Abstract
Androgens regulate biological pathways to promote proliferation, differentiation, and survival of benign and malignant prostate tissue. Androgen receptor (AR) targeted therapies exploit this dependence and are used in advanced prostate cancer to control disease progression. Contemporary treatment regimens involve sequential use of inhibitors of androgen synthesis or AR function. Although targeting the androgen axis has clear therapeutic benefit, its effectiveness is temporary, as prostate tumor cells adapt to survive and grow. The removal of androgens (androgen deprivation) has been shown to activate both epithelial-to-mesenchymal transition (EMT) and neuroendocrine transdifferentiation (NEtD) programs. EMT has established roles in promoting biological phenotypes associated with tumor progression (migration/invasion, tumor cell survival, cancer stem cell-like properties, resistance to radiation and chemotherapy) in multiple human cancer types. NEtD in prostate cancer is associated with resistance to therapy, visceral metastasis, and aggressive disease. Thus, activation of these programs via inhibition of the androgen axis provides a mechanism by which tumor cells can adapt to promote disease recurrence and progression. Brachyury, Axl, MEK, and Aurora kinase A are molecular drivers of these programs, and inhibitors are currently in clinical trials to determine therapeutic applications. Understanding tumor cell plasticity will be important in further defining the rational use of androgen-targeted therapies clinically and provides an opportunity for intervention to prolong survival of men with metastatic prostate cancer.
Introduction
Prostate cancer is the most prevalent malignancy in men, and ranks second as the cause of cancer-related deaths in the developed world (, ). Advanced prostate cancer is initially treated with androgen deprivation therapy (ADT) and subsequently with newer generation androgen-targeted therapies (ATT), approaches which rely on the central role of androgens in tumor development and growth. In the majority of patients, castrate resistant prostate cancer (CRPC) develops and tumor progression occurs despite treatment. The development of agents that more effectively block androgen receptor (AR) activity, such as enzalutamide and abiraterone, has greatly enhanced the clinical armamentarium and extended survival (–). Nonetheless, advanced prostate cancer remains incurable. Tumor cell plasticity induced by androgen deprivation may play a critical role in disease progression, and potentially provides an additional opportunity to further improve cancer control.
Progression to Castrate Resistance
While the exact mechanisms underlying the development of CRPC are not yet known, it arises when cancer cells can either maintain AR signaling in the absence of normal levels of ligand or no longer require activation of this pathway for survival and proliferation. There are a number of mechanisms that can produce this outcome, including altered functionality of the AR due to genomic events, resulting in either promiscuous (, ), constitutively activated (, ), or hypersensitive (, ) states; intraprostatic production of androgens by tumor cells themselves (); and altered growth factor and/or microenvironment signaling (–). Despite the development of multiple strategies that effectively target the androgen axis, disease progression is inevitable. This is underpinned by the accumulation of further genomic abnormalities, outgrowth of different clonal populations of tumor cells, and the adaptive response of cancer cells to therapy. In this review, we focus on adaptive changes induced by therapy, specifically epithelial-to-mesenchymal plasticity (EMP) and neuroendocrine transdifferentiation (NEtD), which may contribute to the development of advanced disease (Figure 1). A better understanding of these processes will contribute to the development of new therapeutic strategies that may potentially enhance the efficacy of androgen-targeted agents and delay disease progression.
Figure 1
Epithelial-To-Mesenchymal Plasticity
Epithelial-to-mesenchymal transition (EMT) is a process by which adherent, polar cells with an otherwise epithelial phenotype develop more migratory and invasive properties through altered gene expression (–). Both EMT and the related process mesenchymal-to-epithelial transition are physiological mechanisms important in development and tissue repair. However, when differentiated epithelium begins to display mesenchymal characteristics it is often a sign of disease progression in cancers (, –). EMT is commonly characterized by the loss of epithelial markers (typically E-cadherin, epithelial cytokeratins, and desmosomes), and gain of mesenchymal markers (such as N-cadherin, vimentin, and fibronectin) and transcriptional repressors of E-cadherin (Twist1, Snai1, Snai2, Zeb1, Zeb2) (, ). EMT has been associated with advanced prostate cancer, and correlated with aggressive behavior and therapy resistance in primary tumors (, –).
Neuroendocrine Transdifferentiation
While men may present with prostate cancer demonstrating various neuroendocrine features (), the prevalence of neuroendocrine differentiation increases following ADT and in CRPC (–). These cells not only express neuropeptides, reminiscent of the normal NE cells of the prostate, but also proteins that are characteristic of prostate epithelial cells [such as prostatic acid phosphatase cytokeratin 8/18 and/or epithelial adhesion molecules and proliferation markers (, )], while AR expression is typically absent or low (). Importantly, the number of NE-like prostate cancer cells is positively associated with the duration of hormone deprivation therapy (–). There are several hypotheses for the origin of NE-like prostate cancer cells. It has been postulated that NE-like cancer cells can arise during disease progression from NE cells of the prostate (). However, the observation that genetic aberrations are common to both the adenocarcinoma and NE-like cells (–) suggests that this is not likely to be a common mechanism. An alternative explanation is that a common progenitor prostate cancer stem cell gives rise to both the NE-like and adenocarcinoma components and both these components continue to evolve and respond to selective pressures in parallel (, , , ). In contrast, NEtD is a process that can enable prostatic adenocarcinoma cells to gain NE characteristics without relying on genetic divergence. NEtD can occur after prolonged androgen deprivation, and has recently been reported in a patient derived xenograft (). This mechanism would potentially enable tumor cells to reduce ATT-induced apoptosis and thus provide an adaptive pathway that would contribute to the development of CRPC ().
Androgens Suppress Neuroendocrine Transdifferentiation
Evidence of NEtD has been observed in both in vitro and in vivo studies. LNCaP cells, an androgen dependent prostate cancer cell line derived from a lymph node metastasis, undergo NEtD when exposed to media lacking androgens (, –). In low-androgen conditions, LNCaP cells take on an altered elongated neuron-like phenotype, gain cytoplasmic secretory granules, and undergo growth arrest. This is accompanied by an increase in expression of NE markers and a decrease in AR and PSA levels. This transdifferentiation is reversible with the addition of androgens (DHT) to the media, an observation consistent with the identical allelic profiles of NEtD LNCaP and parental LNCaP cells. Silencing of the AR using siRNA also induces NEtD in LNCaP cells, suggesting that AR signaling suppresses NEtD (). In vivo studies also provide support for the NEtD model. Castration of nude mice bearing prostate cancer xenografts LNCaP, PC-295, CWR22, and PC-310 increased the number of tumor cells expressing NE markers, consistent with induction of NEtD (–). Furthermore, implantation of primary patient tumor tissues from a population of adenocarcinoma cells implanted under the renal capsule of castrated mice appear to undergo an NEtD en masse as an adaptive response ().
Therapy-Induced EMT
There is accumulating evidence supporting that ADT may induce an EMT, and that this is particularly prominent with the newer generation ATT. ADT has been associated with an increase in the expression of mesenchymal markers N-cadherin, vimentin, Zeb1, Twist1, and Snai2, with a concomitant loss of E-cadherin in patient derived xenografts and clinical prostate tumors (, –). Traditionally, investigations have primarily focused on the effects of targeting AR signaling in prostate cancer cells; however, ADT/ATT is not specific to tumor cells alone. Recent reports demonstrate significant effects of ADT/ATT on the tumor microenvironment, including stromal and immune cells (, , ). For instance, elevated numbers of tumor associated macrophages have been reported in men undergoing ADT (), and these cells have been shown to promote local invasion and metastatic dissemination of tumor cells in response to ADT (, –). Hence, the implications of targeting the androgen axis and its effect on the multiple cell types comprising the tumor microenvironment needs to be assessed when considering therapeutic interventions.
Therapy-Induced EMT and Neuroendocrine Transdifferentiation as Clinical Targets
Therapeutically targeting regulators of EMP/NEtD is an attractive concept that has recently matured to clinical trials (Figure 1). Brachyury is a transcription factor required for the developmental EMT that generates mesoderm by converting epithelial cells into migratory mesenchymal cells (). In tumor cells, including prostate cancer, Brachyury also induces EMT and an invasive phenotype (–). Furthermore, Brachyury is overexpressed at both the transcript and protein level in clinical prostate cancer specimens, and nuclear expression is associated with metastasis (). While the regulation of Brachyury by androgen-targeted therapies has not been addressed, Brachyury motifs were highly enriched in AR bound promoters when LAPC-4 cells were grown in the presence of AR antagonist flutamide (). Furthermore, in silico bioinformatic analysis using transcriptional profiles from clinical prostate cancer specimens and clustering Brachyury co-expressed genes by functional role/signaling pathways demonstrated an enrichment for regulation of neuron differentiation and nervous system development (). An inverse relationship between Brachyury and E-cadherin expression, with a concomitant positive correlation of Brachyury with EMT promoting genes FN1, Snai1, IL8, and TGF-β was also observed. Thus, we hypothesize that targeting Brachyury in the context of ATT may modulate the emergence of both a neuroendocrine phenotype and EMP by preventing, for example, the induction of Brachyury mediated release of migration/invasion promoting soluble factors into the tumor microenvironment (, , ). GI-6301 (Tarmogen) is a Brachyury vaccine () currently in Phase I clinical trial in patients with metastatic or unresectable locally recurrent cancers who have failed previous therapy or have no further therapeutic options (NCT01519817). Recent assessment of data from patients with advanced chordoma in this trial demonstrated safety and a confirmed partial response (), and data from the larger cohort are eagerly awaited.
The receptor tyrosine kinase Axl is implicated in the Snai1-, Snai2-, IL6-, and STAT3-mediated activation of EMT (, ) as well as the metastasis promoting AKT/NF-κB and AKT/Snai2 pathways (, ) in multiple cancer types. Targeting Axl has shown promise in preclinical models of cancer progression (–), and clinical trials are currently underway. BGB324 is a small molecule inhibitor of the Axl receptor tyrosine kinase developed to block EMT with the goal of inhibiting drug-resistance and metastasis. Recent Phase Ia data have demonstrated BGB324 to be safe and well tolerated, and Phase Ib studies commenced in non-small cell lung cancer and acute myeloid leukemia in 2014. Cabozantinib is another tyrosine kinase inhibitor targeting Axl, as well as EMT promoting kinases VEGFR2, RET, KIT, FLT-1/3/4, c-MET, and Tie-2 (–). Clinically significant regression of metastatic tumors in CRPC patients was achieved with cabozantinib treatment in a Phase II trial (). Of course the precise molecular mechanism underpinning this efficacy is not clear and likely involves inhibition of multiple tyrosine kinases in several cell types. Trials investigating whether cabozantinib is a useful addition to ADT in the control of prostate cancer are currently underway (NCT01630590).
MEK inhibitors may also be useful in managing therapy-induced EMP/NEtD. In vitro, MEK inhibitor PD98059 blocked the acquisition of NE-like morphology and prevented the increase in NSE levels usually observed in LNCaP-C33 cells induced to undergo NEtD by androgen-depletion (). Ectopic expression of constitutively active AR in LNCaP cells inhibited RAF/MEK/ERK-induced NSE expression (), demonstrating the central regulatory role of AR in constraining the emergence of this phenotype. Furthermore, the RAF/MEK/ERK pathway has been shown to be necessary for the induction of Twist1, Snai1, and N-cadherin in multiple cancer models (, ). A neoadjuvant trial examining the effect of short-term MEK inhibition (trametinib) prior to radical prostatectomy in the context of ADT on markers of EMT (N-cadherin, vimentin) has recently commenced (NCT01990196).
Finally, Aurora kinase A (AURKA) inhibitors may also be effective in inhibiting ATT-induced EMP/NEtD as they suppress both EMT and NEtD in vitro and in vivo (, ). In cancer cells, AURKA has been demonstrated to play an important role in the genesis of a more mesenchymal phenotype via down-regulation of E-cadherin and up-regulation of vimentin (). Clinical trials examining the role of the inhibitors in prostate cancer are currently ongoing (NCT01799278, NCT01094288).
Despite independent lines of evidence implicating key factors in both EMT and NEtD, the functional and molecular relationship between these states in prostate cancer has not been extensively explored. McKeithen et al. () have demonstrated that the well-established EMT-inducing transcription factor Snai1 induced both EMT and NEtD in LNCaP cells as defined by morphology and marker expression. However, as the data are mostly presented as analyses of bulk populations of cells, it is not possible to determine whether EMT and NEtD phenotypes are co-expressed within individual cells, and are thus intimately linked, or whether these transdifferentiation processes are independent of each other and become activated by influences such as neighboring cells, local microenvironmental cues, or cell intrinsic factors.
Concluding Remarks
Multiple factors are clearly involved in the progression to CRPC during treatment with ATT. Studies over the past two decades have associated blockade of the androgen axis with the increased prevalence of neuroendocrine prostate cancer. These observations, in combination with recent reports of androgen deprivation modulating EMP, suggest novel strategies for therapeutic intervention. Further studies will be required to determine whether these adaptive response pathways have a functional role in the progression to CRPC or are simply a consequence of removing the differentiation pressure imposed by active androgen signaling on prostate cells. Moreover, revealing if and how these plasticity pathways intersect in the androgen-targeted environment will be an intriguing area for future research. Improved understanding of the molecular pathways underlying the adaptive responses to ATT provides opportunities to investigate whether targeted inhibition of these pathways will delay tumor progression and thus improve outcomes for men with prostate cancer.
Statements
Acknowledgments
The authors’ research is supported by the Movember Foundation and the Prostate Cancer Foundation of Australia through a Movember Revolutionary Team Award. Brett G. Hollier is supported by a Queensland Government Smart Futures Fund Fellowship.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
JemalASiegelRXuJWardE. Cancer statistics, 2010. CA Cancer J Clin (2010) 60:277–300.10.3322/caac.20073
2
SiegelRMaJZouZJemalA. Cancer statistics, 2014. CA Cancer J Clin (2014) 64:9–29.10.3322/caac.21208
3
DreicerRMacLeanDSuriAStadlerWMShevrinDHartLet alPhase I/II trial of orteronel (TAK-700) – an investigational 17,20-lyase inhibitor – in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res (2014) 20:1335–44.10.1158/1078-0432.CCR-13-2436
4
JosephJDLuNQianJSensintaffarJShaoGBrighamDet alA clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509. Cancer Discov (2013) 3:1020–9.10.1158/2159-8290.CD-13-0226
5
RathkopfDEMorrisMJFoxJJDanilaDCSlovinSFHagerJHet alPhase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer. J Clin Oncol (2013) 31:3525–30.10.1200/JCO.2013.50.1684
6
HeidenreichABastianPJBellmuntJBollaMJoniauSvan der KwastTet alEAU guidelines on prostate cancer. Part II: treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol (2014) 65:467–79.10.1016/j.eururo.2013.11.002
7
FujimotoNMiyamotoHMizokamiAHaradaSNomuraMUetaYet alProstate cancer cells increase androgen sensitivity by increase in nuclear androgen receptor and androgen receptor coactivators; a possible mechanism of hormone-resistance of prostate cancer cells. Cancer Invest (2007) 25:32–7.10.1080/07357900601130698
8
TsaoCKGalskyMDSmallACYeeTOhWK. Targeting the androgen receptor signalling axis in castration-resistant prostate cancer (CRPC). BJU Int (2012) 110:1580–8.10.1111/j.1464-410X.2012.11445.x
9
AttarRMTakimotoCHGottardisMM. Castration-resistant prostate cancer: locking up the molecular escape routes. Clin Cancer Res (2009) 15:3251–5.10.1158/1078-0432.CCR-08-1171
10
DehmSMSchmidtLJHeemersHVVessellaRLTindallDJ. Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Res (2008) 68:5469–77.10.1158/0008-5472.CAN-08-0594
11
VisakorpiTHyytinenEKoivistoPTannerMKeinanenRPalmbergCet alIn vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet (1995) 9:401–6.10.1038/ng0495-401
12
WalteringKKHeleniusMASahuBManniVLinjaMJJanneOAet alIncreased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens. Cancer Res (2009) 69:8141–9.10.1158/0008-5472.CAN-09-0919
13
LockeJAGunsESLubikAAAdomatHHHendySCWoodCAet alAndrogen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res (2008) 68:6407–15.10.1158/0008-5472.CAN-07-5997
14
LaiJJLaiKPChuangKHChangPYuICLinWJet alMonocyte/macrophage androgen receptor suppresses cutaneous wound healing in mice by enhancing local TNF-alpha expression. J Clin Invest (2009) 119:3739–51.10.1172/JCI39335
15
LobergRDYingCCraigMYanLSnyderLAPientaKJ. CCL2 as an important mediator of prostate cancer growth in vivo through the regulation of macrophage infiltration. Neoplasia (2007) 9:556–62.10.1593/neo.07307
16
LubikAAGunterJHHollierBGEttingerSFazliLStylianouNet alIGF2 increases de novo steroidogenesis in prostate cancer cells. Endocr Relat Cancer (2013) 20:173–86.10.1530/ERC-12-0250
17
SunYWangBELeongKGYuePLiLJhunjhunwalaSet alAndrogen deprivation causes epithelial-mesenchymal transition in the prostate: implications for androgen-deprivation therapy. Cancer Res (2012) 72:527–36.10.1158/0008-5472.CAN-11-3004
18
ZhuPBaekSHBourkEMOhgiKAGarcia-BassetsISanjoHet alMacrophage/cancer cell interactions mediate hormone resistance by a nuclear receptor derepression pathway. Cell (2006) 124:615–29.10.1016/j.cell.2005.12.032
19
AktasBTewesMFehmTHauchSKimmigRKasimir-BauerS. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res (2009) 11:R46.10.1186/bcr2333
20
ChafferCLThompsonEWWilliamsED. Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs (2007) 185:7–19.10.1159/000101298
21
HugoHAcklandMLBlickTLawrenceMGClementsJAWilliamsEDet alEpithelial-mesenchymal and mesenchymal-epithelial transitions in carcinoma progression. J Cell Physiol (2007) 213:374–83.10.1002/jcp.21223
22
SaidNABMWilliamsED. Remodelling the malignant phenotype: impact of EMT. Drug Discov Today Dis Models (2009) 6:21–5.10.1016/j.ddmod.2008.12.002
23
ThompsonEWWilliamsED. EMT and MET in carcinoma-clinical observations, regulatory pathways and new models. Clin Exp Metastasis (2008) 25:591–2.10.1007/s10585-008-9189-8
24
BhanguAWoodGMirnezamiADarziATekkisPGoldinR. Epithelial mesenchymal transition in colorectal cancer: seminal role in promoting disease progression and resistance to neoadjuvant therapy. Surg Oncol (2012) 21:316–23.10.1016/j.suronc.2012.08.003
25
DingWNowakowskiGSKnoxTRBoysenJCMaasMLSchwagerSMet alBi-directional activation between mesenchymal stem cells and CLL B-cells: implication for CLL disease progression. Br J Haematol (2009) 147:471–83.10.1111/j.1365-2141.2009.07868.x
26
KimSHYuMARyuESJangYHKangDH. Indoxyl sulfate-induced epithelial-to-mesenchymal transition and apoptosis of renal tubular cells as novel mechanisms of progression of renal disease. Lab Invest (2012) 92:488–98.10.1038/labinvest.2011.194
27
TurleyEAVeisehMRadiskyDCBissellMJ. Mechanisms of disease: epithelial-mesenchymal transition-does cellular plasticity fuel neoplastic progression?Nat Clin Pract Oncol (2008) 5:280–90.10.1038/ncponc1089
28
DasRGregoryPAHollierBGTilleyWDSelthLA. Epithelial plasticity in prostate cancer: principles and clinical perspectives. Trends Mol Med (2014) 20(11):643–51.10.1016/j.molmed.2014.09.004
29
Marin-AguileraMCodony-ServatJReigOLozanoJJFernandezPLPereiraMVet alEpithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer. Mol Cancer Ther (2014) 13:1270–84.10.1158/1535-7163.MCT-13-0775
30
RenDWangMGuoWHuangSWangZZhaoXet alDouble-negative feedback loop between ZEB2 and miR-145 regulates epithelial-mesenchymal transition and stem cell properties in prostate cancer cells. Cell Tissue Res (2014) 358(3):763–78.10.1007/s00441-014-2001-y
31
EpsteinJIAminMBBeltranHLotanTLMosqueraJMReuterVEet alProposed morphologic classification of prostate cancer with neuroendocrine differentiation. Am J Surg Pathol (2014) 38:756–67.10.1097/PAS.0000000000000208
32
AbrahamssonPAFalkmerSFaltKGrimeliusL. The course of neuroendocrine differentiation in prostatic carcinomas. An immunohistochemical study testing chromogranin A as an “endocrine marker”. Pathol Res Pract (1989) 185:373–80.10.1016/s0344-0338(89)80016-0
33
HiranoDOkadaYMineiSTakimotoYNemotoN. Neuroendocrine differentiation in hormone refractory prostate cancer following androgen deprivation therapy. Eur Urol (2004) 45:586–92.10.1016/j.eururo.2003.11.032
34
ItoTYamamotoSOhnoYNamikiKAizawaTAkiyamaAet alUp-regulation of neuroendocrine differentiation in prostate cancer after androgen deprivation therapy, degree and androgen independence. Oncol Rep (2001) 8:1221.
35
JibornTBjartellAAbrahamssonPA. Neuroendocrine differentiation in prostatic carcinoma during hormonal treatment. Urology (1998) 51:585–9.10.1016/S0090-4295(97)00684-5
36
di Sant’AgnesePA. Neuroendocrine differentiation in carcinoma of the prostate. Diagnostic, prognostic, and therapeutic implications. Cancer (1992) 70:254–68.10.1002/1097-0142(19920701)70:1+<254::AID-CNCR2820701312>3.0.CO;2-E
37
WafaLAPalmerJFazliLHurtado-CollABellRHNelsonCCet alComprehensive expression analysis of L-DOPA decarboxylase and established neuroendocrine markers in neoadjuvant hormone-treated versus varying Gleason grade prostate tumors. Hum Pathol (2007) 38:161–70.10.1016/j.humpath.2006.07.003
38
VashchenkoNAbrahamssonPA. Neuroendocrine differentiation in prostate cancer: implications for new treatment modalities. Eur Urol (2005) 47:147–55.10.1016/j.eururo.2004.09.007
39
YuanT-CVeeramaniSLinF-FKondrikouDZelivianskiSIgawaTet alAndrogen deprivation induces human prostate epithelial neuroendocrine differentiation of androgen-sensitive LNCaP cells. Endocr Relat Cancer (2006) 13:151–67.10.1677/erc.1.01043
40
HuangJYaoJLdi Sant’AgnesePAYangQBournePANaY. Immunohistochemical characterization of neuroendocrine cells in prostate cancer. Prostate (2006) 66:1399–406.10.1002/pros.20434
41
BeltranHTomlinsSAparicioAAroraVRickmanDAyalaGet alAggressive variants of castration-resistant prostate cancer. Clin Cancer Res (2014) 20:2846–50.10.1158/1078-0432.ccr-13-3309
42
HanselDENakayamaMLuoJAbukhdeirAMParkBHBieberichCJet alShared TP53 gene mutation in morphologically and phenotypically distinct concurrent primary small cell neuroendocrine carcinoma and adenocarcinoma of the prostate. Prostate (2009) 69:603–9.10.1002/pros.20910
43
LotanTLGuptaNSWangWToubajiAHaffnerMCChauxAet alERG gene rearrangements are common in prostatic small cell carcinomas. Mod Pathol (2011) 24:820–8.10.1038/modpathol.2011.7
44
PalmgrenJSKaravadiaSSWakefieldMR. Unusual and underappreciated: small cell carcinoma of the prostate. Semin Oncol (2007) 34:22–9.10.1053/j.seminoncol.2006.10.026
45
WilliamsonSRZhangSYaoJLHuangJLopez-BeltranAShenSet alERG-TMPRSS2 rearrangement is shared by concurrent prostatic adenocarcinoma and prostatic small cell carcinoma and absent in small cell carcinoma of the urinary bladder: evidence supporting monoclonal origin. Mod Pathol (2011) 24:1120–7.10.1038/modpathol.2011.56
46
BonkhoffHRembergerK. Differentiation pathways and histogenetic aspects of normal and abnormal prostatic growth: a stem cell model. Prostate (1996) 28:98–106.10.1002/(SICI)1097-0045(199602)28:2<98:AID-PROS4>3.0.CO;2-J
47
BonkhoffHWernertNDhomGRembergerK. Relation of endocrine-paracrine cells to cell proliferation in normal, hyperplastic, and neoplastic human prostate. Prostate (1991) 19:91–8.10.1002/pros.2990190202
48
LinDWyattAWXueHWangYDongXHaegertAet alHigh fidelity patient-derived xenografts for accelerating prostate cancer discovery and drug development. Cancer Res (2014) 74:1272–83.10.1158/0008-5472.CAN-13-2921-T
49
HoroszewiczJSLeongSSKawinskiEKarrJPRosenthalHChuTMet alLNCaP model of human prostatic carcinoma. Cancer Res (1983) 43:1809–18.
50
ShenRDoraiTSzabolesMKatzAEOlssonCAButtyanR. Transdifferentiation of cultured human prostate cancer cells to a neuroendocrine cell phenotype in a hormone-depleted medium. Urol Oncol (1997) 3:67–75.10.1016/S1078-1439(97)00039-2
51
ZelivianskiSVerniMMooreCKondrikovDTaylorRLinM-F. Multipathways for transdifferentiation of human prostate cancer cells into neuroendocrine-like phenotype. Biochim Biophys Acta (2001) 1539:28–43.10.1016/S0167-4889(01)00087-8
52
WrightMETsaiM-JAebersoldR. Androgen receptor represses the neuroendocrine transdifferentiation process in prostate cancer cells. Mol Endocrinol (2003) 17:1726–37.10.1210/me.2003-0031
53
BurchardtTBurchardtMChenMWCaoYde la TailleAShabsighAet alTransdifferentiation of prostate cancer cells to a neuroendocrine cell phenotype in vitro and in vivo. J Urol (1999) 162:1800–5.10.1016/S0022-5347(05)68241-9
54
JongsmaJOomenMHNoordzijMAVan WeerdenWMMartensGJMvan der KwastTHet alKinetics of neuroendocrine differentiation in an androgen-dependent human prostate xenograft model. Am J Pathol (1999) 154:543–51.10.1016/S0002-9440(10)65300-X
55
HussWJGregoryCWSmithGJ. Neuroendocrine cell differentiation in the CWR22 human prostate cancer xenograft: association with tumor cell proliferation prior to recurrence. Prostate (2004) 60:91–7.10.1002/pros.20032
56
JongsmaJOomenMHNoordzijMAVan WeerdenWMMartensGJvan der KwastTHet alAndrogen deprivation of the PC-310 human prostate cancer model system induces neuroendocrine differentiation. Cancer Res (2000) 60:741–8.
57
IzumiKFangLYMizokamiANamikiMLiLLinWJet alTargeting the androgen receptor with siRNA promotes prostate cancer metastasis through enhanced macrophage recruitment via CCL2/CCR2-induced STAT3 activation. EMBO Mol Med (2013) 5:1383–401.10.1002/emmm.201202367
58
LinTHIzumiKLeeSOLinWJYehSChangC. Anti-androgen receptor ASC-J9 versus anti-androgens MDV3100 (enzalutamide) or casodex (bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling. Cell Death Dis (2013) 4:e764.10.1038/cddis.2013.270
59
LinTHLeeSONiuYXuDLiangLLiLet alDifferential androgen deprivation therapies with anti-androgens casodex/bicalutamide or MDV3100/enzalutamide versus anti-androgen receptor ASC-J9(R) lead to promotion versus suppression of prostate cancer metastasis. J Biol Chem (2013) 288:19359–69.10.1074/jbc.M113.477216
60
GannonPOPoissonAODelvoyeNLapointeRMes-MassonAMSaadF. Characterization of the intra-prostatic immune cell infiltration in androgen-deprived prostate cancer patients. J Immunol Methods (2009) 348:9–17.10.1016/j.jim.2009.06.004
61
YamadaT. Caudalization by the amphibian organizer: Brachyury, convergent extension and retinoic acid. Development (1994) 120:3051–62.
62
FernandoRILitzingerMTronoPHamiltonDHSchlomJPalenaC. The T-box transcription factor Brachyury promotes epithelial-mesenchymal transition in human tumor cells. J Clin Invest (2010) 120:533–44.10.1172/JCI38379
63
ImajyoISugiuraTKobayashiYShimodaMIshiiKAkimotoNet alT-box transcription factor Brachyury expression is correlated with epithelial-mesenchymal transition and lymph node metastasis in oral squamous cell carcinoma. Int J Oncol (2012) 41:1985–95.10.3892/ijo.2012.1673
64
RoselliMFernandoRIGuadagniFSpilaAAlessandroniJPalmirottaRet alBrachyury, a driver of the epithelial-mesenchymal transition, is overexpressed in human lung tumors: an opportunity for novel interventions against lung cancer. Clin Cancer Res (2012) 18:3868–79.10.1158/1078-0432.CCR-11-3211
65
ShimodaMSugiuraTImajyoIIshiiKChigitaSSekiKet alThe T-box transcription factor Brachyury regulates epithelial-mesenchymal transition in association with cancer stem-like cells in adenoid cystic carcinoma cells. BMC Cancer (2012) 12:377.10.1186/1471-2407-12-377
66
ThomaC. Prostate cancer: Brachyury – a biomarker for progression and prognosis?Nat Rev Urol (2014) 11:485.10.1038/nrurol.2014.184
67
PeretsRKaplanTSteinIHidasGTayebSAvrahamEet alGenome-wide analysis of androgen receptor targets reveals COUP-TF1 as a novel player in human prostate cancer. PLoS One (2012) 7:e46467.10.1371/journal.pone.0046467
68
PintoFPertega-GomesNPereiraMSVizcainoJRMonteiroPHenriqueRMet alT-box transcription factor Brachyury is associated with prostate cancer progression and aggressiveness. Clin Cancer Res (2014) 20:4949–61.10.1158/1078-0432.CCR-14-0421
69
FernandoRICastilloMDLitzingerMHamiltonDHPalenaC. IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res (2011) 71:5296–306.10.1158/0008-5472.CAN-11-0156
70
HamiltonDHLitzingerMTJalesAHuangBFernandoRIHodgeJWet alImmunological targeting of tumor cells undergoing an epithelial-mesenchymal transition via a recombinant Brachyury-yeast vaccine. Oncotarget (2013) 4:1777–90.
71
HeeryCRSinghHJenniferLMarteJLMadanRAO’Sullivan CoyneGHet alNCI experience using yeast-Brachyury vaccine (GI-6301) in patients with advanced chordoma. J Clin Oncol (2014) 32:abstract 3081.
72
AsieduMKBeauchamp-PerezFDIngleJNBehrensMDRadiskyDCKnutsonKL. Axl induces epithelial-to-mesenchymal transition and regulates the function of breast cancer stem cells. Oncogene (2014) 33:1316–24.10.1038/onc.2013.57
73
PaccezJDVasquesGJCorreaRGVasconcellosJFDuncanKGuXet alThe receptor tyrosine kinase Axl is an essential regulator of prostate cancer proliferation and tumor growth and represents a new therapeutic target. Oncogene (2013) 32:689–98.10.1038/onc.2012.89
74
LiYJiaLRenDLiuCGongYWangNet alAxl mediates tumor invasion and chemosensitivity through PI3K/Akt signaling pathway and is transcriptionally regulated by slug in breast carcinoma. IUBMB Life (2014) 66:507–18.10.1002/iub.1285
75
HollandSJPanAFranciCHuYChangBLiWet alR428, a selective small molecule inhibitor of Axl kinase, blocks tumor spread and prolongs survival in models of metastatic breast cancer. Cancer Res (2010) 70:1544–54.10.1158/0008-5472.CAN-09-2997
76
YeXLiYStawickiSCoutoSEastham-AndersonJKallopDet alAn anti-Axl monoclonal antibody attenuates xenograft tumor growth and enhances the effect of multiple anticancer therapies. Oncogene (2010) 29:5254–64.10.1038/onc.2010.268
77
ZhangYXKnyazevPGCheburkinYVSharmaKKnyazevYPOrfiLet alAXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Res (2008) 68:1905–15.10.1158/0008-5472.CAN-07-2661
78
CastelloneMDCarlomagnoFSalvatoreGSantoroM. Receptor tyrosine kinase inhibitors in thyroid cancer. Best Pract Res Clin Endocrinol Metab (2008) 22:1023–38.10.1016/j.beem.2008.09.012
79
TimarJDomeB. Antiangiogenic drugs and tyrosine kinases. Anticancer Agents Med Chem (2008) 8:462–9.10.2174/187152008784533035
80
YakesFMChenJTanJYamaguchiKShiYYuPet alCabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther (2011) 10:2298–308.10.1158/1535-7163.MCT-11-0264
81
SmithMRSweeneyCJCornPGRathkopfDESmithDCHussainMet alCabozantinib in chemotherapy-pretreated metastatic castration-resistant prostate cancer: results of a phase II nonrandomized expansion study. J Clin Oncol (2014) 32(30):3391–9.10.1200/JCO.2013.54.5954
82
ZhangXQKondrikovDYuanTCLinFFHansenJLinMF. Receptor protein tyrosine phosphatase alpha signaling is involved in androgen depletion-induced neuroendocrine differentiation of androgen-sensitive LNCaP human prostate cancer cells. Oncogene (2003) 22:6704–16.10.1038/sj.onc.1206764
83
HongSKKimJHLinMFParkJI. The Raf/MEK/extracellular signal-regulated kinase 1/2 pathway can mediate growth inhibitory and differentiation signaling via androgen receptor downregulation in prostate cancer cells. Exp Cell Res (2011) 317:2671–82.10.1016/j.yexcr.2011.08.008
84
HouCHLinFLHouSMLiuJF. Cyr61 promotes epithelial-mesenchymal transition and tumor metastasis of osteosarcoma by Raf-1/MEK/ERK/Elk-1/TWIST-1 signaling pathway. Mol Cancer (2014) 13:236.10.1186/1476-4598-13-236
85
KaramitopoulouEZlobecIGloorBKondi-PafitiALugliAPerrenA. Loss of Raf-1 kinase inhibitor protein (RKIP) is strongly associated with high-grade tumor budding and correlates with an aggressive phenotype in pancreatic ductal adenocarcinoma (PDAC). J Transl Med (2013) 11:311.10.1186/1479-5876-11-311
86
WanXBLongZJYanMXuJXiaLPLiuLet alInhibition of Aurora-A suppresses epithelial-mesenchymal transition and invasion by downregulating MAPK in nasopharyngeal carcinoma cells. Carcinogenesis (2008) 29:1930–7.10.1093/carcin/bgn176
87
BeltranHRickmanDSParkKChaeSSSbonerAMacDonaldTYet alMolecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov (2011) 1:487–95.10.1158/2159-8290.cd-11-0130
88
D’AssoroABLiuTQuatraroCAmatoAOpyrchalMLeontovichAet alThe mitotic kinase Aurora-A promotes distant metastases by inducing epithelial-to-mesenchymal transition in ER alpha(+) breast cancer cells. Oncogene (2014) 33:599–610.10.1038/onc.2012.628
89
McKeithenDGrahamTChungLWOdero-MarahV. Snail transcription factor regulates neuroendocrine differentiation in LNCaP prostate cancer cells. Prostate (2010) 70:982–92.10.1002/pros.21132
Summary
Keywords
prostate cancer, epithelial-to-mesenchymal transition, neuroendocrine, androgen deprivation therapy, castrate resistant, tumor cell plasticity, brachyury, Axl
Citation
Nouri M, Ratther E, Stylianou N, Nelson CC, Hollier BG and Williams ED (2014) Androgen-Targeted Therapy-Induced Epithelial Mesenchymal Plasticity and Neuroendocrine Transdifferentiation in Prostate Cancer: An Opportunity for Intervention. Front. Oncol. 4:370. doi: 10.3389/fonc.2014.00370
Received
23 October 2014
Accepted
04 December 2014
Published
23 December 2014
Volume
4 - 2014
Edited by
Andreas Behren, Ludwig Institute for Cancer Research, Australia
Reviewed by
Alessandro Rimessi, University of Ferrara, Italy; Pavel Sluka, Monash University, Australia
Copyright
© 2014 Nouri, Ratther, Stylianou, Nelson, Hollier and Williams.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Elizabeth D. Williams, Australian Prostate Cancer Research Centre Queensland (APCRC-Q), Princess Alexandra Hospital, Level 1, Building 1, 199 Ipswich Road, Woolloongabba, QLD 4102, Australia e-mail: ed.williams@qut.edu.au
†Mannan Nouri and Ellca Ratther have contributed equally to this work.
This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology.
Disclaimer
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