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

Benjamin Dekel*, Sally Metsuyanim, Kai M. Schmidt-Ott, Edi Fridman, Jasmin Jacob-Hirsch, Amos Simon, Jehonathan Pinthus, Yoram Mor, Jonathan Barasch, Ninette Amariglio, Yair Reisner, Naftali Kaminski, Gideon Rechavi

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

118 Scopus citations

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, PEGS, 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 PEGS, DLK1, and MEIS1. Interestingly, ischemic/reperfusion injury to adult mouse kidneys reinduced the expression of PEGS, PEG10, DLK1, and MEIS1, hence simulating embryogenesis. Thus, multiple imprinted and sternness genes that function to expand the renal progenitor cell population may lead to evolution and maintenance of WT.

Original languageEnglish
Pages (from-to)6040-6049
Number of pages10
JournalCancer Research
Volume66
Issue number12
DOIs
StatePublished - 15 Jun 2006

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