Mechanisms of epithelial development and neoplasia in the metanephric kidney

Recent studies on the mechanisms of normal epithelial development in the ki dney, and on the aetiology of renal neoplasms, are converging to reveal rem arkably close relationships between the phenotypes and behaviours of normal ly-developing and neoplastic cells. Normal renal epithelia arise from two s ources; those of the collecting duct system develop by arborisation of an i nitially-unbranched ureteric bud, in a manner similar to the development of other glandular organs, while epithelial nephrons develop via an unusual m esenchyme-to-epithelial transition. Both types of development require contr olled proliferation, cell-cell and cell-matrix interactions, protease activ ity etc., but of the two tissues,the development of the nephrons is arguabl y the more complex. It includes many defined stages, signals and checkpoint s that ensure that events happen at the right time, and that processes such as proliferation, apoptosis and differentiation are properly balanced. Det ailed investigation of renal neoplasms has revealed some to be caused by mu tations 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 tyros ine 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 cel l 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 ar e shut off during terminal differentiation. Their reappearance in tumours s uggests that the cells have 'regressed' in an ontogenic sense, and their bi ology may therefore be understood most clearly by reference to the properti es of normal developing cells rather than cells of a mature kidney.