Molecular Profiling of Isolated Histological Components of Wilms Tumor Implicates a Common Role for the Wnt Signaling Pathway in Kidney and Tumor Development

Abstract

Wilms tumor (WT), a tumor composed of three histological components – blastema (BL), epithelia and stroma – is considered an appropriate model system to study the biological relationship between differentiation and tumorigenesis. To investigate molecular associations between nephrogenesis and WT, the gene expression pattern of individual cellular components was analyzed, using a customized platform containing 4,608 genes. WT gene expression patterns were compared to genes regulated during kidney differentiation. BL had a closer gene expression pattern to the earliest stage of normal renal development. The BL gene expression pattern was compared to that of fetal kidney (FK) and also between FK and mature kidney, identifying 25 common deregulated genes supposedly involved in the earliest events of WT onset. Quantitative RT-PCR was performed, confirming the difference in expression levels for 13 of 16 genes (81.2%) in the initial set and 8 of 13 (61.5%) in an independent set of samples. An overrepresentation of genes belonging to the Wnt signaling pathway was identified, namely PLCG2, ROCK2 and adenomatous polyposis coli (APC). Activation of the Wnt pathway was confirmed in WT, using APC at protein level and PLCG2 at mRNA and protein level. APC showed positive nuclear immunostaining for an independent set of WT samples, similarly to the FK in week 11. Lack of PLCG2 expression was confirmed in WT and in FK until week 18. Taken together, these results provided molecular evidence of the recapitulation of the embryonic kidney by WT as well as involvement of the Wnt pathway in the earliest events of WT onset.

Recurrent somatic mutation in DROSHA induces microRNA profile changes in Wilms tumour

“…We and others have demonstrated that nephrogenesis and Wilms tumorigenesis share gene expression regulation patterns32333435. Furthermore, repression of miRNA maturation through inhibition of DROSHA and DICER1 expression impairs accurate kidney differentiation363738 and promotes tumorigenesis in several cell lines39.…”

The genetic and epigenetic landscapes of hepatoblastomas

“…Although the etiology of embryonal tumors has not been fully clarified, evidence supports the hypothesis of failure in the normal process of differentiation during fetal or postnatal development [3,24]. Several studies have investigated the role of environmental factors during pregnancy that could be causally related to HB development [5], including pre-eclampsia [25], maternal overweight condition during pregnancy [26,27], and treatment for infertility [26].…”

Temporal blastemal cell gene expression analysis in the kidney reveals new Wnt and related signaling pathway genes to be essential for Wilms' tumor onset

“…4, 5 More recently, we have provided evidence that, among the three histological WT components, blastemal cells display a gene expression profile similar to that found in the initial stages of nephrogenesis, suggesting that the blastemal component, and not the whole tumor, preserves the molecular events involved in WT onset. 6 …”