Decrease in LDL receptor-related protein expression and function correlates with advanced stages of Wilms tumors.

Abstract

BACKGROUND: The molecular processes responsible for the invasive phenotype of pediatric Wilms tumors (WT) are poorly understood. A candidate WT suppressor gene (WT1) has been found mutated in a number of these pediatric kidney tumors. However, the disruption of normal WT1 protein function cannot solely explain WT growth. The aim of the present study is to identify new molecular players that regulate the invasive character of WT. PROCEDURE: Fresh frozen samples from 45 renal tumors of Wilms were obtained from the National Wilms Tumor Study Group's Biological Samples Bank. Gelatin zymography, Western blotting, and immunodetection were used to compare tissue biopsies originating from the infiltrating (stage III), metastatic (stage IV), and anaplastic phenotype of Wilms tumors (WT). RESULTS: The expression of the low-density lipoprotein receptor-related protein (LRP) diminished in stage IV and anaplastic WT. Moreover, the expression of RAP, an LRP intracellular chaperone, was also decreased. The diminished expression of LRP and RAP correlated with increased levels of several known extracellular ligands that LRP usually recycles from the extracellular matrix (ECM) environment, including PAI-1, MMP-9, and TIMP-1. The proteolytic processing of MT1-MMP, a functional regulator of LRP, also correlated with the WT invasive phenotype. CONCLUSIONS: The low expression of LRP, whose function is regulated by MT1-MMP and whose activity in recycling ECM-associated proteolytic enzymes becomes drastically diminished in advanced stages of WT, may in part explain the acquired invasive potential of the developing WT pediatric cancer.