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Multiple Imprinted and Stemness Genes Provide a Link between Normal and Tumor Progenitor Cells of the Developing Human Kidney

Departments of ¹ Pediatrics, ² Pathology, ³ Pediatric Hemato-Oncology, and ⁴ Urology, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; ⁵ Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York; ⁶ Department of Immunology, Weizmann Institute of Science, Rehovot, Israel; and ⁷ Simmons Center for Interstitial Lung Disease, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania

Requests for reprints: Benjamin Dekel, Laboratory for Developmental and Regenerative Nephrology, Department of Pediatrics, Safra Children's Hospital, Sheba Medical Center, 52621 Tel Hashomer, Israel. Phone: 972-3-5302517; Fax: 972-3-5305787; E-mail: benjamin.dekel{at}weizmann.ac.il.

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. (Cancer Res 2006; 66(12): 6040-9)

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