p53 accumulation in favorable-histology Wilms tumor is associated with angiogenesis and clinically aggressive disease

Background/Purpose: Unfavorable histology (UH) in Wilms tumor has been linked to malfunction of the p53 tumor suppressor gene, which regulates (1) the endogenous angiogenesis suppressor thrombospondin-1 (TSP-1) and (2) vascular endothelial growth factor (VEGF). The authors hypothesized that clinically aggressive favorable histology Wilms tumor (FH), like UH, but distinct from standard-risk FH disease, would display altered p53/TSP-1 function and upregulated angiogenesis. Methods: Three Wilms tumor specimens manifesting different histology and clinical behavior were obtained: clinically aggressive UH, clinically aggressive FH, and standard-risk FH disease. Xenografts were induced intrarenally in athymic mice. P53, TSP-1, and VEGF status and neovascularity were assessed in tumor tissues. Lungs were evaluated for metastasis. Results: Clinically aggressive FH Wilms tumor displayed progressive alteration in p53/TSP-1 status and upregulation of VEGF. Such alteration was observed in the UH tumor, but was absent from the standard-risk FH tumor. Xenografts from clinically aggressive tumors displayed brisk neoangiogenesis and yielded lung metastases. Conclusions: This is the first report of altered p53/TSP-1 function in association with clinically aggressive behavior in FH Wilms tumor. These characteristics were not observed in parallel studies of a nonaggressive FH tumor. Loss of wild-type p53 function may contribute to disease progression in FH Wilms tumor, in part by upregulation of VEGF.