors (WTs) are genetically heterogeneous kidney tumors whose cells of origin are unknown. Tumors with WT1 mutations and concomitant loss of the wild-type allele represent a distinct subgroup, frequently associated with mutations in CTNNB1. Here, we describe the establishment and characterization of long-term cell cultures derived from five individual WTs with WT1 mutations. Three of these tumor cell lines also had CTNNB1 mutations and an activated canonical Wnt signaling pathway as measured by beta-catenin/T cell-specific transcription factor (TCF) transcriptional activity. Four of the five Wilms cell lines had a stable normal karyotype for at least 25 passages, and four lines showed loss of heterozygosity of chromosome 11p due to mitotic recombination in 11p11. Gene expression profiling revealed that the WT cell lines are highly similar to human mesenchymal stem cells (MSCs) and FACS analysis demonstrated the expression of MSC-specific surface proteins CD105, CD90 and CD73. The stem cell like nature of the WT cells is further supported by their adipogenic, chondrogenic, osteogenic and myogenic differentiation potentials. By generating multipotent mesenchymal precursors from paraxial mesoderm (PAM) in tissue culture using embryonal stem cells, gene expression profiles of PAM and MSCs were described. Using these published gene sets, we found coexpression of a large number of genes in WT cell lines, PAM and MSCs. Lineage plasticity is indicated by the simultaneous expression of genes from the mesendodermal and neuroectodermal lineages. We conclude that WTs with WT1 mutations have specific traits of PAM, which is the source of kidney stromal cells.
Royer-Pokora
Brigitte
B
Institute of Human Genetics and Anthropology, Heinrich-Heine University, Düsseldorf D-40225, Germany. royer@uni-duesseldorf.de
Busch
Maike
M
Beier
Manfred
M
Duhme
Constanze
C
de Torres
Carmen
C
Mora
Jaume
J
Brandt
Artur
A
Royer
Hans-Dieter
HD
D000595:Amino Acid Sequence; D045744:Cell Line, Tumor / Q000166:cytology*; D019070:Cell Lineage / Q000235:genetics; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016162:Genes, Wilms Tumor; D006801:Humans; D007621:Karyotyping; D007680:Kidney Neoplasms / Q000235:genetics*; D019656:Loss of Heterozygosity; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009396:Wilms Tumor / Q000235:genetics*; D051176:beta Catenin / Q000235:genetics
C495270:CTNNB1 protein, human; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D051176:beta Catenin