title: A luminal epithelial stem cell that is a cell of origin for prostate cancer.
abstract: In epithelial tissues, the lineage relationship between normal progenitor cells and cell type(s) of origin for cancer has been poorly understood. Here we show that a known regulator of prostate epithelial differentiation, the homeobox gene Nkx3-1, marks a stem cell population that functions during prostate regeneration. Genetic lineage-marking demonstrates that rare luminal cells that express Nkx3-1 in the absence of testicular androgens (castration-resistant Nkx3-1-expressing cells, CARNs) are bipotential and can self-renew in vivo, and single-cell transplantation assays show that CARNs can reconstitute prostate ducts in renal grafts. Functional assays of Nkx3-1 mutant mice in serial prostate regeneration suggest that Nkx3-1 is required for stem cell maintenance. Furthermore, targeted deletion of the Pten tumour suppressor gene in CARNs results in rapid carcinoma formation after androgen-mediated regeneration. These observations indicate that CARNs represent a new luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer.
authors.affiliation: Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Marianna
authors.initials: M
authors.lastname: Kruithof-de Julio
authors.forename: Kyriakos D
authors.initials: KD
authors.lastname: Economides
authors.forename: David
authors.initials: D
authors.lastname: Walker
authors.forename: Hailong
authors.initials: H
authors.lastname: Yu
authors.forename: M Vivienne
authors.initials: MV
authors.lastname: Halili
authors.forename: Ya-Ping
authors.initials: YP
authors.lastname: Hu
authors.forename: Sandy M
authors.initials: SM
authors.lastname: Price
authors.forename: Cory
authors.initials: C
authors.lastname: Abate-Shen
authors.forename: Michael M
authors.initials: MM
authors.lastname: Shen
mesh_terms: D000728:Androgens / Q000172:deficiency / Q000378:metabolism; D000818:Animals; D002369:Castration; D002454:Cell Differentiation; D002455:Cell Division; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D005786:Gene Expression Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D051059:PTEN Phosphohydrolase / Q000172:deficiency / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D012038:Regeneration; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000728:Androgens; D018398:Homeodomain Proteins; C102837:Nkx3-1 protein, mouse; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse