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Multiple imprinted and stemness genes provide a link between normal and tumor progenitor cells of the developing human kidney

Item Type:Article
Title:Multiple imprinted and stemness genes provide a link between normal and tumor progenitor cells of the developing human kidney
Creators Name:Dekel, B. and Metsuyanim, S. and Schmidt-Ott, K.M. and Fridman, E. and Jacob-Hirsch, J. and Simon, A. and Pinthus, J. and Mor, Y. and Barasch, J. and Amariglio, N. and Reisner, Y.
Abstract:Wilms' tumor (WT), the embryonic kidney malignancy, is suggested to evolve from a progenitor cell population of uninduced metanephric blastema, which typically gives rise to nephrons. However, apart from blastema, WT specimens frequently contain cells that have differentiated into renal tubular or stromal phenotypes, complicating their analysis. We aimed to define tumor-progenitor genes that function in normal kidney development using WT xenografts (WISH-WT), in which the blastema accumulates with serial passages at the expense of differentiated cells. Herein, we did transcriptional profiling using oligonucleotide microarrays of WISH-WT, WT source, human fetal and adult kidneys, and primary and metastatic renal cell carcinoma. Among the most significantly up-regulated genes in WISH-WT, we identified a surprising number of paternally expressed genes (PEG1/MEST, PEG3, PEG5/NNAT, PEG10, IGF2, and DLK1), as well as Meis homeobox genes [myeloid ecotropic viral integration site 1 homologue 1 (MEIS1) and MEIS2], which suppress cell differentiation and maintain self-renewal. A comparison between independent WISH-WT and WT samples by real-time PCR showed most of these genes to be highly overexpressed in the xenografts. Concomitantly, they were significantly induced in human fetal kidneys, strictly developmentally regulated throughout mouse nephrogenesis and overexpressed in the normal rat metanephric blastema. Furthermore, in vitro differentiation of the uninduced blastema leads to rapid down-regulation of PEG3, DLK1, and MEIS1. Interestingly, ischemic/reperfusion injury to adult mouse kidneys reinduced the expression of PEG3, PEG10, DLK1, and MEIS1, hence simulating embryogenesis. Thus, multiple imprinted and stemness genes that function to expand the renal progenitor cell population may lead to evolution and maintenance of WT.
Keywords:Gene Expression Profiling, Genomic Imprinting, Homeodomain Proteins, Kidney, Kidney Neoplasms, Inbred BALB C Mice, Nude Mice, SCID Mice, Multigene Family, Neoplasm Proteins, Neoplasm Transplantation, Neoplastic Stem Cells, Oligonucleotide Array Sequence Analysis, Heterologous Transplantation, Wilms Tumor, Animals, Mice, Rats
Source:Cancer Research
Publisher:American Association for Cancer Research
Page Range:6040-6049
Date:15 June 2006
Official Publication:https://doi.org/10.1158/0008-5472.CAN-05-4528
PubMed:View item in PubMed

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