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Keywords:

  • adaptation;
  • castration-resistance;
  • clonal selection;
  • prostate cancer

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Development of CRPC
  5. Adaptation model
  6. Clonal selection model
  7. Genetic/epigenetic alterations pertinent to both models
  8. Prostate stem/progenitor cells and the clonal selection model
  9. Conclusion and future prospects
  10. Acknowledgments
  11. Conflict of interest
  12. References

Prostate cancer is a leading cause of cancer deaths in men worldwide. Management of the disease has remained a great challenge and even more so is the aggressive advanced stage with castration-resistant behavior. The mechanisms and timing of development of castration-resistant prostate cancer are unclear and remain debatable. Progression to castration-resistant prostate cancer is undoubtedly multifactorial, with a number of molecular-genetic aberrations implicated. However, a key question that remains unanswered is: when in the evolution of prostate cancer do the changes that confer castration resistance occur? Earlier attempts to address this question led to two proposed models: the “adaptation” and the “clonal selection” models. Although the prevailing hypothesis is the adaptation model, there is recent evidence in favor of the clonal selection model. Clarification of the model development of castration-resistant prostate cancer might significantly alter our diagnostic and therapeutic strategies, and potentially lead to improved outcome of management of this daunting condition. Here we review existing knowledge and current research findings addressing the timing of events in the course of prostate cancer progression to castration-resistant prostate cancer.


Abbreviations & Acronyms
ADT

androgen deprivation therapy

AIPC

androgen-independent prostate cancer

AR

androgen receptor

CARN

castration-resistant NKX3-1-expressing cells

CRPC

castration-resistant prostate cancer

CRSC

castration-resistant luminal stem cell-like cell

CSC

cancer stem cell

GF

growth factors

HRPC

hormone-refractory prostate cancer

PCa

prostate cancer

PIN

prostatic intraepithelial neoplasia

PTEN

phosphatase and tensin homolog deleted on chromosome ten

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Development of CRPC
  5. Adaptation model
  6. Clonal selection model
  7. Genetic/epigenetic alterations pertinent to both models
  8. Prostate stem/progenitor cells and the clonal selection model
  9. Conclusion and future prospects
  10. Acknowledgments
  11. Conflict of interest
  12. References

Prostate cancer is the second leading cause of cancer deaths among men in the USA.[1] Mortality from the disease is mainly a result of the aggressive and, to date, incurable CRPC. It was previously called either AIPC or HRPC, because it was believed that prostate cancer cells attain this state when they no longer require androgens or AR function for their growth and survival. However, there is consensus from results of recent studies that advanced prostate cancer still depends on androgens and AR function despite castrate levels of testosterone,[2, 3] thus it is now more often referred to as CRPC.

The pioneer work of Huggins and Hodges in the 1940s,[4, 5] which showed the androgen-dependent nature of the prostate gland and prostate cancer cells, has had the most significant impact on the treatment of advanced prostate cancer. Numerous research has focused on unraveling the mechanisms underlining the development of CRPC, and proffering solutions for its effective treatment. Current strategies aim to exploit the specific molecular-genetic characteristics of individual cancers for effective diagnostic and therapeutic development. However, despite significant progress in this field, only marginal improvement in treatment outcome of advanced and CRPC have been achieved so far.

The mechanism and timing of the development of CRPC are constantly being debated. Two mechanisms that have been proposed to address this question are the “adaptation” model and the “clonal selection” model (Fig. 1). The adaptation model suggests that primary prostate cancer is composed of homogeneous cells, in terms of their androgen requirement, and castration resistance emerges through genetic/epigenetic conversion of androgen-dependent cells to androgen-independent cells. Whereas the clonal selection model proposes that primary prostate cancer cells are heterogeneous, with regards to their androgen requirement, of which a minority is a clone of pre-existing castration-resistant cells. In an androgen-deprived environment, these castration-resistant cells are selected for their survival and proliferative advantage. Although the prevailing view is the “adaptation” model,[6] it is by no means conclusive due to emerging contradicting evidence from several recent studies (Table 1). In the present article, we reviewed existing knowledge and current research findings addressing the timing of events in the course of prostate cancer progression to CRPC.

figure

Figure 1. Models of CRPC. The clonal selection model suggests that prostate cancer is composed of heterogeneous cells of which a minority are a pre-existing clone of castration-resistant cells (the scanty darker cells) with the predominant cells being androgen-dependent (light brown cells) in an androgen-deprived environment after ADT; the castration-resistant cells are selected for their survival and proliferative advantage, whereas the androgen-dependent cells are eliminated, thus giving rise to a preponderance of the castration-resistant cells manifesting as recurrence and a castration resistant prostate cancer. Whereas the adaptation model proposes that primary prostate cancer is initially homogeneous, made up of only androgen-dependent cells, and that castration resistance arises as an adaptive change after androgen deprivation through genetic/epigenetic conversion of some of the previously androgen-dependent cells to castration-resistant cells.

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Table 1. Evidence in support of adaptation and clonal selection models of CRPC
AdaptationClonal selection
In vitro study 
  • Growth-stimulatory effects of androgen-induced autocrine growth factor(s) secreted from Shionogi carcinoma 115 cells on androgen-unresponsive cancer cells in a paracrine mechanism: Suggests that hormone-unresponsive cells are formed from hormone-responsive cells with the aid of GF in a paracrine manner.[7]
  • Evidence of clonal outgrowth of androgen-independent prostate cancer cells from androgen-depended tumors through a two-step process: They concluded that prostate cancer contains heterogeneous mixtures of cells and androgen deprivation provided selective pressure for the outgrowth of androgen-independent cells.[8]
Animal study 
  • The Shionogi mouse mammary carcinoma cells study showed that multiple cycles of transplantation and castration-induced apoptosis were required before the tumor progressed to an androgen-independent state.[9-11]
  • The emergence of androgen-independent growth is the result of an adaptive process involving the expression of protooncogenes such as c-fos and c-myc.[12]
  • TRAMP adenocarcinoma of the mouse study: Tumors that developed in castrated mice were poorly differentiated in contrast to non-castrated controls, suggesting prostate cancer is heterogeneous at the onset, thus androgen independence occurs early in prostate cancer.[13]
  • Fluctuation studies in the Dunning rat adenocarcinoma: Castration led to the proliferation of androgen independent cells as an early event, prostate cancer is heterogeneous with a pre-existing clone of androgen independent cells.[14, 15]
  • Prostate stem/progenitor cell has been suggested by studies to be the cell of origin of prostate cancer and it has similar molecular and genetic characteristics with the CRPC cell.[16]
Clinical study 
  • PTEN loss in advanced prostate cancer: Greater than 50% of advanced prostate cancer cells had PTEN deletion compared to early cancer, suggesting PTEN loss is an adaptive change.[17-20]
  • AR mutations in advanced prostate cancer, suggesting an adaptive change due to the altered hormonal environment.[21, 22]
  • PTEN loss in early prostate cancer, a characteristic of CRPC cells.[23-25]
  • AR mutations in early human prostate cancer, suggesting the pre-existence of an androgen-independent clone.[26-30]

Development of CRPC

  1. Top of page
  2. Abstract
  3. Introduction
  4. Development of CRPC
  5. Adaptation model
  6. Clonal selection model
  7. Genetic/epigenetic alterations pertinent to both models
  8. Prostate stem/progenitor cells and the clonal selection model
  9. Conclusion and future prospects
  10. Acknowledgments
  11. Conflict of interest
  12. References

Primary prostate cancer cells retain the androgen dependent characteristic of normal prostate cells, and thus respond to androgen withdrawal by a combination of growth arrest and apoptosis. After the initial response to androgen deprivation therapy, all metastatic prostate cancer cells eventually resume growth and progress to an unresponsive and aggressive castration-resistant state. However, studies have shown that CRPC continues to depend on androgens and AR function for growth and survival despite castrate levels of testosterone through several possible mechanisms.[2, 3] It has become obvious that androgen biosynthesis and AR function are significantly altered in CRPC, with the ultimate goal of efficient utilization of limited androgen supply. The observed response of CRPC to secondary hormonal manipulations (e.g. the androgen synthesis inhibitor, abiraterone, and second generation androgen receptor blocker, MDV3100) lays credence to this assertion. Several mechanisms have been implicated, including AR gene amplification, alteration of AR co-repressors/co-activators, copy number gain and gain of function mutations. These alterations manifest as: hypersensitive AR (AR being able to respond to minute levels of androgen), promiscuous AR (widened AR specificity to include non-androgens), the outlaw AR (AR activation by ligand-independent pathways) and intratumoral, autocrine and paracrine androgen synthesis. Discussion of these pathways is outside the scope of this review, they have been discussed in detail in other reviews.[31, 32]

Adaptation model

  1. Top of page
  2. Abstract
  3. Introduction
  4. Development of CRPC
  5. Adaptation model
  6. Clonal selection model
  7. Genetic/epigenetic alterations pertinent to both models
  8. Prostate stem/progenitor cells and the clonal selection model
  9. Conclusion and future prospects
  10. Acknowledgments
  11. Conflict of interest
  12. References

Evidence in earlier studies that support the “adaptation” model can be drawn from the results of studying the androgen-dependent Shionogi mouse mammary carcinoma. Mouse mammary carcinoma (Shionogi carcinoma 115) was developed in 1964[33] when human prostate cancer cell lines or xenograft and murine autochthonous prostate cancer models were yet to be available. The Shionogi carcinoma 115 was exploited to delineate the mechanisms by which androgens control cell proliferation in hormone responsive tumors, especially breast and prostate cancers, because of its unique androgen-dependent property. Several studies observed that the frequency of androgen-independent cells in the Shionogi tumors that regress after castration is much lower than in recurrent hormone refractory tumors, suggesting that androgen-dependent cells adapt to an altered hormonal environment, possibly by acquiring growth-promoting and survival properties.[9-11] Conclusions were drawn from further studies that the emergence of androgen-independent growth is the result of an adaptive process involving the expression of protooncogenes, such as c-fos and c-myc[12] or secreted GF, which act in a paracrine manner.[7] There are, however, a number of limitations to these conclusions. First, results obtained from mouse mammary carcinoma were extrapolated to prostate cancer solely because of their shared characteristic of androgen dependence. Second, all earlier studies were based on observations of gross changes in cells proliferation or regression in an altered hormonal environment without inquiring into molecular, genetic and biochemical changes that accompanied androgen withdrawal during the transformation of the cells to a castration-resistant state.

Subsequent advances in technology paved the way for studies that focused on the molecular events of prostate cancer progression to CRPC. The fact that prostate cancer cells depend on androgens for proliferation led to the suspicion that androgen-independent growth might arise from altered responsiveness of AR or disruption of the intracellular androgen signaling pathways. Aberrations in AR show an abnormal function, probably through reduced specificity of the AR-binding domain and receptor hypersensitivity. It was also hypothesized that the selective pressure of ADT promotes mutations in the androgen signaling pathway. For instance, AR mutation is common, with a frequency as high as 50% in advanced prostate cancer,[26, 34-36] suggesting it is an adaptive change in response to an altered hormonal environment leading to eventual emergence of androgen independence.[21, 22] However, with the development of more sensitive assay techniques, AR mutation and altered expression, though to a lesser extent, also occur in primary prostate cancer before androgen deprivation therapy.[26-30] This argues against an adaptive process and supports the possible pre-existence of androgen-independent cells with altered AR at the stage of cancer initiation. One could also argue that if the pre-existing cells with AR mutation account for only a minority of the tumor cells at the outset, detection might be difficult or impossible until the cells predominate when selected by ADT.

Clonal selection model

  1. Top of page
  2. Abstract
  3. Introduction
  4. Development of CRPC
  5. Adaptation model
  6. Clonal selection model
  7. Genetic/epigenetic alterations pertinent to both models
  8. Prostate stem/progenitor cells and the clonal selection model
  9. Conclusion and future prospects
  10. Acknowledgments
  11. Conflict of interest
  12. References

The clonal selection hypothesis arose from some early studies mainly on the Dunning R-3327-H rat prostate adenocarcinoma model, which mimics many of the properties of human prostate cancer (androgen dependence, AR and prostate-specific antigen expression). Using fluctuation analyses, researchers compared the doubling times of tumors and discovered that the difference in tumor growth rate observed between the castrated and intact animals could not be a result of environmental adaptation.[14, 15] They thus concluded that prostate cancer is composed of heterogeneous cells, of which a minority is a pre-existing clone of castration-resistant cells. When exposed to an androgen-deprived environment, these cells are selected for their survival and proliferative advantage, whereas the androgen-dependent cells are eliminated, giving rise to recurrence and a castration-resistant state. With subsequent advances in transgenic technology, Gingrich et al. sought to directly examine the impact of androgen ablation on the progression of prostate cancer to the state of castration resistance using the transgenic adenocarcinoma of the mouse prostate (TRAMP) model, developed by abrogating functional expression of the p53 and Rb tumor suppressor genes. They concluded that molecular events leading to androgen independence and metastasis occur early in the natural history of prostate cancer and these changes remain silent until selective pressure of androgen deprivation is applied.[13]

Using human prostate cancer cell lines (LAPC-4 and LAPC-9), Graft et al. carried out serial dilution and fluctuation analysis in male and female mice.[8] They found that prostate cancer progresses to androgen independence through two distinct stages: initially escaping dependence on androgen for survival and, subsequently, for growth. The latter stage of androgen independence, they argue, resulted from clonal expansion of androgen independent cells that are present at a frequency of approximately 1 per 105–106 androgen-dependent cells. Thus, they concluded that prostate cancer contains heterogeneous mixture of cells that vary in their dependence on androgen and that ADT provides selective pressure leading to outgrowth of androgen independent cancers. However, as compelling as these results might be, one can argue that the inability to isolate the supposed pre-existing androgen-independent cells in early primary prostate cancer before ADT questions the validity of such a conclusion. It is therefore obvious that more studies are required to isolate the pre-existing cells and elucidate their specific molecular-genetics that confer castration-resistant characteristics. The answer to this query is now increasingly being supported by the identification of prostate cancer stem-cells, as will be discussed subsequently in the present review. The two models are shown in Figure 1, with their supporting evidence summarized in Table 1.

Genetic/epigenetic alterations pertinent to both models

  1. Top of page
  2. Abstract
  3. Introduction
  4. Development of CRPC
  5. Adaptation model
  6. Clonal selection model
  7. Genetic/epigenetic alterations pertinent to both models
  8. Prostate stem/progenitor cells and the clonal selection model
  9. Conclusion and future prospects
  10. Acknowledgments
  11. Conflict of interest
  12. References

Prostate cancer initiation and progression to CRPC is believed to be a consequence of accumulation of multiple genetic alterations. Several types of genetic aberrations including mutations, deletions, copy number alterations and gene fusions have been identified in prostate cancer affecting a large number of oncogenes (e.g. C-MYC, BCL-2 and ERG) and tumor suppressor genes (e.g. PTEN, NKX3-1 and p53).[17, 37-40] Some of these alterations are thought to be adaptive changes in response to androgen deprivation as prostate cancer progresses to CRPC, whereas others are early events that facilitate tumor initiation and subsequent progression. Critical alterations that drive prostate cancer initiation and/or progression are to be briefly discussed below.

PTEN

PTEN has been identified as a tumor suppressor gene in many cancers including prostate cancer.[41] The loss of this gene has often been associated with prostate cancer progression to an advanced and castration-resistant state. PTEN was initially observed by earlier studies to be frequently mutated or deleted in advanced prostate cancer,[17-20] some reported its loss of function or deletion in greater than 50% of advanced prostate cancers.[17, 19] These observations suggest that PTEN loss is probably an adaptive change to the selective pressure of ADT during prostate cancer progression and this confers survival and proliferative advantages on the cancer cells, which eventually transform to a castration-resistant state (adaptation model; Fig. 1).

However, improvements in assay techniques led to the identification PTEN loss in subsequent studies on early (primary) prostate cancer, albeit at a lower frequency. Graff et al.[23] suggested that PTEN mutations in prostate cancer cells might be an early event that is independent of the selective pressure of androgen blockade, a number of other studies also had similar conclusions.[24, 25] Thus, one could hypothesise that these PTEN null prostate cancer cells might be a pre-existing minority clone of cells at the onset of disease, but remain quiescent until selected for their survival and proliferative advantage by ADT such that the observed increase in the frequency of PTEN loss is a product of proliferation and subsequent preponderance of the pre-existing PTEN null, castration-resistant cancer cells rather than a late acquired event (Fig. 1). More recent studies on PTEN have further lay credence to the clonal selection model by showing that PTEN loss is a characteristic of a putative pre-existing cell that is thought to be responsible for prostate cancer initiation/progression to CRPC (the prostate cancer stem-cell hypothesis).

NKX3-1

NKX3-1 is a homeobox transcription factor gene located at 8p21.2. Loss of heterozygosity at chromosome 8p is a common genetic aberration in early primary prostate cancer and high-grade PIN.[42, 43] NKX3-1 depends on androgens for expression, and regulates the embryological development and differentiation of prostate epithelial cells. Decreased expression of NKX3-1 is associated with prostate cancer initiation, and further reduction is often seen in prostate cancer progression.[44] Earlier studies suggested a progressive decline and often complete loss of NKX3-1 expression in advanced prostate cancer.[45] Recent studies using highly sensitive techniques and antibodies, however, showed that NKX3-1 alterations can be detected in all stages of prostate cancer though at lower levels in advanced disease.[46]

C-MYC

The alteration of the 8q24 chromosomal region that harbors the C-MYC protooncogene is often associated with prostate cancer and especially the aggressive, advanced disease. The C-MYC protein is a transcription factor that regulates several cellular processes including cell growth and proliferation, cell cycle progression, transcription, differentiation, apoptosis, and cellular motility. Its deregulation might lead to genomic instability, uncontrolled cell proliferation, immortalization and independence of growth factors.[47, 48] It was first shown in prostate cancer by Fleming et al. that C-MYC expression is significantly higher in prostate cancer than BPH and normal prostate epithelial cells.[49] This finding was subsequently confirmed by other researchers.[50, 51] C-MYC alteration was more commonly observed as most tumors progress to advanced and metastatic stages.[50-53] Metastatic prostate cancer was shown to have over 20% frequency of C-MYC amplification compared with just 2–8% in primary tumors.[51, 52] Thus, C-MYC amplification was generally believed to be an adaptive change in the progression of prostate cancer. Only a few recent studies have shown C-MYC amplification or overexpression in both PIN and primary prostate cancer.[54] Based on the evidence from these studies, one could make the assumption that C-MYC alteration probably plays a role at some point in prostate cancer progression to CRPC, but the exact mechanism and its relative contribution to the process is unclear.

BCL-2

BCL-2 is an anti-apoptotic oncoprotein upregulated in many human cancers. It was first implicated in the molecular pathogenesis of human follicular lymphoma[55] and subsequently in other tumors including prostate cancer. It confers survival properties to tumor cells by impeding the normal cellular apoptotic mechanisms that regulate cell turnover,[56, 57] thus augmenting cell proliferation and tumor growth. Earlier works showed the frequent association of BCL-2 overexpression with prostate cancer progression to CRPC. McDonnell et al. found that all CRPC samples stained positive for BCL-2, whereas 70% of the androgen-dependent tumors were negative.[58] Similar results were reported by other researchers.[59-65] In prostate cancer cell lines, increased BCL-2 expression in androgen-independent LNCaP cells promotes androgen-independent growth of the cells,[62, 66] and conversely experimental inhibition of BCL-2 expression results in delayed progression of prostate cancer cells to an androgen-independent state.[67] However, the therapeutic benefits of BCL-2 inhibition could not be shown in an in vivo study.[68] Recent evidence has shown that BCL-2 expression can also increase in PIN, as well as in normal basal epithelial cells,[64, 65, 69-71] and during progression from PIN to advanced prostate cancer,[69] suggesting that BCL-2 protein expression is associated with early prostate tumorigenesis. The increased expression in basal epithelial cells, which are thought to the cells of origin of prostate cancer and CRPC, offers support to the clonal selection hypothesis.

p53

The observation that wild-type p53 suppresses growth of human prostate cancer cell lines containing mutant p53 alleles strengthened the suspicion of its role in prostate cancinogenesis.[72] Several studies have shown a consistent association of p53 mutations with prostate cancer; however, the frequency of detected alterations is relatively low (0–50%) compared with that seen in other cancers (60–80% in breast, lung and colon cancers).[73, 74] The results from most studies suggested a higher tendency of p53 gene mutation during prostate cancer progression to advanced, metastatic/castration-resistant disease with absent or infrequent mutations in early primary prostate cancer.[73, 75-81] Further evidence was obtained from a recent large-scale study by Schlomm et al. of 2514 prostate cancer specimens from radical prostatectomy, in which the p53 mutation was found in just 2.5% of the samples.[75] Thus, p53 mutations in prostate cancer might be an adaptive change in the progression to CRPC.

On the contrary, there are some studies suggesting that p53 mutations occur relatively early in prostate cancer, and might also be detected in normal prostate epithelium and PIN. Heidenberg et al. found up to 80% of p53 mutations in some cases of primary prostate cancer, although they also found that the frequency of mutations increases as the tumor progresses.[81] There are also reports of p53 mutation in the normal prostatic epithelium of prostate cancer patients.[82, 83] These findings suggest that p53 mutations might be acquired early, in preneoplastic or at least at the onset of prostate cancer.

TMPRSS2-ERG

The fusion of TMPRSS2, an androgen regulated gene, to the oncogenic ETS transcription family genes (ERG, ETV1 and ETV4), is implicated in prostate cancer initiation and frequently observed in clinically localized prostate cancer.[84-88] Studies have shown that the most common gene rearrangement seen in more than 50% of primary prostate cancer is TMPRSS2-ERG gene fusion.[84, 85, 89] TMPRSS2-ERG is generated by heterogeneous intronic deletion between TMPRSS2 and ERG in close proximity on chromosome 21q22.2–3, this leads to overexpression of the oncogenic ETS genes[90] and, consequently, enhanced cell proliferation and carcinogenesis. A study by Perner et al. showed the association of TMPRSS2-ERG with HGPIN, suggesting it as an early molecular event associated with invasion and organ-confined androgen-dependent prostate cancer.[89] Although the TMPRSS2-ERG fusion gene is highly relevant in androgen-dependent prostate cancer, it has been shown to be bypassed in late stage castration-resistant prostate cancer in which oncogenic ERG is overexpressed through other mechanisms independent of TMPRESS2.[91]

From the above discussion it is obvious that there is evidence for and against either model. However, genetic/epigenetic aberrations previously thought to be exclusively or predominantly associated with advanced prostate cancer are now increasingly detected in early and premalignant disease because of the increasing sophistication and sensitivity of current assay techniques. These findings have built a strong case for the clonal selection model as the probable dominant model. It must also be noted, however, that the variable observations by researchers might also be a reflection of the complexity of the process of prostate cancer initiation/progression, and the limitations of prevailing knowledge and technology. In addition, the molecular-genetic heterogeneity, and subtle geographic and racial differences of prostate cancers only serves to complicate the interpretation of a number of these findings. Thus, further research and improvement in technology might elucidate the process.

Prostate stem/progenitor cells and the clonal selection model

  1. Top of page
  2. Abstract
  3. Introduction
  4. Development of CRPC
  5. Adaptation model
  6. Clonal selection model
  7. Genetic/epigenetic alterations pertinent to both models
  8. Prostate stem/progenitor cells and the clonal selection model
  9. Conclusion and future prospects
  10. Acknowledgments
  11. Conflict of interest
  12. References

The strongest evidence for the clonal selection model of CRPC comes from the CSC hypothesis. CSCs are a minority of tumor cells capable of self-renewal and differentiation.[16, 92-97] The putative pre-existing castration-resistant cells alluded to by the clonal selection model share the same characteristics with prostate CSCs. The CSC model proposes that cells within a tumor are heterogeneous and exist in a hierarchical lineage relationship with different proliferative potentials. The concept was first described and became well established in acute myeloid leukemia,[98] and to date it remains the prototype against which others are judged. However, CSCs, unlike normal stem cells, differentiate and self-renew in a dysregulated manner.

CSCs have been identified in solid tumors including prostate cancer. Collins et al. isolated from prostate cancer prostatectomy specimens and characterized putative prostate CSCs (CD44+, 2β1hi+, CD133+) with self-renewal properties for the first time. They estimated that approximately 0.1% of tumor cells showed this phenotype.[99] Subsequent studies provided further evidence that tumorigenic stem cells are responsible for prostate cancer initiation, and progression to androgen-independence and resistance to cell death.[92, 96, 100] The putative prostate CSCs are thought to arise from multilineage stem cells, which either develop this capacity by accumulation of genetic alterations over time[93, 97, 101, 102] or as an alternative hypothesis, might be the result of an arrest of differentiation in stem cell development.[94, 103] These cells are thought to constitute a minority of the prostate cancer cells and remain so as the tumor progresses. Only after ADT are they selected for their growth and survival advantage (castration-resistance), and proliferate to predominate as CRPC. Facilitated by new tools, such as transgenic mouse and lineage tracing, a number of recent studies have provided further evidence that corroborates the clonal selection model. By lineage tracking, Wang et al. identified a small population of luminal cells in the mouse prostate known as CARN, which have survived androgen depletion and express NKX3-1.[103] When androgen is restored in the mice, CARN can give rise to basal, luminal and neuroendocrine cells in prostate regeneration assay. Furthermore, when PTEN is deleted in these cells, they can form carcinomas. They thus concluded that CARN can serve as cells of origin of prostate cancer. That study provides direct evidence for the existence of castration resistant cell clones, but also raises the questions of whether CARN exist in the prostate before castration and whether the human prostate also contains CARN. To address these questions, Germann et al. took advantage of the human prostate cancer BM18 xenograft model which is highly castration-sensitive and identified CRSC with properties similar to CARN.[104] CRSCs express luminal markers including NKX3-1, CK18 and a low level of AR, and can reinitiate tumor growth after androgen restoration. That study thus shows the existence of CARN in human prostate cancer cells, which might be responsible for the development of CRPC. We expect that future studies will provide additional proof for the existence of CARN in primary prostate cancer, and settle the debate once and for all.

Conclusion and future prospects

  1. Top of page
  2. Abstract
  3. Introduction
  4. Development of CRPC
  5. Adaptation model
  6. Clonal selection model
  7. Genetic/epigenetic alterations pertinent to both models
  8. Prostate stem/progenitor cells and the clonal selection model
  9. Conclusion and future prospects
  10. Acknowledgments
  11. Conflict of interest
  12. References

Current evidence appears to be in favor of the clonal selection model (Table 1); however, it is still difficult to clearly establish any of the models as the definite or exclusive mechanism. It is also possible that both models independently or cooperatively contribute to the development of CRPC in a patient. The revelation of such information holds potential benefits, especially with regards to the timing and mode of therapeutic intervention. If the suggestion of the pre-existence of a clone of CRPC cells with prostate cancer stem/progenitor cell properties holds, then therapeutic strategies directed at eliminating these cells at the time the tumor is apparently “androgen sensitive” will probably have curative outcomes compared with those that seek to reverse or curtail established CRPC. It is on this basis that some researchers argue for the use of combination therapy targeting both the androgen dependent and independent cells simultaneously rather than waiting for CRPC to ensue. In contrast, if the adaptation model is the prevailing model, then a search for the specific genetic and molecular mechanisms that occur in these transformed cells will provide useful therapeutic targets directed at the later stages of the disease and targeted strategies can be developed to prevent the transformation of previously androgen-dependent cells to a castration-resistant state. With new insights into the molecular pathogenesis of this disease, it is hoped that emerging novel therapeutic targets will provide more effective and durable treatment outcomes.

Acknowledgments

  1. Top of page
  2. Abstract
  3. Introduction
  4. Development of CRPC
  5. Adaptation model
  6. Clonal selection model
  7. Genetic/epigenetic alterations pertinent to both models
  8. Prostate stem/progenitor cells and the clonal selection model
  9. Conclusion and future prospects
  10. Acknowledgments
  11. Conflict of interest
  12. References

This work was supported by grants from the National Institutes of Health (1R01GM090293-0109 to L.-C.L.) and the Department of Defense (W81XWH-08-1-0260 to L.-C.L.). MA is supported by the UCSF-SIU Research fellowship.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Development of CRPC
  5. Adaptation model
  6. Clonal selection model
  7. Genetic/epigenetic alterations pertinent to both models
  8. Prostate stem/progenitor cells and the clonal selection model
  9. Conclusion and future prospects
  10. Acknowledgments
  11. Conflict of interest
  12. References