Search tips
Search criteria 


Logo of ccLink to Publisher's site
Cell Cycle. 2013 February 15; 12(4): 579–586.
PMCID: PMC3594258

New insights into prostate cancer stem cells

Xin Chen, 1 Kiera Rycaj, 1 Xin Liu, 1 , 2 and Dean G. Tang 1 , 3 , 4 ,*


Prostate cancer (PCa) remains one of the most prevalent malignancies affecting men in the western world. The etiology for PCa development and molecular mechanisms underlying castration-resistant progression are incompletely understood. Emerging evidence from many tumor systems has shown the existence of distinct subpopulations of stem like-cancer cells termed cancer stem cells (CSCs), which may be involved in tumor initiation, progression, metastasis and therapy resistance. Prostate cancer stem cells (PCSCs) have also been identified using different experimental strategies in distinct model systems. In this brief review, we summarize our current knowledge of normal prostate stem/progenitor cells, highlight recent progress on PCSCs, expound on the potential cell-of-origin for PCa and discuss the involvement of PCSCs in PCa progression and castration resistance. Elucidation of the phenotypic and functional properties and molecular regulation of PCSCs will help us better understand PCa biology and may lead to development of novel therapeutics targeting castration-resistant PCa cells.

Keywords: prostate cancer, cancer stem cells, prostate cancer stem cells, differentiation, therapy resistance


Prostate cancer (PCa) is one of the most commonly diagnosed cancers affecting men in the western world,1 with an estimated 241,740 new cases and 28,170 cancer-related deaths in the United States in 2012.2 PCa is a multifocal disease, and its clinical progression is closely related to aging.1 PCa develops over a long period of time from normal prostate to prostatic intraepithelial neoplasia (PIN) then to early- and late-stage PCa and finally to metastatic PCa.3 Localized early-stage PCa can be well treated by radical prostatectomy with good prognosis.4,5 By contrast, advanced PCa is mainly treated with androgen-deprivation therapy (ADT), but most cases will eventually fail ADT, recur and result in a lethal disease termed “castration resistant prostate cancer (CRPC).”1,4-7 Both primary PCa and CRPC can metastasize to many different organs, including the bone, lung, liver, etc., and once metastasis occurs the disease becomes incurable.5 Despite a great deal of progress made in clinical treatments as well as in basic research on PCa in the past decades, the underlying mechanisms of PCa development, progression, recurrence and metastasis are incompletely understood.1,6

Like many other cancer types, PCa is heterogeneous with respect to both histo-structures and cellular composition. For example, although most localized, early-stage PCa are mainly composed of differentiated glandular structures in which cells are positive for prostate-specific antigen (PSA) and androgen receptor (AR), poorly differentiated or undifferentiated areas can also be detected where cells are largely negative for PSA and AR expression. On the other hand, advanced PCa mainly consist of poorly differentiated or undifferentiated areas, but differentiated regions can also be seen.8-10 The heterogeneous expression patterns of PSA and AR in PCa cells imply the existence of distinct cell subpopulations, i.e., PSA+AR+, PSA+AR-, PSA-AR+ and PSA-AR-.8 A recent study analyzed the Docetaxel-tolerant phenotype in both untreated primary human PCa (HPCa) and metastatic samples, and found that all tumors contained two subpopulation of PCa cells, i.e., cytokeratin (CK) 18+/19+ and CK18-/CK19- cells.11

Tumor cell heterogeneity can be explained by two models: the clonal evolution (stochastic) model and the cancer stem cell (hierarchical) model. The two models may not necessarily be mutually exclusive.12-14 The clonal evolution model postulates that genetic and epigenetic alterations in some cancer cells confer a growth/survival advantage resulting in a dominant clone, and all tumor cells in the clone have similar tumor-initiating capacities.12,15,16 In comparison, recent evidence suggests that cancers cells in many human tumors are organized hierarchically, and only a subset of the cancer cells is endowed with tumor-initiating and long-term tumor-propagating activity. These tumor-initiating cells possess many phenotypic and functional properties associated with normal stem cells (SCs) and thus are often termed cancer stem cells (CSCs). CSCs have been proposed to be responsible for tumor initiation, progression, metastasis and treatment resistance.12-14,17-22 The first direct evidence of CSCs came from seminal work by Dick and his colleagues in the 1990s.23,24 Since then, CSC have been reported in many solid tumors, including cancers of the breast,25-27 colon,28-30 brain,31-33 prostate,8,11,34-55 pancreas,56 lung57,58 and liver.59,60 The revived studies on CSCs have generated novel insights on our understanding of the etiology and mechanisms of cancers and shed new light on developing therapeutics targeting the population of cancer cells that is largely refractory to the current standard-of-care therapies. In this brief review, we summarize our current knowledge of normal prostate stem/progenitor cells, highlight recent progress on prostate CSCs (PCSCs), expound on the cell-of-origin for PCa and PCSCs and discuss the potential involvement of PCSCs in PCa progression, castration resistance and distant metastasis.

Normal Prostate Stem/Progenitor Cells

Both human and mouse prostatic glands contain three distinct, differentiated epithelial cells: basal, luminal and neuroendocrine cells.1,61 Basal cells are localized in the basal layer above the basement membrane and express markers such as CK5, CK14, CD44, CD133, p63, Bcl-2 and low levels of AR. Luminal cells sit above the basal layer, secrete prostatic proteins and express markers such as CK8, CK18, CK19, PSA, prostatic acid phosphatase (PAP), CD57 and high levels of AR. Neuroendocrine cells are rare, and are positive for synaptophaysin and chromogranin A.1,61 Newly emerged evidence reveals that epigenetic modifications may be involved in prostate tissue differentiation. For instance, the levels of 5-hydroxymethylcytosine seem to be more abundant in normal human prostate luminal cells, compared with the low levels in basal cells.62 This finding suggests the potential use of certain epigenetic modification(s) as a marker for prostate luminal cell differentiation.

SCs are defined as cells that have both self-renewal and multi-lineage differentiation abilities.20 Among the various ways to functionally characterize SCs, transplantation and lineage tracing are the most popular approaches.13,63 Transplantation assays use florescence-activated cell sorting (FACS) to isolate candidate SCs via cell surface markers, followed by functional characterization of SC properties in a xenograft, syngeneic or allogeneic model to see whether these cells have the ability to reconstitute tissues/organs from which they are derived. Transplantation assays tend to over-estimate the frequency of SCs. It is also unclear if the transplantation-based assay accurately mimics the natural regeneration process of the SCs in the orthotopic site. Finally, this method induces trauma in the recipient mice and leads to a wound-healing response, which may compound data interpretation. By comparison, lineage tracing is utilized to characterize SC development and properties in vivo by using a stem cell-specific Cre reporter line in the tissue of interest. Limitations of this approach include choice of promoters, specificity and sensitivity of promoters, incomplete tracing of cell lineages due to variability of promoter strength and the uncertainty of its relevance to humans. In addition to transplantation and lineage-tracing approaches, the label-retaining strategy is used to enrich SCs based on their slow-cycling and quiescent traits.64 Moreover, side population (SP) and ALDEFLUOR assays have been widely employed to enrich SCs by virtue of the heightened detoxification capacities in the SCs.65,66

Normal adult murine prostate regresses after castration with more than 90% of luminal cells and a small population of basal cells undergoing apoptosis. However, the prostate returns to normal size when androgen is restored,63,67 and such regression-regeneration manipulations can be repeated for multiple cycles, providing indirect early evidence for the presence of prostate SCs (PSCs) that may resist castration. Many recent studies, by employing the above-mentioned approaches, have provided more direct evidence for murine PSCs. In tissue recombination assays, a PSC-containing cell population is isolated by cell surface markers and combined with embryonic urogenital mesenchyme (UGM). The cell mix is then transplanted to the kidney capsule of recipient mice to test if the candidate PSCs can form new prostatic ducts.68 For instance, Sca-1+ prostatic basal cells are quiescent and positive for integrin α6 (CD49f) and Bcl-2 and possess a higher capacity to regenerate prostatic gland-like structures compared with the corresponding Sca-1- cells.69,70 Prospectively purified Lin-Sca-1+CD49f+ basal cells (LSCs) can establish spheres and colonies in vitro as well as regenerate prostatic ducts in renal grafts,71 and murine PSCs could be further enriched by sorting for Trop2hi LSC cells.72 A recent study shows that single Lin-Sca-1+CD133+CD44+CD117+ prostatic cells are capable of reconstituting a prostate in the kidney capsule of recipient mice, and CD117 is preferentially expressed in murine prostatic basal cells and exclusively in human prostate basal cells.73 Early studies in Wilson’s lab demonstrated that slow-cycling (label-retaining) PSCs were localized mostly in the basal layer of the proximal prostate tubules, and that the relative quiescence of the murine PSCs was maintained by TGFβ produced from the stroma.74 In support, a recent study in animal models shows that the dormancy of adult murine PSCs is likely to be mediated by a positive reciprocal regulatory loop formed from Notch and TGFβ signaling pathways.75

Using lineage tracing with different promoters, several studies have generated evidence that the prostate stem/progenitor cells with regenerative activity may also be localized in the luminal layer. For example, Wang et al. used an Nkx3.1-Cre mouse line to identify a small subset of luminal cells that survive castration (thus called CARNs for castration-resistant Nkx3.1-expressing cells), can self-renew in vivo and regenerate a prostate in renal grafts.76 Choi et al. showed that there exist lineage-restricted unipotent prostate progenitor cells in both basal and luminal layers.77 Liu et al. conducted lineage tracing in their PSA-CreER(T2) mouse model to show that luminal cells can survive, proliferate and regenerate during cycles of regression and regeneration.78 Finally, Ousset et al. demonstrated that there are multipotent stem cells in the basal layer that can differentiate into all epithelial prostate cells (basal, luminal and neuroendocrine cells) as well as unipotent basal and luminal progenitors, which together contribute to the prostate postnatal development.79

The PSCs in humans are mainly inferred from correlative and in vitro experiments and all seem to have a basal origin. These include cells that express high levels of integrin α2β1,80 CD133,81 ABCG237 and Trop2.72 Using marker-independent methods, Garraway et al. have shown that a small population of human prostate cells is able to generate prostaspheres bearing a basal phenotype (CD44+CD49f+CK5+p63+Trop2+CK8-AR-PSA-), and these sphere-forming cells are capable of inducing prostatic gland structures in vivo.82


A CSC is defined as a cell within a tumor that is endowed with unlimited self-renewal ability and can also regenerate non/low tumorigenic progeny.13,14,20,21 The “gold” standard to characterize CSC activities is to examine whether a candidate CSC-containing cell population has the ability to initiate serially transplantable tumors in immunodeficient mice that histopathologically resemble the parental tumor.17 Most CSC studies have employed similar experimental strategies that are used to enrich normal SCs,13,14,18,21 including transplantation assays using FACS-sorted cells via cell surface markers,23-25 SP34 and ALDEFLUOR assays83 as well as lineage-tracing studies.84-86

Several populations of PCSCs have been reported.8,11,34-55 For example, the CD44+α2β1+CD133+ HPCa cells are highly clonogenic and seem to have certain CSC properties.38 In long-term cultured PCa cell lines (e.g., Du145) and xenograft models (i.e., LAPC9, LAPC4), the CD44+ PCa cells preferentially express “stemness” genes, are largely quiescent and more tumorigenic and metastatic than the isogenic CD44- PCa cells.35 Follow-up studies reveal that the CD44+α2β1+ PCa cell population in the LAPC9 model is further enriched in PCSCs.36 Other PCSCs have been uncovered via different cell surface markers such as CD133,43,87 CXCR443,54 and TRA-1-60/CD151/CD166.49

Marker-independent approaches have also been employed to enrich PCSCs. For instance, SP cells are much more tumorigenic (> 100-fold) than non-SP cells in the LAPC9 model.34 ALDH+ PCa cells possess high tumorigenic and metastatic potential.47,48 A recent study has shown that HPCa samples contain cells capable of establishing serially passagable prostaspheres, which bear the phenotype of CD49b+CD49f+CD44+DeltaNp63+Nestin+CD133+.46 PCa cell holoclones harbor long-term self-renewing CSCs in contrast to cells in either meroclones or paraclones.42 Using a lentiviral reporter system in long-term PCa cell lines (e.g., LNCaP), xenograft models (e.g., LAPC9, LAPC4) and primary HPCa samples, we have recently shown that the less differentiated PCa cell population expressing little differentiation marker PSA (i.e., PSA-/lo) harbors long-term self-renewing PCSCs that resist castration.8 Compared with the isogenic PSA+ PCa cells, the PSA-/lo cells possess multiple SC features. First, PSA-/lo PCa cells are more clonal and clonogenic (sphere-forming). Second, PSA-/lo cells are more quiescent and slow cycling. Third, PSA-/lo cells overexpress dozens of SC-related genes (e.g., Nanog, CD44, SPP1, etc.). Fourth, PSA-/lo cells are more resistant to stress (e.g., paclitaxel) and castration. Fifth, PSA-/lo cells regenerate serially transplantable tumors that histologically resemble parental tumors. Finally, a small population of PSA-/lo cells can undergo asymmetric cell division to self-renew and generate PSA+ cells. Importantly, the PSA-/lo PCa cell population is still heterogeneous with true PCSCs that possess high castration-resistant tumor-regenerating activity, representing an even smaller subpopulation. In support of this conjecture, we could further fractionate a subpopulation of ALDH+CD44+α2β1+ cells from the PSA-/lo cell population, and show that these cells could regenerate serially transplantable tumors in fully castrated mice.8 Another recent study found a small subset of CK18-/CK19- cells in docetaxel-resistant cell lines (Du145-DR and 22Rv1-DR) and primary as well as metastatic PCa patient samples that express low levels of differentiation marker (HLA).11 Using a lentiviral reporter system, this group has shown that CK18-/CK19- cells in both Du145-DR and 22Rv1-DR models can survive docetaxel exposure and acquire chemoresistance via upregulation of Notch and Hedgehog signaling, whereas targeting these two pathways can abolish the chemoresistance both in vitro and in vivo.11 Of note, a small subset of HLA- cells from both xenografts and primary patient samples are much more tumorigenic than the bulk HLA+ cells,11 suggesting that HLA- PCa cells may be enriched in PCSCs that are chemoresistant. Taken together, these studies8,11 imply that less differentiated PCa cells (e.g., PSA-/lo, HLA+), compared with the bulk differentiated PCa cells, may be highly enriched in PCSCs that drive tumor development and mediate resistance to both chemotherapy and castration.

Recently accumulated evidence has implicated several molecules and signaling pathways in regulating PCSC activity. For example, Nanog, a homeodomain transcription factor that plays a vital role in regulating ES cell pluripotency, seems to be also important for PCSC activity and tumorigenicity. Thus, its expression is enriched in CD44+ PCa cells, and its knockdown inhibits tumor regeneration, whereas its inducible overexpression confers castration-resistant PCa development.40,41 An unbiased microRNA (miRNA) library screening led to the identification of a tumor-suppressive microRNA, miR-34a, that was depleted in the CD44+ PCa cells.50 Subsequent studies reveal that miR-34a functions as a powerful negative regulator of CD44+, tumorigenic and metastatic PCSCs by directly targeting CD44.50 The above discussions illustrate a positive (i.e., Nanog) and negative (i.e., miR-34a) regulator of PCSCs. “Less differentiated” CK18-/CK19- (HLA-) PCa cells are highly resistant to docetaxel treatment as a result of activation of both Notch and Hedgehog pathways.11 Consequently, targeting these two signaling pathways abrogates docetaxel resistance in CK19- cells via inhibition of AKT and Bcl-2.11 Other work has generated evidence that PCSCs may also be regulated by the PTEN/PI3K/AKT45 and NFκB pathways.49 Potentially, these reported regulators of PCSCs may all become therapeutic targets (for positive regulators) or tools (for negative regulators such as miR-34a) for the treatment of PCa, especially in the context of CRPC.

The majority of the aforementioned studies on human PCSCs employed xenograft transplantation models with the knowledge that the residual immune response in recipient mice may confound data interpretation due to species incompatibility. Therefore, studies on mouse PCSCs may circumvent this problem. The Sca-1+, but not Sca-1-, murine prostate cells, upon lentiviral-mediated overexpression of AKT1, can initiate PIN,70 a precursor lesion to PCa, suggesting that Sca-1+ cells with high AKT expression/activity could function as the cells-of-origin for PCa development. In the Pten-null mouse PCa model, a small population of PCa cells manifested as Lin-Sca-1+CD49fhi (i.e., LSC) possess PCSC properties, as these cells have high sphere-forming and tumorigenic potential compared with other isogenic subpopulations.88 As with the human PCSCs, potential regulators of mouse PCSCs have also been reported. For example, protospheres from Pten/p53-null mice harbor tumorigenic stem/progenitor cells with heightened levels of AKT and AR signaling pathways.89 Bmi-1, a Polycomb group transcriptional repressor, helps to maintain the self-renewal capacities of adult mouse p63+ PSCs90 and, of note, inhibition of Bmi-1 appears to slow down PCa initiation in Pten-null mice.90 This study90 also suggests that PCSC properties may be regulated at the chromatin level. Recently, the same group reported that the intracellular domain of Trop2, an EpCAM family member of cell surface receptors, is important for regulating the self-renewal capacity of normal PSCs and, when overexpressed, is sufficient to initiate PIN in vivo,91 implying that Trop2 is not just a phenotypic marker but may be functionally indispensible for the activity of normal PSCs and PCSCs.

Cell-of-Origin for PCa and PCSCs

In the past decade, the topic of ”cell-of-origin” for PCa has attracted enormous attention in the field. As of now, which subpopulation of the cells represents the real PCa cell-of-origin is still under debate. At the histopathalogical level, > 95% of untreated primary PCa present as acinus carcinoma (i.e., adenocarcinoma) in which luminal-like cells expressing AR and PSA predominate and basal-like cells are rare.1 Hence it has been presumed that normal prostate luminal cells may serve as an oncogenic transformation target for PCa. There are several pieces of evidence to support this postulation. For instance, Shen’s group deleted Pten in the CARNs of castrated host (Nkx3.1CreERT2/+;Pten+/+), and found that such a deletion leads to high-grade PIN and carcinoma after regression-regeneration cycles,76 suggesting that the CARNs may serve as the cell-of-origin for PCa. Choi et al. used the lineage-tracing strategy in both basal-specific (K14-CreERTg/Tg; mTmGTg/Tg) and luminal-specific (K8-CreERT2Tg/Tg; mTmGTg/Tg) inducible Cre systems, and observed that prostate luminal cells are more susceptible to direct malignant transformation upon Pten deletion, whereas basal cells appear to need to first differentiate into the transformation-competent luminal cells before oncogenic transformation can take place.77 Interestingly, transgenic overexpression of certain gene(s) (e.g., PKCε) in murine prostatic luminal cellular compartment could also lead to PIN.92 Taken together, these animal model studies suggest that murine prostate luminal cells can function as the cells of origin for PCa.

By contrast, studies using tissue recombination/transplantation assays suggest that prostate basal cells are more likely the targets of malignant transformation. Lawson et al. have reported that overexpression of transcription factor ERG1, the fusion partner of TMPRSS2, in murine prostate basal/stem cells results in dysplasia and PIN, whereas the similar phenotype cannot be seen with luminal or stromal cells.93 Moreover, they found that combinatorial overexpression of AKT and AR in murine basal/stem cells, but not luminal cells, leads to poorly differentiated carcinoma.93 Remarkably, when overexpressing ERG, AKT and AR in benign human prostate basal cells (CD49fhiTrop2hi) and luminal cells (CD49floTrop2hi), only basal cells are susceptible to malignant transformation and can initiate PCa in immunodeficient mice, regenerating PCa resembling patient tumors histologically.94 A recent report has shown that recombination of cancer-associated fibroblasts with integrin α2β1hi human prostate basal cells (from non-tumorigenic BPH-1 cells) regenerates tumor grafts.95 In summation, these results suggest that both human and murine prostate basal cells can serve as cells-of-origin for PCa.

Regardless of the cell-of-origin for PCa, it is critical that the concept must not be confused with PCSCs. In former studies, we generally focus on a subpopulation of normal prostate cells that has the potential to serve as the cellular targets of malignant transformation to become a cancer cell upon specific genetic alteration(s) and in certain experimental models. However, in the latter studies, PCSCs are referred to as the subsets of cancer cells in established tumors that possess certain SC activities. Certainly, it is possible that the cells of origin for PCa may have acquired SC features and have thus become PCSCs.

Studies of CSCs in other cancer types suggest that CSCs may originate from their normal counterparts for normal SCs, and CSCs in some tissues seem to share phenotypic markers.23,24 Nevertheless, CSCs may also originate from progenitors or differentiated cells.96,97 Interestingly, recent work from our lab and others has hinted that PCSCs appear to be generally less differentiated, manifested by no or low levels of expression of differentiation makers such as PSA8 and CK18/CK19 (HLA).11 Moreover, the abundance of immature PCSCs seems to correlate with tumor aggressiveness,8,11 consistent with CSCs in other tumors.98


Both androgen and AR are crucial in the development of normal prostate and PCa.1 ADT is the mainstay treatment for advanced PCa patients by either surgical and/or chemical castration.1 However, most PCa patients eventually fail ADT and develop CRPC, which is untreatable. CRPC represents one of the major clinical challenges, and the exact etiology remains elusive. Many possible mechanisms have been put forth to explain the emergence of CRPC, most of which center on AR and AR signaling and include AR amplification, AR mutation, overexpression of ligand-less AR splice isoforms and increased AR-independent and survival pathways.1,6,7 Studies on PCSCs, however, may help explain some uncertainties and offer fresh insights regarding CRPC development.

A study from Tanaka et al. indicates that the expression levels of N-cadherin are high in CRPC xenografts and primary metastatic HPCa samples.99 Ectopic expression of N-cadherin in androgen-dependent PCa (ADPC) cells leads to a castration-resistant phenotype, whereas specific monoclonal antibody targeting of N-cadherin dramatically delays CRPC progression.99 Of interest, the relative abundance of N-cadherin+ cells gradually increases in the late-stage CRPC xenografts.99 These data indicate that N-cadherin+ cells and/or the N-cadherin molecule itself plays a vital role in CRPC development. Another recent study shows that stem-like cancer cells exist in the BM18 xenograft model, which express both SC-related markers (e.g., Nanog) and luminal markers (e.g., Nkx3.1), but not basal or neuroendocrine markers.53 Moreover, cancer cells expressing a luminal phenotype can regenerate new tumors after androgen replacement,53 suggesting that SC-like cancer cells with the luminal progenitor phenotypes might be candidate cells of origin for CRPC. A cell surface marker, CD166, is found to be highly expressed in human CRPC samples, and, importantly, LSChiCD166hi cells in the Pten-null model have much enhanced sphere-formation abilities compared with the other subpopulations,55 suggesting that the CD166hi cell population may be enriched in castration-resistant PCSCs. Work from our lab indicates that PSA-/lo PCa cells are more clonal and clonogenic than the corresponding bulk PSA+ PCa cells in androgen-deficient conditions in vitro and are more tumorigenic than PSA+ cells in fully castrated mice.8 These observations suggest that the PSA-/lo PCa cell population likely harbors castration-resistant variants that pre-exist in the tumors. Remarkably, castration-resistant PCa cells can be further enriched in the PSA-/lo cell population by fractionating for ALDH+CD44+α2β1+ cells, which are significantly more tumorigenic and can regenerate serially transplantable tumors in fully castrated hosts,8 raising the possibility that such cells may be future therapeutic targets for CRPC.

Challenges and Perspective

The newly revived CSC concept has attracted much attention, and CSCs have been studied in various tumor systems, including PCa.12-14,17-22 Elucidating the phenotypic and functional properties as well as molecular regulators of PCSCs should help us to better understand the etiology of and mechanisms responsible for PCa development. As in other tumors, many seemingly divergent PCSC populations have been reported, and one of the main challenges is to delineate the interrelationship between various phenotypically different PCSCs.

Most PCSCs so far reported have been based on studies in long-term cultured cell lines, xenograft models or mouse PCa models.13 For example, we have identified distinct subpopulations of PCa cells, mostly in several well-characterized xenograft models, that are enriched in PCSC activity including CD44+,35 CD44+α2β1+,36 and PSA-/lo cells.8 Little is known concerning whether human primary PCa also harbors tumorigenic SC-like cancer cells, and whether different patient tumors may have distinct PCSCs. The paucity in our knowledge in this regard is related to one of the major hurdles well-known in the field, i.e., it is extremely difficult to reconstitute HPCa development in an immunodeficient host by using single HPCa cells,100 explaining why cell lines and xenograft models are typically used for PCSC studies. Future efforts should be directed to developing reliable tumor reconstitution protocols, so that this critical challenge can be directly tackled.

Tissue recombination assays have shown that both normal murine93 and human94 prostate basal cells appear to be the primary cells-of-origin for PCa. In contrast, lineage-tracing studies demonstrate that murine prostate luminal cells seem to be more competent in functioning as the cells-of-origin for PCa.76,77 It is presently unclear why the two experimental approaches give rise to different results and conclusions. Suffice it to say that we should not exclude the possibility that human prostate luminal cells may also be susceptible to oncogenic transformation, given that similar lineage-tracing strategy is not feasible in humans. Furthermore, development of a specific culture medium favoring human prostate luminal cells is needed to conduct side-by-side comparisons in assays based on tissue recombination and transplantations.

CRPC represents one of the most challenging stages for PCa treatment. Although castration-resistant PCSCs have not yet been uncovered in primary human PCa samples, recent studies have provided hints that some PCSC subpopulations may express low levels of AR and intrinsically be resistant to castration.8,11,55,99 It is conceivable that the expansion of such cells may promote CRPC development. As a result, these castration-resistant PCa cells may represent potential cellular targets for novel drug development. Future studies with improved tumor-reconstitution protocols and model systems are required to identify castration-resistant PCSCs in patient tumors at different clinical stages, and the success of which will facilitate future therapeutic development and benefit PCa patients.


The work in the authors’ lab was supported in part by grants from NIH (R01-CA155693-01A), Department of Defense (W81XWH-11-1-0331), CPRIT funding (RP120380) and the MD Anderson Cancer Center the Center for Cancer Epigenetics and Laura and John Arnold Foundation RNA Center pilot grant (to D.G.T.). X.C. was supported in part by Cockrell fellowship and X.L. by a predoctoral fellowship at the Center for Stem Cells and Development from MD Anderson Cancer Center. K.R. was supported by an NIH T32 postdoctoral training grant.



androgen-deprivation therapy
androgen-dependent prostate cancer
androgen-independent prostate cancer
androgen receptor
castration-resistant Nkx3.1-expressing cells
castration-resistant prostate cancer
cancer stem cells
florescence-activated cell sorting
(primary) human prostate cancer
Lin-Sca-1+CD49f+ cells
prostate cancer stem cells
prostate intraepithelial neoplasia
prostate specific antigen
prostate stem cells
stem cells
side population

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.



1. Shen MM, Abate-Shen C. Molecular genetics of prostate cancer: new prospects for old challenges. Genes Dev. 2010;24:1967–2000. doi: 10.1101/gad.1965810. [PubMed] [Cross Ref]
2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin. 2012;62:10–29. doi: 10.3322/caac.20138. [PubMed] [Cross Ref]
3. Abate-Shen C, Shen MM. Molecular genetics of prostate cancer. Genes Dev. 2000;14:2410–34. doi: 10.1101/gad.819500. [PubMed] [Cross Ref]
4. Cooperberg MR, Moul JW, Carroll PR. The changing face of prostate cancer. J Clin Oncol. 2005;23:8146–51. doi: 10.1200/JCO.2005.02.9751. [PubMed] [Cross Ref]
5. Li H, Tang DG. Prostate cancer stem cells and their potential roles in metastasis. J Surg Oncol. 2011;103:558–62. doi: 10.1002/jso.21806. [PubMed] [Cross Ref]
6. Feldman BJ, Feldman D. The development of androgen-independent prostate cancer. Nat Rev Cancer. 2001;1:34–45. doi: 10.1038/35094009. [PubMed] [Cross Ref]
7. Debes JD, Tindall DJ. Mechanisms of androgen-refractory prostate cancer. N Engl J Med. 2004;351:1488–90. doi: 10.1056/NEJMp048178. [PubMed] [Cross Ref]
8. Qin J, Liu X, Laffin B, Chen X, Choy G, Jeter CR, et al. The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell. 2012;10:556–69. doi: 10.1016/j.stem.2012.03.009. [PMC free article] [PubMed] [Cross Ref]
9. Azmi AS, Sarkar FH. Prostate cancer stem cells: molecular characterization for targeted therapy. Asian J Androl. 2012;14:659–60. doi: 10.1038/aja.2012.62. [PMC free article] [PubMed] [Cross Ref]
10. Mulholland DJ. PSA-negative/low prostate cancer cells: the true villains of CRPC? Asian J Androl. 2012;14:663–4. doi: 10.1038/aja.2012.69. [PMC free article] [PubMed] [Cross Ref]
11. Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, Castillo-Martin M, Quinn SA, Rodriguez-Barrueco R, et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell. 2012;22:373–88. doi: 10.1016/j.ccr.2012.07.016. [PubMed] [Cross Ref]
12. Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 2009;138:822–9. doi: 10.1016/j.cell.2009.08.017. [PubMed] [Cross Ref]
13. Tang DG. Understanding cancer stem cell heterogeneity and plasticity. Cell Res. 2012;22:457–72. doi: 10.1038/cr.2012.13. [PMC free article] [PubMed] [Cross Ref]
14. Visvader JE, Lindeman GJ. Cancer stem cells: current status and evolving complexities. Cell Stem Cell. 2012;10:717–28. doi: 10.1016/j.stem.2012.05.007. [PubMed] [Cross Ref]
15. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194:23–8. doi: 10.1126/science.959840. [PubMed] [Cross Ref]
16. Baylin SB, Jones PA. A decade of exploring the cancer epigenome - biological and translational implications. Nat Rev Cancer. 2011;11:726–34. doi: 10.1038/nrc3130. [PMC free article] [PubMed] [Cross Ref]
17. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, et al. Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006;66:9339–44. doi: 10.1158/0008-5472.CAN-06-3126. [PubMed] [Cross Ref]
18. Clevers H. The cancer stem cell: premises, promises and challenges. Nat Med. 2011;17:313–9. doi: 10.1038/nm.2304. [PubMed] [Cross Ref]
19. Magee JA, Piskounova E, Morrison SJ. Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell. 2012;21:283–96. doi: 10.1016/j.ccr.2012.03.003. [PubMed] [Cross Ref]
20. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–11. doi: 10.1038/35102167. [PubMed] [Cross Ref]
21. Nguyen LV, Vanner R, Dirks P, Eaves CJ. Cancer stem cells: an evolving concept. Nat Rev Cancer. 2012;12:133–43. [PubMed]
22. Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, Melo JV, et al. Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer. 2012;12:767–75. doi: 10.1038/nrc3368. [PubMed] [Cross Ref]
23. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–8. doi: 10.1038/367645a0. [PubMed] [Cross Ref]
24. Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730–7. doi: 10.1038/nm0797-730. [PubMed] [Cross Ref]
25. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–8. doi: 10.1073/pnas.0530291100. [PubMed] [Cross Ref]
26. Pece S, Tosoni D, Confalonieri S, Mazzarol G, Vecchi M, Ronzoni S, et al. Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content. Cell. 2010;140:62–73. doi: 10.1016/j.cell.2009.12.007. [PubMed] [Cross Ref]
27. Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C, et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007;131:1109–23. doi: 10.1016/j.cell.2007.10.054. [PubMed] [Cross Ref]
28. O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature. 2007;445:106–10. doi: 10.1038/nature05372. [PubMed] [Cross Ref]
29. Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, et al. Identification and expansion of human colon-cancer-initiating cells. Nature. 2007;445:111–5. doi: 10.1038/nature05384. [PubMed] [Cross Ref]
30. Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F, et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem Cell. 2007;1:389–402. doi: 10.1016/j.stem.2007.08.001. [PubMed] [Cross Ref]
31. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401. doi: 10.1038/nature03128. [PubMed] [Cross Ref]
32. Eyler CE, Wu Q, Yan K, MacSwords JM, Chandler-Militello D, Misuraca KL, et al. Glioma stem cell proliferation and tumor growth are promoted by nitric oxide synthase-2. Cell. 2011;146:53–66. doi: 10.1016/j.cell.2011.06.006. [PMC free article] [PubMed] [Cross Ref]
33. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60. doi: 10.1038/nature05236. [PubMed] [Cross Ref]
34. Patrawala L, Calhoun T, Schneider-Broussard R, Zhou J, Claypool K, Tang DG. Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2- cancer cells are similarly tumorigenic. Cancer Res. 2005;65:6207–19. doi: 10.1158/0008-5472.CAN-05-0592. [PubMed] [Cross Ref]
35. Patrawala L, Calhoun T, Schneider-Broussard R, Li H, Bhatia B, Tang S, et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene. 2006;25:1696–708. doi: 10.1038/sj.onc.1209327. [PubMed] [Cross Ref]
36. Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG. Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+alpha2beta1+ cell population is enriched in tumor-initiating cells. Cancer Res. 2007;67:6796–805. doi: 10.1158/0008-5472.CAN-07-0490. [PubMed] [Cross Ref]
37. Huss WJ, Gray DR, Greenberg NM, Mohler JL, Smith GJ. Breast cancer resistance protein-mediated efflux of androgen in putative benign and malignant prostate stem cells. Cancer Res. 2005;65:6640–50. doi: 10.1158/0008-5472.CAN-04-2548. [PubMed] [Cross Ref]
38. Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005;65:10946–51. doi: 10.1158/0008-5472.CAN-05-2018. [PubMed] [Cross Ref]
39. Gu G, Yuan J, Wills M, Kasper S. Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res. 2007;67:4807–15. doi: 10.1158/0008-5472.CAN-06-4608. [PubMed] [Cross Ref]
40. Jeter CR, Badeaux M, Choy G, Chandra D, Patrawala L, Liu C, et al. Functional evidence that the self-renewal gene NANOG regulates human tumor development. Stem Cells. 2009;27:993–1005. doi: 10.1002/stem.29. [PMC free article] [PubMed] [Cross Ref]
41. Jeter CR, Liu B, Liu X, Chen X, Liu C, Calhoun-Davis T, et al. NANOG promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene. 2011;30:3833–45. doi: 10.1038/onc.2011.114. [PMC free article] [PubMed] [Cross Ref]
42. Li H, Chen X, Calhoun-Davis T, Claypool K, Tang DG. PC3 human prostate carcinoma cell holoclones contain self-renewing tumor-initiating cells. Cancer Res. 2008;68:1820–5. doi: 10.1158/0008-5472.CAN-07-5878. [PubMed] [Cross Ref]
43. Miki J, Furusato B, Li H, Gu Y, Takahashi H, Egawa S, et al. Identification of putative stem cell markers, CD133 and CXCR4, in hTERT-immortalized primary nonmalignant and malignant tumor-derived human prostate epithelial cell lines and in prostate cancer specimens. Cancer Res. 2007;67:3153–61. doi: 10.1158/0008-5472.CAN-06-4429. [PubMed] [Cross Ref]
44. Hurt EM, Kawasaki BT, Klarmann GJ, Thomas SB, Farrar WL. CD44+ CD24(-) prostate cells are early cancer progenitor/stem cells that provide a model for patients with poor prognosis. Br J Cancer. 2008;98:756–65. doi: 10.1038/sj.bjc.6604242. [PMC free article] [PubMed] [Cross Ref]
45. Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, García-Echeverría C, et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA. 2009;106:268–73. doi: 10.1073/pnas.0810956106. [PubMed] [Cross Ref]
46. Guzmán-Ramírez N, Völler M, Wetterwald A, Germann M, Cross NA, Rentsch CA, et al. In vitro propagation and characterization of neoplastic stem/progenitor-like cells from human prostate cancer tissue. Prostate. 2009;69:1683–93. doi: 10.1002/pros.21018. [PubMed] [Cross Ref]
47. Li T, Su Y, Mei Y, Leng Q, Leng B, Liu Z, et al. ALDH1A1 is a marker for malignant prostate stem cells and predictor of prostate cancer patients’ outcome. Lab Invest. 2010;90:234–44. doi: 10.1038/labinvest.2009.127. [PMC free article] [PubMed] [Cross Ref]
48. van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Lippitt JM, Guzmán-Ramírez N, et al. High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer. Cancer Res. 2010;70:5163–73. doi: 10.1158/0008-5472.CAN-09-3806. [PubMed] [Cross Ref]
49. Rajasekhar VK, Studer L, Gerald W, Socci ND, Scher HI. Tumour-initiating stem-like cells in human prostate cancer exhibit increased NFκB signalling. Nat Commun. 2011;2:162. doi: 10.1038/ncomms1159. [PMC free article] [PubMed] [Cross Ref]
50. Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011;17:211–5. doi: 10.1038/nm.2284. [PMC free article] [PubMed] [Cross Ref]
51. Liu C, Kelnar K, Vlassov AV, Brown D, Wang J, Tang DG. Distinct microRNA expression profiles in prostate cancer stem/progenitor cells and tumor-suppressive functions of let-7. Cancer Res. 2012;72:3393–404. doi: 10.1158/0008-5472.CAN-11-3864. [PMC free article] [PubMed] [Cross Ref]
52. Mulholland DJ, Kobayashi N, Ruscetti M, Zhi A, Tran LM, Huang J, et al. Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Res. 2012;72:1878–89. doi: 10.1158/0008-5472.CAN-11-3132. [PMC free article] [PubMed] [Cross Ref]
53. Germann M, Wetterwald A, Guzmán-Ramirez N, van der Pluijm G, Culig Z, Cecchini MG, et al. Stem-like cells with luminal progenitor phenotype survive castration in human prostate cancer. Stem Cells. 2012;30:1076–86. doi: 10.1002/stem.1087. [PubMed] [Cross Ref]
54. Dubrovska A, Elliott J, Salamone RJ, Telegeev GD, Stakhovsky AE, Schepotin IB, et al. CXCR4 expression in prostate cancer progenitor cells. PLoS ONE. 2012;7:e31226. doi: 10.1371/journal.pone.0031226. [PMC free article] [PubMed] [Cross Ref]
55. Jiao J, Hindoyan A, Wang S, Tran LM, Goldstein AS, Lawson D, et al. Identification of CD166 as a surface marker for enriching prostate stem/progenitor and cancer initiating cells. PLoS ONE. 2012;7:e42564. doi: 10.1371/journal.pone.0042564. [PMC free article] [PubMed] [Cross Ref]
56. Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67:1030–7. doi: 10.1158/0008-5472.CAN-06-2030. [PubMed] [Cross Ref]
57. Curtis SJ, Sinkevicius KW, Li D, Lau AN, Roach RR, Zamponi R, et al. Primary tumor genotype is an important determinant in identification of lung cancer propagating cells. Cell Stem Cell. 2010;7:127–33. doi: 10.1016/j.stem.2010.05.021. [PMC free article] [PubMed] [Cross Ref]
58. Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A, et al. Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ. 2008;15:504–14. doi: 10.1038/sj.cdd.4402283. [PubMed] [Cross Ref]
59. Yang ZF, Ho DW, Ng MN, Lau CK, Yu WC, Ngai P, et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell. 2008;13:153–66. doi: 10.1016/j.ccr.2008.01.013. [PubMed] [Cross Ref]
60. Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO. CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell. 2011;9:50–63. doi: 10.1016/j.stem.2011.06.005. [PubMed] [Cross Ref]
61. Tang DG, Patrawala L, Calhoun T, Bhatia B, Choy G, Schneider-Broussard R, et al. Prostate cancer stem/progenitor cells: identification, characterization, and implications. Mol Carcinog. 2007;46:1–14. doi: 10.1002/mc.20255. [PubMed] [Cross Ref]
62. Haffner MC, Chaux A, Meeker AK, Esopi DM, Gerber J, Pellakuru LG, et al. Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget. 2011;2:627–37. [PMC free article] [PubMed]
63. Wang ZA, Shen MM. Revisiting the concept of cancer stem cells in prostate cancer. Oncogene. 2011;30:1261–71. doi: 10.1038/onc.2010.530. [PubMed] [Cross Ref]
64. Cotsarelis G, Cheng SZ, Dong G, Sun TT, Lavker RM. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell. 1989;57:201–9. doi: 10.1016/0092-8674(89)90958-6. [PubMed] [Cross Ref]
65. Zhou S, Schuetz JD, Bunting KD, Colapietro AM, Sampath J, Morris JJ, et al. The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype. Nat Med. 2001;7:1028–34. doi: 10.1038/nm0901-1028. [PubMed] [Cross Ref]
66. Kastan MB, Schlaffer E, Russo JE, Colvin OM, Civin CI, Hilton J. Direct demonstration of elevated aldehyde dehydrogenase in human hematopoietic progenitor cells. Blood. 1990;75:1947–50. [PubMed]
67. English HF, Santen RJ, Isaacs JT. Response of glandular versus basal rat ventral prostatic epithelial cells to androgen withdrawal and replacement. Prostate. 1987;11:229–42. doi: 10.1002/pros.2990110304. [PubMed] [Cross Ref]
68. Cunha GR, Lung B. The possible influence of temporal factors in androgenic responsiveness of urogenital tissue recombinants from wild-type and androgen-insensitive (Tfm) mice. J Exp Zool. 1978;205:181–93. doi: 10.1002/jez.1402050203. [PubMed] [Cross Ref]
69. Burger PE, Xiong X, Coetzee S, Salm SN, Moscatelli D, Goto K, et al. Sca-1 expression identifies stem cells in the proximal region of prostatic ducts with high capacity to reconstitute prostatic tissue. Proc Natl Acad Sci USA. 2005;102:7180–5. doi: 10.1073/pnas.0502761102. [PubMed] [Cross Ref]
70. Xin L, Lawson DA, Witte ON. The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis. Proc Natl Acad Sci USA. 2005;102:6942–7. doi: 10.1073/pnas.0502320102. [PubMed] [Cross Ref]
71. Lawson DA, Xin L, Lukacs RU, Cheng D, Witte ON. Isolation and functional characterization of murine prostate stem cells. Proc Natl Acad Sci USA. 2007;104:181–6. doi: 10.1073/pnas.0609684104. [PubMed] [Cross Ref]
72. Goldstein AS, Lawson DA, Cheng D, Sun W, Garraway IP, Witte ON. Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristics. Proc Natl Acad Sci USA. 2008;105:20882–7. doi: 10.1073/pnas.0811411106. [PubMed] [Cross Ref]
73. Leong KG, Wang BE, Johnson L, Gao WQ. Generation of a prostate from a single adult stem cell. Nature. 2008;456:804–8. doi: 10.1038/nature07427. [PubMed] [Cross Ref]
74. Tsujimura A, Koikawa Y, Salm S, Takao T, Coetzee S, Moscatelli D, et al. Proximal location of mouse prostate epithelial stem cells: a model of prostatic homeostasis. J Cell Biol. 2002;157:1257–65. doi: 10.1083/jcb.200202067. [PMC free article] [PubMed] [Cross Ref]
75. Valdez JM, Zhang L, Su Q, Dakhova O, Zhang Y, Shahi P, et al. Notch and TGFβ form a reciprocal positive regulatory loop that suppresses murine prostate basal stem/progenitor cell activity. Cell Stem Cell. 2012;11:676–88. doi: 10.1016/j.stem.2012.07.003. [PMC free article] [PubMed] [Cross Ref]
76. Wang X, Kruithof-de Julio M, Economides KD, Walker D, Yu H, Halili MV, et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature. 2009;461:495–500. doi: 10.1038/nature08361. [PMC free article] [PubMed] [Cross Ref]
77. Choi N, Zhang B, Zhang L, Ittmann M, Xin L. Adult murine prostate basal and luminal cells are self-sustained lineages that can both serve as targets for prostate cancer initiation. Cancer Cell. 2012;21:253–65. doi: 10.1016/j.ccr.2012.01.005. [PMC free article] [PubMed] [Cross Ref]
78. Liu J, Pascal LE, Isharwal S, Metzger D, Ramos Garcia R, Pilch J, et al. Regenerated luminal epithelial cells are derived from preexisting luminal epithelial cells in adult mouse prostate. Mol Endocrinol. 2011;25:1849–57. doi: 10.1210/me.2011-1081. [PubMed] [Cross Ref]
79. Ousset M, Van Keymeulen A, Bouvencourt G, Sharma N, Achouri Y, Simons BD, et al. Multipotent and unipotent progenitors contribute to prostate postnatal development. Nat Cell Biol. 2012;14:1131–8. doi: 10.1038/ncb2600. [PubMed] [Cross Ref]
80. Collins AT, Habib FK, Maitland NJ, Neal DE. Identification and isolation of human prostate epithelial stem cells based on alpha(2)beta(1)-integrin expression. J Cell Sci. 2001;114:3865–72. [PubMed]
81. Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci. 2004;117:3539–45. doi: 10.1242/jcs.01222. [PubMed] [Cross Ref]
82. Garraway IP, Sun W, Tran CP, Perner S, Zhang B, Goldstein AS, et al. Human prostate sphere-forming cells represent a subset of basal epithelial cells capable of glandular regeneration in vivo. Prostate. 2010;70:491–501. [PMC free article] [PubMed]
83. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1:555–67. doi: 10.1016/j.stem.2007.08.014. [PMC free article] [PubMed] [Cross Ref]
84. Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C. Defining the mode of tumour growth by clonal analysis. Nature. 2012;488:527–30. doi: 10.1038/nature11344. [PubMed] [Cross Ref]
85. Schepers AG, Snippert HJ, Stange DE, van den Born M, van Es JH, van de Wetering M, et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science. 2012;337:730–5. doi: 10.1126/science.1224676. [PubMed] [Cross Ref]
86. Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG, et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature. 2012;488:522–6. doi: 10.1038/nature11287. [PMC free article] [PubMed] [Cross Ref]
87. Vander Griend DJ, Karthaus WL, Dalrymple S, Meeker A, DeMarzo AM, Isaacs JT. The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. Cancer Res. 2008;68:9703–11. doi: 10.1158/0008-5472.CAN-08-3084. [PMC free article] [PubMed] [Cross Ref]
88. Mulholland DJ, Xin L, Morim A, Lawson D, Witte O, Wu H. Lin-Sca-1+CD49fhigh stem/progenitors are tumor-initiating cells in the Pten-null prostate cancer model. Cancer Res. 2009;69:8555–62. doi: 10.1158/0008-5472.CAN-08-4673. [PMC free article] [PubMed] [Cross Ref]
89. Abou-Kheir WG, Hynes PG, Martin PL, Pierce R, Kelly K. Characterizing the contribution of stem/progenitor cells to tumorigenesis in the Pten-/-TP53-/- prostate cancer model. Stem Cells. 2010;28:2129–40. doi: 10.1002/stem.538. [PubMed] [Cross Ref]
90. Lukacs RU, Memarzadeh S, Wu H, Witte ON. Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell. 2010;7:682–93. doi: 10.1016/j.stem.2010.11.013. [PMC free article] [PubMed] [Cross Ref]
91. Stoyanova T, Goldstein AS, Cai H, Drake JM, Huang J, Witte ON. Regulated proteolysis of Trop2 drives epithelial hyperplasia and stem cell self-renewal via β-catenin signaling. Genes Dev. 2012;26:2271–85. doi: 10.1101/gad.196451.112. [PubMed] [Cross Ref]
92. Benavides F, Blando J, Perez CJ, Garg R, Conti CJ, DiGiovanni J, et al. Transgenic overexpression of PKCε in the mouse prostate induces preneoplastic lesions. Cell Cycle. 2011;10:268–77. doi: 10.4161/cc.10.2.14469. [PMC free article] [PubMed] [Cross Ref]
93. Lawson DA, Zong Y, Memarzadeh S, Xin L, Huang J, Witte ON. Basal epithelial stem cells are efficient targets for prostate cancer initiation. Proc Natl Acad Sci USA. 2010;107:2610–5. doi: 10.1073/pnas.0913873107. [PubMed] [Cross Ref]
94. Goldstein AS, Huang J, Guo C, Garraway IP, Witte ON. Identification of a cell of origin for human prostate cancer. Science. 2010;329:568–71. doi: 10.1126/science.1189992. [PMC free article] [PubMed] [Cross Ref]
95. Taylor RA, Toivanen R, Frydenberg M, Pedersen J, Harewood L, Collins AT, et al. Australian Prostate Cancer Bioresource Human epithelial basal cells are cells of origin of prostate cancer, independent of CD133 status. Stem Cells. 2012;30:1087–96. doi: 10.1002/stem.1094. [PubMed] [Cross Ref]
96. Lim E, Vaillant F, Wu D, Forrest NC, Pal B, Hart AH, et al. kConFab Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers. Nat Med. 2009;15:907–13. doi: 10.1038/nm.2000. [PubMed] [Cross Ref]
97. Yang ZJ, Ellis T, Markant SL, Read TA, Kessler JD, Bourboulas M, et al. Medulloblastoma can be initiated by deletion of Patched in lineage-restricted progenitors or stem cells. Cancer Cell. 2008;14:135–45. doi: 10.1016/j.ccr.2008.07.003. [PMC free article] [PubMed] [Cross Ref]
98. Zhou BB, Zhang H, Damelin M, Geles KG, Grindley JC, Dirks PB. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov. 2009;8:806–23. doi: 10.1038/nrd2137. [PubMed] [Cross Ref]
99. Tanaka H, Kono E, Tran CP, Miyazaki H, Yamashiro J, Shimomura T, et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat Med. 2010;16:1414–20. doi: 10.1038/nm.2236. [PMC free article] [PubMed] [Cross Ref]
100. Pienta KJ, Abate-Shen C, Agus DB, Attar RM, Chung LW, Greenberg NM, et al. The current state of preclinical prostate cancer animal models. Prostate. 2008;68:629–39. doi: 10.1002/pros.20726. [PMC free article] [PubMed] [Cross Ref]

Articles from Cell Cycle are provided here courtesy of Landes Bioscience