NEPHROBLASTOMA (WILMS-TUMOR) - A MODEL SYSTEM OF ABERRANT RENAL DEVELOPMENT

Wilms' tumor, or nephroblastoma, is a developmental malignancy of the kidney that affects approximately 1 in 10,000 children between 1 and 6 years of age. Typically, the histology of nephroblastoma reveals a di sorganized renal developmental process showing blastema and epithelia randomly interspersed in varying amounts of stroma. This developmental disruption is associated with the loss of function of the tumor suppr essor gene WT-1. This gene, located on chromosome 11 at band p13, code s for a zinc finger protein that may act as a transcriptional represso r. Familial cases of Wilms' tumor fit Knudson's ''two hit'' model, acc ording to which a germ line mutation of one WT-1 allele predisposes to the tumor while an additional somatic mutation of the other allele ca uses malignant transformation. Originally proposed for retinoblastoma, this model defines the nature of the tumor suppressor gene as a gene that is tumorigenic when inactivated. However, not all Wilms' tumor ca ses fit this model because the majority of Wilms' tumors do not show a mutation of WT-1. For Wilms' tumor, the loss of tumor suppression app ears to be more complex than for retinoblastoma. Some of the mechanism s recognized to date involve dominant negative WT-1 mutations, interac tion of the WT-1 gene product with other mutated transcription factors such as p53, loss of imprinting, and mutations of other tumor suppres sor genes at 11p15 or other loci. Although classic Wilms' tumor is ass ociated with good prognosis (85% survival), its anaplastic form is oft en fatal. Despite the plethora of knowledge gained in recent years, Wi lms' tumor remains the center of attention for further investigation b ecause it offers opportunities for studying normal kidney development, for understanding the molecular basis for clinically important anapla stic forms, as well as for elucidating the molecular mechanisms of tum or suppressor genes. To facilitate this task, Wilms' tumor heterotrans plants have been established in nude mice. This provides an indefinite source of tumor tissue and a means to test their growth properties in response to drug treatments or molecular genetic manipulations. Furth ermore, the establishment of stable Wilms' tumor cell lines is essenti al to investigating further the molecular basis of tumorigenesis using recombinant DNA technology. Copyright (C) 1994 by W.B. Saunders Compa ny