Temporal Analysis Of Kidney Differentiation And Wilms Tumor Revealed Conserved Transcriptional Mechanisms And Pointed Genes Putatively Determinant For Tumor Onset

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Conserved mechanisms between organ differentiation and tumorigenesis may reveal early events in tumor onset. Wilms tumor (WT) originates from metanephric blastema cells, which were unable to complete the differentiation process, resulting in a tumor composed by three histological components, blastema, epithelia and stroma. We previously demonstrated that blastemal component presents molecular characteristics highly similar to the earliest stages of kidney development, suggesting that it retains the key molecular events responsible for WT onset. In this study, aiming to identify early molecular factors potentially involved in WT arising, expression of 326 genes belonging to transduction signaling pathways was evaluated in cells of the metanephric blastema in four temporal kidney differentiation stages in mice (from 15.5 days post-coitum to the fully differentiated kidney), and in blastemal cells of WT and human differentiated kidneys. To evaluate nephrogenesis in mouse and WT in human, we developed a model that allows the hybridization of target molecules of both species in the same cDNA microarray platform. Expression behavior of 18 genes in the earliest stage of kidney differentiation were recapitulated by WT, where 11 were down-regulated in WT and reported an increasing expression during nephrogenesis and 7 were up-regulated in WT and presented a decreasing expression during nephrogenesis. Non-supervised hierarchical clustering based on the expression of 18 genes grouped differentiated kidneys from human and mouse, and discriminated both from WT samples, which were grouped with the earliest kidney stages, validating the model proposed by this study. Independent groups of samples were used for validation at mRNA and protein levels. mRNA expression were confirmed by quantitative RT-PCR in 5 out of 9 genes (55.6%) in an independent group containing 35 WT samples, where CRABP2, IGF2, PAX2 and WNT5B were up and TIMP2 was down regulated in WT. Additionally, intensity labeling of protein codified by 8 genes was evaluated by immunohistochemistry in 145 blastemal components of WT and 5 proteins (62.5%) showed concordant data with mRNA levels. CRABP2, GRK7, IGF2, HDGF and TESK1 were up-regulated in blastemal component of WT. As far as we know, WNT5B, FZD2, GRK7, TESK1 and TIMP3 were associated to WT for the first time. As the deregulation of these genes in blastemal component is probably an early event involved in WT onset and may be present in the most tumor cells, these genes are good candidates to be tested as therapeutic targets. Supported by FAPESP. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3427.