transforming-growth-factor-alpha and Wilms-Tumor

Recent studies on the mechanisms of normal epithelial development in the kidney, and on the aetiology of renal neoplasms, are converging to reveal remarkably close relationships between the phenotypes and behaviours of normally-developing and neoplastic cells. Normal renal epithelia arise from two sources; those of the collecting duct system develop by arborisation of an initially-unbranched ureteric bud, in a manner similar to the development of other glandular organs, while epithelial nephrons develop via an unusual mesenchyme-to-epithelial transition. Both types of development require controlled proliferation, cell-cell and cell-matrix interactions, protease activity etc., but of the two tissues, the development of the nephrons is arguably the more complex. It includes many defined stages, signals and checkpoints that ensure that events happen at the right time, and that processes such as proliferation, apoptosis and differentiation are properly balanced. Detailed investigation of renal neoplasms has revealed some to be caused by mutations in molecules with known roles in normal nephrogenesis (e.g. Wilms' tumour and the WT-1 gene, renal cell carcinoma and the c-met receptor tyrosine kinase gene), some to be caused by mutations in genes expressed during normal development (e.g. renal cell carcinoma and the TSC-2 gene, renal cell carcinoma of the clear cell variety and the VHL gene). Furthermore, these and other tumours of unknown aetiology re-express genes such as Pax-2 that are expressed during the normal mesenchyme-to-epithelium transition but are shut off during terminal differentiation. Their re-appearance in tumours suggests that the cells have 'regressed' in an ontogenic sense, and their biology may therefore be understood most clearly by reference to the properties of normal developing cells rather than cells of a mature kidney.

Topics: Animals; Carcinoma, Renal Cell; DNA-Binding Proteins; Genes, Tumor Suppressor; Humans; Kidney; Kidney Neoplasms; Nephrons; Nuclear Proteins; Paired Box Transcription Factors; PAX2 Transcription Factor; PAX8 Transcription Factor; Repressor Proteins; Trans-Activators; Transcription Factors; Transforming Growth Factor alpha; Tuberous Sclerosis Complex 2 Protein; Tumor Suppressor Proteins; Urothelium; von Hippel-Lindau Disease; Wilms Tumor

This study reevaluates the potential role of different tumour markers as prognostic indicators in untreated nephroblastoma.. Expression of a broad panel of tumour markers was investigated by means of immunohistochemical analysis in 43 WT patients. Patients were treated by radical nephrectomy and had a mean follow-up of 11.9 years.. Generally, all the tumour markers studied were expressed in normal kidney tissue and at variable levels in the three cell types of WT (blastema, epithelium and stroma). Immunoreactive blastemal (Bcl-X, Bcl-2 and CD44s) and epithelial (Bcl-X, Bcl-2 and MIB-1) cells were present in the majority of tumours. No correlation was found between their expression and pathological stages. Univariate analysis showed that blastemal WT-1, TGF-α, VEGF, MIB-1 and p27 Kip1 were indicative for clinical progression. In a multivariate analysis, WT-1 protein expression by blastemal cells was an independent prognostic marker for clinical progression.. The blastemal WT-1, TGF-α, VEGF, MIB-1 and p27Kip1 expression correlate with clinical progression in untreated nephroblastoma. Therefore, their expression may be of value in identifying patients with a high propensity to develop distant metastases.

Topics: Adolescent; Biomarkers, Tumor; Cyclin-Dependent Kinase Inhibitor p27; Disease Progression; Female; Follow-Up Studies; Humans; Immunohistochemistry; Kidney Neoplasms; Male; Nephrectomy; Predictive Value of Tests; Prognosis; Transforming Growth Factor alpha; Treatment Outcome; Ubiquitin-Protein Ligases; Vascular Endothelial Growth Factor A; Wilms Tumor; WT1 Proteins