The developmental programme for genesis of the entire kidney is recapitulated in Wilms tumour

Abstract

Wilms tumour (WT) is an embryonal tumour that recapitulates kidney development. The normal kidney is formed from two distinct embryological origins: the metanephric mesenchyme (MM) and the ureteric bud (UB). It is generally accepted that WT arises from precursor cells in the MM; however whether UB-equivalent structures participate in tumorigenesis is uncertain. To address the question of the involvement of UB, we assessed 55 Wilms tumours for the molecular features of MM and UB using gene expression profiling, immunohistochemsitry and immunofluorescence. Expression profiling primarily based on the Genitourinary Molecular Anatomy Project data identified molecular signatures of the UB and collecting duct as well as those of the proximal and distal tubules in the triphasic histology group. We performed immunolabeling for fetal kidneys and WTs. We focused on a central epithelial blastema pattern which is the characteristic of triphasic histology characterized by UB-like epithelial structures surrounded by MM and MM-derived epithelial structures, evoking the induction/aggregation phase of the developing kidney. The UB-like epithelial structures and surrounding MM and epithelial structures resembling early glomerular epithelium, proximal and distal tubules showed similar expression patterns to those of the developing kidney. These observations indicate WTs can arise from a precursor cell capable of generating the entire kidney, such as the cells of the intermediate mesoderm from which both the MM and UB are derived. Moreover, this provides an explanation for the variable histological features of mesenchymal to epithelial differentiation seen in WT.

The genetic changes of Wilms tumour

“…It has long been thought that WT arises from the metanpehric mesenchyme, with gene expression correlating with early nephrogenesis (54). Recently, molecular profiles of WT with classic triphasic histology (blastemal, epithelial and stromal elements) have also matched those of the ureteric bud (55). Furthermore, many of the mutated genes found in WT are key regulators of the entire process (Figure 1).…”

Ureteric Bud-derivatives in Wilms Tumor and Nephrogenic Rest

“…A recent global gene expression analysis uncovered genes expressed in distinct compartments of the developing kidney as well as in WT (4). The presence of UB-like epithelial structures in WT has been confirmed by immunohistochemistry (3,4). Recently, we showed that KRT17 expression is restricted to cells of the UB in foetal kidneys and, therefore, it can be used as biomarker to detect UB derivatives (5).…”

Variant profiles of genes mapping to chromosome 16q loss in Wilms tumors reveals link to cilia-related genes and pathways

“…An early stage of this process involves the two-way induction of differentiation induced by the contact of the ureteric bud with the metanephric mesenchyme generating waves of differentiation signals as the bud invades the blastemal mass. During this process the kidney goes through differentiation into primitive stages of a pro-nephros and a meso-nephros which are normally degraded to give rise to the metanephric kidney [ 16 ]. Importantly, cilia have been shown to play an important role in early stages of this process [ 17 ] and ciliary structures can be seen in Wilms tumors reflecting their early stage in developmental arrest [ 18 ].…”