A luminal epithelial stem cell that is a cell of origin for prostate cancer.
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.
Wang
Xi
X
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
M
Economides
Kyriakos D
KD
Walker
David
D
Yu
Hailong
H
Halili
M Vivienne
MV
Hu
Ya-Ping
YP
Price
Sandy M
SM
Abate-Shen
Cory
C
Shen
Michael M
MM
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
D000728:Androgens; D018398:Homeodomain Proteins; C102837:Nkx3-1 protein, mouse; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse