title: Multiple imprinted and stemness genes provide a link between normal and tumor progenitor cells of the developing human kidney.
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.
authors.affiliation: Department of Pediatrics, Chaim Sheba Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. benjamin.dekel@weizmann.ac.il
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dekel
authors.forename: Sally
authors.initials: S
authors.lastname: Metsuyanim
authors.forename: Kai M
authors.initials: KM
authors.lastname: Schmidt-Ott
authors.forename: Edi
authors.initials: E
authors.lastname: Fridman
authors.forename: Jasmin
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Amos
authors.initials: A
authors.lastname: Simon
authors.forename: Jehonathan
authors.initials: J
authors.lastname: Pinthus
authors.forename: Yoram
authors.initials: Y
authors.lastname: Mor
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barasch
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Yair
authors.initials: Y
authors.lastname: Reisner
authors.forename: Naftali
authors.initials: N
authors.lastname: Kaminski
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
mesh_terms: D000818:Animals; D020869:Gene Expression Profiling; D018392:Genomic Imprinting; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D007668:Kidney / Q000196:embryology / Q000254:growth & development; D007680:Kidney Neoplasms / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D005810:Multigene Family; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D014183:Transplantation, Heterologous; D009396:Wilms Tumor / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C000616391:MEIS1 protein, human; C000616392:Meis1 protein, mouse; D000075064:Myeloid Ecotropic Viral Integration Site 1 Protein; D009363:Neoplasm Proteins