Gene Expression in Wilms’ Tumor Mimics the Earliest Committed Stage in the Metanephric Mesenchymal-Epithelial Transition

Abstract

Wilms' tumor (WT) has been considered a prototype for arrested cellular differentiation in cancer, but previous studies have relied on selected markers. We have now performed an unbiased survey of gene expression in WTs using oligonucleotide microarrays. Statistical criteria identified 357 genes as differentially expressed between WTs and fetal kidneys. This set contained 124 matches to genes on a microarray used by Stuart and colleagues (Stuart RO, Bush KT, Nigam SK: Changes in global gene expression patterns during development and maturation of the rat kidney. Proc Natl Acad Sci USA 2001, 98:5649-5654) to establish genes with stage-specific expression in the developing rat kidney. Mapping between the two data sets showed that WTs systematically overexpressed genes corresponding to the earliest stage of metanephric development, and underexpressed genes corresponding to later stages. Automated clustering identified a smaller group of 27 genes that were highly expressed in WTs compared to fetal kidney and heterologous tumor and normal tissues. This signature set was enriched in genes encoding transcription factors. Four of these, PAX2, EYA1, HBF2, and HOXA11, are essential for cell survival and proliferation in early metanephric development, whereas others, including SIX1, MOX1, and SALL2, are predicted to act at this stage. SIX1 and SALL2 proteins were expressed in the condensing mesenchyme in normal human fetal kidneys, but were absent (SIX1) or reduced (SALL2) in cells at other developmental stages. These data imply that the blastema in WTs has progressed to the committed stage in the mesenchymal-epithelial transition, where it is partially arrested in differentiation. The WT-signature set also contained the Wnt receptor FZD7, the tumor antigen PRAME, the imprinted gene NNAT and the metastasis-associated transcription factor E1AF.

Wnt5a Signaling Induces Proliferation and Survival of Endothelial Cells In Vitro and Expression of MMP-1 and Tie-2

“…Hu95Av2 GeneChips were purchased from Affymetrix (Santa Clara, CA). Microarray and probes were prepared and used as described before (Li et al, 2002), with three different samples per overexpressed gene. To analyze the GeneChip data from the Wnt5a, Wnt1, and LacZ control cells, we used the GeneSpring software package (Agilent Technologies, Wilmington, DE), first filtering to obtain all genes (Affymetrix probe sets) with Affymetrix presence calls in at least three experimental samples, then further filtering to obtain all genes with expression at least 1.5-fold greater than the experiment mean in at least two samples, and lastly carrying out ANOVA with a p value cutoff of 0.01 to find all genes that differed in their mRNA expression as a function of experimental condition (Wnt5a vs.…”

Targeted therapy aimed at cancer stem cells: Wilms’ tumor as an example

“…In fact, WT research has already provided significant information regarding the genetic and epigenetic events leading to the development of pediatric tumors. Specifically, global gene and chromatin analysis comparing WT to the renal progenitor pool of the developing human kidney has linked early renal stem/progenitor genes to WT oncogenesis [4][5][6][7][8][9][10].…”

Cell cycle regulation of the human Six1 homeoprotein is mediated by APCCdh1

“…(Li et al, 2003;Zheng et al, 2003;Ozaki et al, 2004). Gene amplification and overexpression of Six1 is observed in human cancers, where it confers developmental properties on adult cells leading to an increase in both proliferation and metastasis (Li et al, 2002;Coletta et al, 2004;Reichenberger et al, 2005;Yu et al, 2006). The pro-proliferative role of Six1 has been documented in both breast cancer and in rhabdomyosarcoma, although it has been most rigorously examined in breast cancer cells where it plays a role in entrance into and progression through S phase and in the G 2 cell cycle checkpoint (Ford et al, 1998;Coletta et al, 2004;Yu et al, 2006).…”