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PMID: 19741607 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, U.S. Gov't, Non-P.H.S.

A luminal epithelial stem cell that is a cell of origin for prostate cancer.

Nature ·Vol. 461 ·No. 7263 ·2009-09-24 ·Pages 495-500

Wang X, Kruithof-de Julio M, Economides KD, Walker D, Yu H, Halili MV, Hu YP, Price SM, Abate-Shen C, Shen MM

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.

MeSH Terms
Androgens/deficiency,metabolism Animals Castration Cell Differentiation Cell Division Cell Lineage Cell Transformation, Neoplastic Epithelial Cells/metabolism,pathology,transplantation Gene Expression Regulation Homeodomain Proteins/genetics,metabolism Kidney Male Mice Mice, Inbred C57BL Mice, Nude Neoplastic Stem Cells/metabolism,pathology,transplantation PTEN Phosphohydrolase/deficiency,genetics Prostatic Neoplasms/genetics,metabolism,pathology Regeneration Transcription Factors/genetics,metabolism
Chemicals
Androgens Homeodomain Proteins Nkx3-1 protein, mouse Transcription Factors PTEN Phosphohydrolase Pten protein, mouse
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Wang Xi
Department of Medicine, Herbert Irving Comprehensive Cancer Center, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
Kruithof-de Julio Marianna
Economides Kyriakos D
Walker David
Yu Hailong
Halili M Vivienne
Hu Ya-Ping
Price Sandy M
Abate-Shen Cory
Shen Michael M
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature08361
Published
2009-09-24
Epub
2009-00-09
Pages
495-500
Language
English
Region
England
NLM ID
0410462
PMCID
PMC2800362
Subset
IM
Grants
NCI NIH HHS · U01 CA084294-10 · United States
NCI NIH HHS · U01 CA084294 · United States
NIDDK NIH HHS · R01 DK076602-05 · United States
NIDDK NIH HHS · R01 DK076602 · United States
NCI NIH HHS · P01 CA154293 · United States
External Links
PubMed source DOI: 10.1038/nature08361 PMC Full Text View journal details
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