Pediatric tumors provide some of the most compelling examples of development gone awry and are unique in that this aberrant development results from a clear interplay of both familial and environmental factors. Of these, Wilms~ tumor, the predominant solid tumor of childhood, caricatures normal renal development, an observation consistent with the subversion of differentiation-inducing molecules in tumorigenesis. To focus on those molecules, which have remained elusive despite some 40 years of scrutiny, we have devised tissue culture models that permit the characterization of factors critical to normal renal development. Recently, we established that basic fibroblast growth factor (bFGF) can mediate the early morphogenic events in tubulogenesis: the condensation of mesenchyme and upregulation of early markers of condensation, including Wt1, met, and now wnt-4. Furthermore, we have found thataddition of a heparin-binding factor from pituitary extract in combination with bFGF induces epithelia with markers appropriate for renal tubules, including Wt1, met, wnt-4, and the transcription factor lim-1. We are attempting to identify this factor. In addition, we found that unbranched buds could be induced to branch in a defined medium in the absence of mesenchyme. We have now established that a combination of growth factors, which are expressed in mesenchyme, mediate this process and have implicated hepatocyte growth factor, an FGF family member, and transforming growth factor-alpha. We also have evidence that some of the same factors required for bud growth are produced by renal mesenchymal tumors, which caricature renal stroma in the developing kidney, and that these factors may participate in the pathogenesis of these tumors. Thus, we have demonstrated that soluble factors can mediate both tubulogenesis of metanephric mesenchyme and branching morphogenesis of ureteric bud and in so doing have developed methods for individually evaluating these processes. As a result, we can now effectively establish which factors expressed in developing renal tissues actually mediate the various molecular events in renal differentiation. As factors are identified, we will apply this information to our study of renal tumorigenesis.
