Role of prostate cancer stem-like cells in the development of antiandrogen resistance

Abstract

Androgen deprivation therapy (ADT) is the standard of care treatment for advance stage prostate cancer. Treatment with ADT develops resistance in multiple ways leading to the development of castration-resistant prostate cancer (CRPC). Present research establishes that prostate cancer stem-like cells (CSCs) play a central role in the development of treatment resistance followed by disease progression. Prostate CSCs are capable of self-renewal, differentiation, and regenerating tumor heterogeneity. The stemness properties in prostate CSCs arise due to various factors such as androgen receptor mutation and variants, epigenetic and genetic modifications leading to alteration in the tumor microenvironment, changes in ATP-binding cassette (ABC) transporters, and adaptations in molecular signaling pathways. ADT reprograms prostate tumor cellular machinery leading to the expression of various stem cell markers such as Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1), Prominin 1 (PROM1/CD133), Indian blood group (CD44), SRY-Box Transcription Factor 2 (Sox2), POU Class 5 Homeobox 1(POU5F1/Oct4), Nanog and ABC transporters. These markers indicate enhanced self-renewal and stemness stimulating CRPC evolution, metastatic colonization, and resistance to antiandrogens. In this review, we discuss the role of ADT in prostate CSCs differentiation and acquisition of CRPC, their isolation, identification and characterization, as well as the factors and pathways contributing to CSCs expansion and therapeutic opportunities.

Keywords

Prostate cancer / second-generation antiandrogens / cancer stem cells / castration resistance prostate cancer / androgen deprivation therapy

References

[1] Gunner C,Rosario DJ.The modern role of androgen deprivation therapy in the management of localised and locally advanced prostate cancer.J Clin Urol2016;9:24-9 PMCID:PMC5356175

[2] Crawford ED,Lawrentschuk N.Androgen-targeted therapy in men with prostate cancer: evolving practice and future considerations.Prostate Cancer Prostatic Dis2019;22:24-38 PMCID:PMC6370592

[3] Perera M,Klotz L.Intermittent versus continuous androgen deprivation therapy for advanced prostate cancer.Nat Rev Urol2020;17:469-81

[4] Karantanos T,Thompson TC.Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches.Oncogene2013;32:5501-11 PMCID:PMC3908870

[5] Saad F,Suzuki K.Treatment of nonmetastatic castration-resistant prostate cancer: focus on second-generation androgen receptor inhibitors.Prostate Cancer Prostatic Dis2021;24:323-34 PMCID:PMC8134049

[6] Formaggio N,Theurillat JP.Loss and revival of androgen receptor signaling in advanced prostate cancer.Oncogene2021;40:1205-16 PMCID:PMC7892335

[7] Perlmutter MA.Androgen deprivation therapy in the treatment of advanced prostate cancer.Rev Urol2007;9:S3-8 PMCID:PMC1831539

[8] Vaishampayan UN,Monk P 3rd.Clinical efficacy of enzalutamide vs bicalutamide combined with androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: a randomized clinical trial.JAMA Netw Open2021;4:e2034633 PMCID:PMC7838941

[9] Spratt DE,Roy S.Prostate radiotherapy with adjuvant androgen deprivation therapy (ADT) improves metastasis-free survival compared to neoadjuvant ADT: an individual patient meta-analysis.J Clin Oncol2021;39:136-44 PMCID:PMC8189640

[10] Thoma C.Prostate cancer: 2-year ADT improves survival in patients receiving high-dose radiotherapy.Nat Rev Urol2015;12:181

[11] Kim M,Jeong IG.Androgen deprivation therapy during and after post-prostatectomy radiotherapy in patients with prostate cancer: a case control study.BMC Cancer2018;18:271 PMCID:PMC5845289

[12] Shore ND.Current and future management of locally advanced and metastatic prostate cancer.Rev Urol2020;22:110-23 PMCID:PMC7672503

[13] Singh AB.Physiology and pathophysiology of male sex hormones.2004;15:408-9

[14] Merlet J,Moreau E,Habert R.Male fetal germ cells are targets for androgens that physiologically inhibit their proliferation.Proc Natl Acad Sci U S A2007;104:3615-20 PMCID:PMC1805536

[15] Mizokami A,Izumi K.Prostate cancer stromal cells and LNCaP cells coordinately activate the androgen receptor through synthesis of testosterone and dihydrotestosterone from dehydroepiandrosterone.Endocr Relat Cancer2009;16:1139-55

[16] Barnes KA,Galvão DA,Chambers SK.Nutrition care guidelines for men with prostate cancer undergoing androgen deprivation therapy: do we have enough evidence?.Prostate Cancer Prostatic Dis2019;22:221-34

[17] Higano CS.Side effects of androgen deprivation therapy: monitoring and minimizing toxicity.Urology2003;61:32-8

[18] Nguyen PL,Basaria S.Adverse effects of androgen deprivation therapy and strategies to mitigate them.Eur Urol2015;67:825-36

[19] Álvarez-Maestro M,Chanca P.Androgen deprivation therapy in patients with prostate cancer increases serum levels of thromboxane A₂: cardiovascular Implications.Front Cardiovasc Med2021;8:653126 PMCID:PMC8076684

[20] Lee HY,Teoh JY.Abiraterone and enzalutamide had different adverse effects on the cardiovascular system: a systematic review with pairwise and network meta-analyses.Prostate Cancer Prostatic Dis2021;24:244-52

[21] Alumkal JJ,Lu E.Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance.Proc Natl Acad Sci U S A2020;117:12315-23 PMCID:PMC7275746

[22] Montgomery RB,Vessella R.Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth.Cancer Res2008;68:4447-54 PMCID:PMC2536685

[23] Li J,Cao S.Membrane-associated androgen receptor (AR) potentiates its transcriptional activities by activating heat shock protein 27 (HSP27).J Biol Chem2018;293:12719-29 PMCID:PMC6102137

[24] He Y,Ye Z.A noncanonical AR addiction drives enzalutamide resistance in prostate cancer.Nat Commun2021;12:1521 PMCID:PMC7943793

[25] Shu SK,Coppola D.Phosphorylation and activation of androgen receptor by Aurora-A.J Biol Chem2016;291:22854 PMCID:PMC5077229

[26] Sumiyoshi T,Yamasaki T.Clinical utility of androgen receptor gene aberrations in circulating cell-free DNA as a biomarker for treatment of castration-resistant prostate cancer.Sci Rep2019;9:4030 PMCID:PMC6411952

[27] Wadosky KM.Molecular mechanisms underlying resistance to androgen deprivation therapy in prostate cancer.Oncotarget2016;7:64447-70 PMCID:PMC5325456

[28] Jernberg E,Wikström P.Clinical relevance of androgen receptor alterations in prostate cancer.Endocr Connect2017;6:R146-61 PMCID:PMC5640574

[29] Watson PA,Sawyers CL.Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer.Nat Rev Cancer2015;15:701-11 PMCID:PMC4771416

[30] Huang Y,Liang X.Molecular and cellular mechanisms of castration resistant prostate cancer.Oncol Lett2018;15:6063-76 PMCID:PMC5876469

[31] Culig Z.Molecular mechanisms of enzalutamide resistance in prostate cancer.Curr Mol Biol Rep2017;3:230-5 PMCID:PMC5700216

[32] Huang H,Liu F.Reciprocal network between cancer stem-like cells and macrophages facilitates the progression and androgen deprivation therapy resistance of prostate cancer.Clin Cancer Res2018;24:4612-26

[33] Moltzahn F.Cancer stem cells in prostate cancer.Transl Androl Urol2013;2:242-53 PMCID:PMC4708185

[34] Plaks V,Werb Z.The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells?.Cell Stem Cell2015;16:225-38 PMCID:PMC4355577

[35] Kim J,Knoblich JA.Human organoids: model systems for human biology and medicine.Nat Rev Mol Cell Biol2020;21:571-84 PMCID:PMC7339799

[36] Batlle E.Cancer stem cells revisited.Nat Med2017;23:1124-34

[37] Prajapati A,Mistry B.Prostate stem cells in the development of benign prostate hyperplasia and prostate cancer: emerging role and concepts.Biomed Res Int2013;2013:107954 PMCID:PMC3722776

[38] Collins AT.Prostate cancer stem cells.Eur J Cancer2006;42:1213-8

[39] Xin L,Witte ON.The Sca-1 cell surface marker enriches for a prostate-regenerating cell subpopulation that can initiate prostate tumorigenesis.Proc Natl Acad Sci U S A2005;102:6942-7 PMCID:PMC1087514

[40] Rizzo S,Hudson DL.Prostate epithelial stem cells.Cell Prolif2005;38:363-74 PMCID:PMC6496238

[41] Heer R.Hunterian Lecture. Characterisation of human prostate epithelial progenitor differentiation in response to androgens.Ann R Coll Surg Engl2011;93:424-8 PMCID:PMC3369323

[42] Butler W.Neuroendocrine cells of the prostate: histology, biological functions, and molecular mechanisms.Precis Clin Med2021;4:25-34 PMCID:PMC8023015

[43] Harris KS.Prostate cancer stem cell markers drive progression, therapeutic resistance, and bone metastasis.Stem Cells Int2017;2017:8629234 PMCID:PMC5485361

[44] Zhang K,Wang L.Current stem cell biomarkers and their functional mechanisms in prostate cancer.Int J Mol Sci2016;17:1163 PMCID:PMC4964535

[45] Li S,Lyu B,Hu GF.Chemosensitization of prostate cancer stem cells in mice by angiogenin and plexin-B2 inhibitors.Commun Biol2020;3:26 PMCID:PMC6962460

[46] Kerr BA,Smith AK.CD117⁺ cells in the circulation are predictive of advanced prostate cancer.Oncotarget2015;6:1889-97 PMCID:PMC4359340

[47] Chen X,Liu X.Defining a population of stem-like human prostate cancer cells that can generate and propagate castration-resistant prostate cancer.Clin Cancer Res2016;22:4505-16 PMCID:PMC5010458

[48] Yu C,Dai J.ALDH activity indicates increased tumorigenic cells, but not cancer stem cells, in prostate cancer cell lines.In Vivo2011;25:69-76.

[49] Miyazawa K,Nakai D,Suzuki K.Immunohistochemical expression of four different stem cell markers in prostate cancer: high expression of NANOG in conjunction with hypoxia-inducible factor-1α expression is involved in prostate epithelial malignancy.Oncol Lett2014;8:985-92 PMCID:PMC4114613

[50] Collins AT,Hyde C,Maitland NJ.Prospective identification of tumorigenic prostate cancer stem cells.Cancer Res2005;65:10946-51

[51] Clark DW.Aldehyde dehydrogenases in cancer stem cells: potential as therapeutic targets.Ann Transl Med2016;4:518 PMCID:PMC5233526

[52] Castellón EA,Lillo J.Molecular signature of cancer stem cells isolated from prostate carcinoma and expression of stem markers in different Gleason grades and metastasis.Biol Res2012;45:297-305

[53] Rhodes DR,Otte AP,Rubin MA.Multiplex biomarker approach for determining risk of prostate-specific antigen-defined recurrence of prostate cancer.J Natl Cancer Inst2003;95:661-8

[54] Ugolkov AV,Luan C.Expression analysis of putative stem cell markers in human benign and malignant prostate.Prostate2011;71:18-25

[55] Trerotola M,Goel HL.CD133, Trop-2 and α2β1 integrin surface receptors as markers of putative human prostate cancer stem cells.Am J Transl Res2010;2:135-44 PMCID:PMC2855629

[56] Matsika A,Day C.Cancer stem cell markers in prostate cancer: an immunohistochemical study of ALDH1, SOX2 and EZH2.Pathology2015;47:622-8

[57] Narayanan R.Therapeutic targeting of the androgen receptor (AR) and AR variants in prostate cancer.Asian J Urol2020;7:271-83 PMCID:PMC7385518

[58] Ku SY,Beltran H.Towards precision oncology in advanced prostate cancer.Nat Rev Urol2019;16:645-54 PMCID:PMC6858516

[59] Guerrero J,Gómez F,Bernales S.Enzalutamide, an androgen receptor signaling inhibitor, induces tumor regression in a mouse model of castration-resistant prostate cancer.Prostate2013;73:1291-305

[60] Ojo D,Wong N,Tang D.Prostate cancer stem-like cells contribute to the development of castration-resistant prostate cancer.Cancers (Basel)2015;7:2290-308 PMCID:PMC4695890

[61] Yu B,Luo H.Androgen receptor splicing variant 7 (ARV7) inhibits docetaxel sensitivity by inactivating the spindle assembly checkpoint.J Biol Chem2021;296:100276 PMCID:PMC7948795

[62] Li T,Mei Y.ALDH1A1 is a marker for malignant prostate stem cells and predictor of prostate cancer patients’ outcome.Lab Invest2010;90:234-44 PMCID:PMC3552330

[63] Efremov YR,Potter EA.Cancer stem cells: emergent nature of tumor emergency.Front Genet2018;9:544 PMCID:PMC6250818

[64] Leão R,Figueiredo A.Cancer stem cells in prostate cancer: implications for targeted therapy.Urol Int2017;99:125-36

[65] Xu T,Wang L.Prostate tumor cells with cancer progenitor properties have high telomerase activity and are rapidly killed by telomerase interference.Prostate2011;71:1390-400 PMCID:PMC3123672

[66] Rajasekhar VK,Gerald W,Scher HI.Tumour-initiating stem-like cells in human prostate cancer exhibit increased NF-κB signalling.Nat Commun2011;2:162 PMCID:PMC3105310

[67] John J, Powell K, Conley-Lacomb MK, Chinni SR. TMPRSS2-ERG Fusion gene expression in prostate tumor cells and its clinical and biological significance in prostate cancer progression.J Cancer Sci Ther2012;4:94-101 PMCID:PMC3527835

[68] Nishida S,Torigoe T.Prostate cancer stem-like cells/cancer-initiating cells have an autocrine system of hepatocyte growth factor.Cancer Sci2013;104:431-6 PMCID:PMC7657102

[69] Zhang C,Dong DL.3D culture technologies of cancer stem cells: promising ex vivo tumor models.J Tissue Eng2020;11:2041731420933407 PMCID:PMC7318804

[70] Vander Griend DJ,Dalrymple S.The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells.Cancer Res2008;68:9703-11 PMCID:PMC3072758

[71] Kanwal R,Walker E.Acquisition of tumorigenic potential and therapeutic resistance in CD133+ subpopulation of prostate cancer cells exhibiting stem-cell like characteristics.Cancer Lett2018;430:25-33

[72] Santaliz-Ruiz LE, Xie X, Old M, Teknos TN, Pan Q. Emerging role of nanog in tumorigenesis and cancer stem cells.Int J Cancer2014;135:2741-8 PMCID:PMC4065638

[73] Verma S,Kalayci FNC.Androgen deprivation induces transcriptional reprogramming in prostate cancer cells to develop stem cell-like characteristics.Int J Mol Sci2020;21:9568 PMCID:PMC7765584

[74] Sun Y,Ma X.The influence of cell cycle regulation on chemotherapy.Int J Mol Sci2021;22:6923 PMCID:PMC8267727

[75] Qiu H,Luo Q.Cancer stem cells: a potential target for cancer therapy.Cell Mol Life Sci2015;72:3411-24

[76] Glumac PM.The role of CD133 in cancer: a concise review.Clin Transl Med2018;7:18 PMCID:PMC6035906

[77] Yang L,Zhao G.Targeting cancer stem cell pathways for cancer therapy.Signal Transduct Target Ther2020;5:8 PMCID:PMC7005297

[78] Hurwitz MD.Chemotherapy and radiation for prostate cancer.Transl Androl Urol2018;7:390-8 PMCID:PMC6043747

[79] Yeku O.Immune therapy for prostate cancer.Cancer J2016;22:334-41 PMCID:PMC5117426

[80] Wang Z,Wang Y.Targeting prostate cancer stem-like cells by an immunotherapeutic platform based on immunogenic peptide-sensitized dendritic cells-cytokine-induced killer cells.Stem Cell Res Ther2020;11:123 PMCID:PMC7079411

[81] Han L,Gong T,Sun X.Cancer stem cells: therapeutic implications and perspectives in cancer therapy.Acta Pharmaceutica Sinica B2013;3:65-75

[82] Zhang K,Wang X.WNT/β-catenin directs self-renewal symmetric cell division of hTERT^high prostate cancer stem cells.Cancer Res2017;77:2534-47

[83] Zhang Z,Li J.Inhibition of the Wnt/β-catenin pathway overcomes resistance to enzalutamide in castration-resistant prostate cancer.Cancer Res2018;78:3147-62 PMCID:PMC6004251

[84] Le PN,Jimeno A.Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28.Pharmacol Ther2015;146:1-11 PMCID:PMC4304994

[85] Schneider JA.Revisiting the role of Wnt/β-catenin signaling in prostate cancer.Mol Cell Endocrinol2018;462:3-8 PMCID:PMC5550366

[86] Kelsey R.Prostate cancer: foxy-5 in prostate cancer model.Nat Rev Urol2017;14:638

[87] Raman S,To M.Structure-guided design fine-tunes pharmacokinetics, tolerability, and antitumor profile of multispecific frizzled antibodies.Proc Natl Acad Sci U S A2019;116:6812-7 PMCID:PMC6452705

[88] Singh SK,Bae S.Selective targeting of the hedgehog signaling pathway by PBM nanoparticles in docetaxel-resistant prostate cancer.Cells2020;9:1976 PMCID:PMC7563377

[89] Fu J,Nanta R.NPV-LDE-225 (Erismodegib) inhibits epithelial mesenchymal transition and self-renewal of glioblastoma initiating cells by regulating miR-21, miR-128, and miR-200.Neuro Oncol2013;15:691-706 PMCID:PMC3661095

[90] Gonnissen A,McKee CM.The hedgehog inhibitor GANT61 sensitizes prostate cancer cells to ionizing radiation both in vitro and in vivo.Oncotarget2016;7:84286-98 PMCID:PMC5356662

[91] Rinkenbaugh AL.The NF-κB pathway and cancer stem cells.Cells2016;5:16

[92] Kaltschmidt C,Benhidjeb T.A role for NF-κB in organ specific cancer and cancer stem cells.Cancers (Basel)2019;11:655 PMCID:PMC6563002

[93] Pietzak EJ.Neoadjuvant treatment of high-risk, clinically localized prostate cancer prior to radical prostatectomy.Curr Urol Rep2016;17:37

[94] Heath EI,Vaishampayan U.A phase II trial of 17-allylamino-17-demethoxygeldanamycin in patients with hormone-refractory metastatic prostate cancer.Clin Cancer Res2008;14:7940-6 PMCID:PMC3085545

[95] Vidal AC,Moreira DM.Aspirin, NSAIDs, and risk of prostate cancer: results from the REDUCE study.Clin Cancer Res2015;21:756-62 PMCID:PMC4334741

[96] Ranganathan P,Capobianco AJ.Notch signalling in solid tumours: a little bit of everything but not all the time.Nat Rev Cancer2011;11:338-51

[97] Takebe N,Harris PJ.Targeting notch, hedgehog, and Wnt pathways in cancer stem cells: clinical update.Nat Rev Clin Oncol2015;12:445-64 PMCID:PMC4520755

[98] Stein MN,Mayer TM.A randomized phase II study of bicalutamide (BIC) followed by placebo or gamma secretase inhibitor RO4929097 (RO492) in men with rising PSA.J Clin Oncol2012;30:219

[99] Begicevic RR.ABC transporters in cancer stem cells: beyond chemoresistance.Int J Mol Sci2017;18:2362 PMCID:PMC5713331

[100] Liao CP,Liang M.Cancer stem cells and microenvironment in prostate cancer progression.Horm Cancer2010;1:297-305

[101] Giddings EL,Wu MH.Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance.Nat Commun2021;12:2804 PMCID:PMC8121950

[102] Rybalchenko V,Van Coppenolle F.Verapamil inhibits proliferation of LNCaP human prostate cancer cells influencing K+ channel gating.Mol Pharmacol2001;59:1376-87

[103] Kawahara T,Ide H.The role of NFATc1 in prostate cancer progression: cyclosporine a and tacrolimus inhibit cell proliferation, migration, and invasion.Prostate2015;75:573-84