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.2009 Sep 24;461(7263):495-500.
doi: 10.1038/nature08361. Epub 2009 Sep 9.

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

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

Xi Wang et al. Nature..

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.

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Figure 1
Figure 1. Expression ofNkx3.1 in epithelial cells of the intact and regressed anterior prostate
a, Schematic prostate duct in the intact, regressed, and regenerated states. Most luminal cells undergo apoptosis during regression, whereas most basal cells survive; hence, the process of regeneration primarily produces luminal cells.b, Nkx3.1 expression in all luminal cells of the wild-type intact prostate.c, Nkx3.1 expression is mostly absent in regressed prostate, except for rare castration-resistant Nkx3.1-expressing cells (CARNs, arrows.d, Expression of Nkx3.1 in regenerated prostate, showing similarity tob.e, Immunostaining for Nkx3.1 and β-catenin shows clustering of CARNs.f, g, CARNs are strictly luminal, as shown by lack of co-staining for Nkx3.1 (arrows) and p63 (f), and by co-localization of Nkx3.1 (arrows) with cytokeratin 18 (CK18) (g). Scale bars correspond to 25 microns.
Figure 2
Figure 2. Bipotentiality and self-renewal of CARNsin vivo
a, Strategy for lineage-marking experiment.b, Timeline for the experiment.c, YFP does not co-localize with p63 in lineage-marked cells of a castrated and tamoxifen-inducedNkx3.1CreERT2/+; R26R-YFP/+ anterior prostate.d, Clusters of YFP+ cells in a lineage-marked and regenerated prostate.e, Co-localization of YFP and cytokeratin 5 (CK5) in lineage-marked basal cells (arrows) of a regenerated prostate.f, Time-line for self-renewal experiment.g–i, Co-localization of Nkx3.1, YFP, and BrdU immunostaining (arrow) in anterior prostate, shown as an overlay (g) and individual channels (h, i); YFP+BrdU+ neighbors are indicated (arrowheads).j, Strategy for four-round serial regression/regeneration assay of long-term CARNs self-renewal.k, l, Clusters of YFP+ cells in the lineage-marked prostate after four rounds of serial regression/regeneration. Scale bars correspond to 25 microns.
Figure 3
Figure 3. Generation of prostatic ducts in renal grafts by single lineage-marked CARNs
a, Strategy for tissue recombinant/renal graft analyses using a single YFP+ cell (or single YFP− cell as a control).b, c, Hematoxylin-eosin (H&E) staining of prostatic ducts in a graft derived from a single YFP+ cell; note presence of basal cells (arrows) and secretions (c).d, All epithelial cells in single-YFP+ derived duct express YFP, including p63+ basal cells (arrows).e–g, Expression of luminal marker CK18 (e), basal marker p63 (f), and neuroendocrine marker synaptophysin (Syn) (g) in ducts from single YFP+ cells.h, i, Expression of androgen receptor (AR) (h) and Nkx3.1 (i) confirm prostate identity of ducts.j, Summary of single-cell transplantation data. Scale bars ind–f, h, i correspond to 25 microns, inb, c, g to 50 microns.
Figure 4
Figure 4.Nkx3.1 mutants display prostate epithelial defects in a serial regeneration assay
a, Time-line for analysis of label-retaining cells (LRCs).b–d, Overlap of CARNs with LRCs in a serially regressed prostate, shown as an overlay (b) and individual panels (c, d). Arrow inb–d indicates a Nkx3.1+BrdU+ cell; arrowhead in c indicates a CARN that is BrdU−.e, Time-line for serial regression/regeneration analyses.f, g, Decreased number of LRCs (arrows) inNkx3.1−/− anterior prostate (g) relative to wild-type controls (f) after serial regeneration.h, Decreased volume ofNkx3.1−/− anterior prostate relative to wild-type andNkx3.1+/− prostates following serial regeneration, and to intact wild-type andNkx3.1−/− prostates. Error bars correspond to one standard deviation. Scale bars correspond to 25 microns.
Figure 5
Figure 5. The CARNs population contains a cell type of origin for prostate cancer
a, Time-line for inducible conditional deletion ofPten in CARNs.b–e, Hematoxylin-eosin (H&E) staining of anterior prostate from controlNkx3.1CreERT2/+; Pten+/+ (b, d) andNkx3.1CreERT2/+; Ptenflox/flox mice (c, e), shown at low-power (b, c) and high-power (d, e). TheNkx3.1CreERT2/+; Ptenflox/flox prostate contains high-grade PIN/carcinoma lesions with local invasive epithelium (arrows,e).f, g, Detection of p63+ basal cells shows loss of basal cells except at the periphery (arrows,g) of PIN/carcinoma lesions.h, i, Elevated Ki67 immunostaining in PIN/carcinoma lesions.j, k, Phospho-Akt immunostaining with cell membrane localization (arrows,k) in PIN/carcinoma lesions.l, m, Pten immunostaining is ubiquitous in controlNkx3.1CreERT2/+; Pten+/+ prostate epithelium, but is restricted to basal cells and scattered luminal cells in inducedNkx3.1CreERT2/+; Ptenflox/flox prostate. Scale bars correspond to 100 microns.
Figure 6
Figure 6. Possible lineage relationships in the prostate epithelium
a, Independent stem cells for basal and luminal epithelium may give rise to differentiated cell types through multipotent progenitors (MPP) and transit-amplifying progenitors, with some bipotentiality (dashed arrows). In this model, CARNs would correspond to the luminal stem cells.b, Alternatively, stem cells for prostate organogenesis may be basal, but luminal transit-amplifying cells, including CARNs, can acquire stem cell properties during regeneration (red arrows), thus acting as facultative or “potential” stem cells.
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