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 rapidcarcinomaformationafterandrogen-mediatedregeneration.TheseobservationsindicatethatCARNs representanew luminal stem cell population that is an efficient target for oncogenic transformation in prostate cancer. The prostate represents an excellent system for studying the function and molecular regulation of adult epithelial stem cells in the context of both tissue regeneration and cancer. The prostate epithelium is comprised of three differentiated cell types: luminal secretory cells, basalcellsandneuroendocrinecells(Fig.1a) 1 .Androgen-deprivation leads to rapid apoptosis of approximately 90% of luminal cells and a small percentage of basal cells, although a stable cell number is maintainedintheregressedstate 2,3 .Afterre-administrationofandrogens, the prostate epithelium regenerates over roughly 2weeks 2–4 , and is capable of more than 15 rounds of serial regression/regeneration 5,6 , indicating that the prostate epithelium contains a long-term population of castration-resistant stem cells. Substantial evidence supports the existence of a basal stem cell population in the prostate 7 , consistent with analyses of progenitor cells in other epithelial tissues 8 . In particular, subpopulations of basal cells isolated using cell-surface markers show bipotentiality and self-renewal in explant culture and tissue grafts 9–13 . Furthermore, singleLin 2 Sca-1 1 CD133 1 CD44 1 CD117 1 cells,whicharepredominantly basal in the mouse and exclusively basal in the human, can reconstitute prostatic ducts in renal grafts 14 . However, explants from p63 (also known as Trp63)-null mice can form prostate tissue and undergoseveralroundsofserialregression/regenerationintheabsence of basal cells 15 , suggesting the existence of a distinct luminal stem cell population. Until now, however, luminal stem cells have not been identified in the prostate or other stratified epithelial tissues. Althoughbasalstem/progenitorcellshavebeenproposedtorepresent