Embryonális eredetű vesetumorok molekuláris pathologiája

Abstract

In 1882 Cohnheim postulated that “ein Fehler, eine Unregelmässigkeit der embryonalen Anlage ist, in der die eigentliche Ursache der späteren Geschwulst gesucht werden muss”, e.g. an error and impaired regulation in embryonic „Anlage“ may later lead to tumor development. „Aber was wir als angeboren verlangen, ist ja nicht die Geschwulst, sondern lediglich die Anlage dazu, d.h. nach der von uns proponirten Formulirung die Existenz desjenigen über das physiologische Maass hinaus producirten Zellenquantum, aus dem eine Geschwulst sich entwickeln kann“ e.g. we expect the new-born to bring not the tumor itself, but merely the superabundant cell material into the world, from the latter a tumor may develop. The development of kidney underlies a complex molecular genetic process involving several signal transduction pathways. The temporary and spatial expression of genes, the changing gradient of proteins within the emerging structures control the differentiation of approximately 25 functionally and morphologically distinct cells of the nephron and the stroma. Termination of nephrogenesis and differentiation of specialized cell types along the nephron is a well-coordinated molecular process. Taking into account the finely tuned relationship between growth- and differentiation controlling signals, changes (e.g. mutation or altered gene dosage of any genes involved) may disturb the balance and favor cell proliferation and inhibit the terminal differentiation. To produce the appropriate number of cells for development of approximately 200 thousand to 2 million nephron, cells in the renewing blastemal niche undergo a forced mitotic activity resulting in variable level of errors, e.g. in an embryonal genetic noise. The disturbance of embryonal differentiation may lead to inborn developmental syndromes such as CAKUT (congenital anomalies of the kidney and urinary tract). In this relation might be interesting to notice that 40% of renal functional failure in childhood is associated with CAKUT. It is not surprising that several differentiation error is associated with pre-neoplastic lesions and tumors. Wilms' tumor (WT) has already been recognized as a useful model to explore tumor development from “not differentiated superabundant” embryonic rest cells, e.g. nephrogenic rests (NR) as proposed by Cohnheim in 1882. Molecular genetic studies confirmed the connection between WT and impaired differentiation during kidney development. Several genes which are expressed spatially and temporally during early nephrogenesis, especially during the mesenchyme to epithelium transition (MET), have already been implicated in the molecular biology of WT.