Cancer stem cells in neuroblastoma therapy resistance

Abstract

Neuroblastoma (NB) is the most common cancer of infancy and accounts for nearly one tenth of pediatric cancer deaths. This mortality rate has been attributed to the > 50% frequency of relapse despite intensive, multimodal clinical therapy in patients with progressive NB. Given the disease’s heterogeneity and developed resistance, attaining a cure after relapse of progressive NB is highly challenging. A rapid decrease in the timeline between successive recurrences is likely due to the ongoing acquisition of genetic rearrangements in undifferentiated NB-cancer stem cells (CSCs). In this review, we present the current understanding of NB-CSCs, their intrinsic role in tumorigenesis, their function in disease progression, and their influence on acquired therapy resistance and tumor evolution. In particular, this review focus on the intrinsic involvement of stem cells and signaling in the genesis of NB, the function of pre-existing CSCs in NB progression and therapy response, the formation and influence of induced CSCs (iCSCs) in drug resistance and tumor evolution, and the development of a CSC-targeted therapeutic approach.

Keywords

Neuroblastoma / therapy resistance / cancer stem cells / clonal selection / drug resistance / induced cancer stem cell

References

[1] Marc TG,Smith MA.Ries LAG,Gurney JG,Tamra T.Sympathetic nervous system tumors..Cancer incidence and survival among children and adolescents: United States SEER program 1975-1995. USA NCI Pub;1999;65-72

[2] Gurney JG,Ross JA.Ries LAG,Gurney JG,Tamra T.Cancer among infants..Cancer incidence and survival among children and adolescents: United States SEER program 1975-1995. USA NCI Pub;1999;149-56

[3] Morgenstern DA,Irwin MS.Current and future strategies for relapsed neuroblastoma: challenges on the road to precision therapy..J Pediatr Hematol Oncol2013;35:337-47

[4] Smith MA,Altekruse SF,Melbert DL.Outcomes for children and adolescents with cancer: challenges for the twenty-first century..J Clin Oncol2010;28:2625-34 PMCID:PMC2881732

[5] American Cancer SocietyCancer facts & figures 2019. Atlanta: American Cancer Society.2019;1:1-76

[6] Santana VM,McGregor LM.Disease control intervals in high-risk neuroblastoma..Cancer2008;112:2796-801

[7] Simon T,Borkhardt A,De Carolis B.Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: results of German trials..Pediatr Blood Cancer2011;56:578-83

[8] Lau L,Weitzman S,Baruchel S.Factors influencing survival in children with recurrent neuroblastoma..J Pediatr Hematol Oncol2004;26:227-32

[9] Berthold F,Breu H,Erttmann R.The recurrence patterns of stages I, II and III neuroblastoma: experience with 77 relapsing patients..Ann Oncol1996;7:183-7

[10] Molenaar JJ,Koster J,van Noesel CJ.Cyclin D1 and CDK4 activity contribute to the undifferentiated phenotype in neuroblastoma..Cancer Res2008;68:2599-609

[11] Moll UM,Bénard J.Wild-type p53 protein undergoes cytoplasmic sequestration in undifferentiated neuroblastomas but not in differentiated tumors..Proc Natl Acad Sci U S A1995;92:4407-11 PMCID:PMC41953

[12] Barbieri E,Capasso M,Hsu DM.Histone chaperone CHAF1A inhibits differentiation and promotes aggressive neuroblastoma..Cancer Res2014;74:765-74

[13] Bhaskara VK,Rao JS.Intermittent hypoxia regulates stem-like characteristics and differentiation of neuroblastoma cells..PLoS One2012;7:e30905 PMCID:PMC3281893

[14] Schleiermacher G,Delattre O.Recent insights into the biology of neuroblastoma..Int J Cancer2014;135:2249-61

[15] Abdullah LN.Mechanisms of chemoresistance in cancer stem cells..Clin Transl Med2013;2:3 PMCID:PMC3565873

[16] Alisi A,Locatelli F.Multidrug resistance and cancer stem cells in neuroblastoma and hepatoblastoma..Int J Mol Sci2013;14:24706-25 PMCID:PMC3876137

[17] Ross RA.Human neuroblastoma stem cells..Semin Cancer Biol2007;17:241-7

[18] Ross RA,Spengler BA.A role for distinct cell types in determining malignancy in human neuroblastoma cell lines and tumors..Cancer Lett2003;197:35-9

[19] Reynolds BA.Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system..Science1992;255:1707-10

[20] Linabery AM.Trends in childhood cancer incidence in the US (1992-2004)..Cancer2008;112:416-32

[21] Kohler BA,McCarthy BJ,Ries LA.Annual report to the nation on the status of cancer, 1975-2007, featuring tumors of the brain and other nervous system..J Natl Cancer Inst2011;103:714-36 PMCID:PMC3086878

[22] de Weille J.On the genesis of neuroblastoma and glioma..Int J Brain Sci2014;2014:14

[23] Kerosuo L.What is bad in cancer is good in the embryo: importance of EMT in neural crest development..Semin Cell Dev Biol2012;23:320-32 PMCID:PMC3345076

[24] Albino D,Moretti S,Mirisola V.Gene expression profiling identifies eleven DNA repair genes down-regulated during mouse neural crest cell migration..Int J Dev Biol2011;55:65-72

[25] Crane JF.Neural crest stem and progenitor cells..Annu Rev Cell Dev Biol2006;22:267-86

[26] Mohlin SA,Påhlman S.Neuroblastoma aggressiveness in relation to sympathetic neuronal differentiation stage..Seminars Cancer Biol2011;21:276-82

[27] Craft AW.Poor prognosis neuroblastoma: is screening the answer?.Br J Cancer Suppl1992;18:S96-101 PMCID:PMC2149668

[28] Sawada T.Past and future of neuroblastoma screening in Japan..Am J Pediatr Hematol Oncol1992;14:320-6

[29] Jiang M,Lahti JM.The connections between neural crest development and neuroblastoma..Curr Top Dev Biol2011;94:77-127 PMCID:PMC3633592

[30] Walton JD,Thomas SK,Guo HF.Characteristics of stem cells from human neuroblastoma cell lines and in tumors..Neoplasia2004;6:838-45 PMCID:PMC1531688

[31] Longo L,Schena F,Devoto M.Genetic predisposition to familial neuroblastoma: identification of two novel genomic regions at 2p and 12p..Hum Hered2007;63:205-11

[32] Mosse YP,Longo L,Wood A.Identification of ALK as a major familial neuroblastoma predisposition gene..Nature2008;455:930-5 PMCID:PMC2672043

[33] Melotte V,Ongenaert M,de Bruïne AP.The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications..FASEB J2010;24:4153-66

[34] Bosse KR,Cole KA,Schnepp RW.Common variation at BARD1 results in the expression of an oncogenic isoform that influences neuroblastoma susceptibility and oncogenicity..Cancer Res2012;72:2068-78 PMCID:PMC3328617

[35] Oldridge DA,Weichert-Leahey N,Sussman R.Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism..Nature2015;528:418-21 PMCID:PMC4775078

[36] Schnepp RW,Attiyeh EF,Chodosh SE.A LIN28B-RAN-AURKA signaling network promotes neuroblastoma tumorigenesis..Cancer cell2015;28:599-609 PMCID:PMC4643330

[37] Schramm A,Assenov Y,Peifer M.Mutational dynamics between primary and relapse neuroblastomas..Na Genet2015;47:872-7

[38] Gaisie G,Young LW.Coexistent neuroblastoma and Hirschsprung’s disease - another manifestation of the neurocristopathy?.Pediatr Radiol1979;8:161-3

[39] Roshkow JE,Berdon WE.Hirschsprung’s disease, Ondine’s curse, and neuroblastoma-manifestations of neurocristopathy..Pediatr Radiol1988;19:45-9

[40] Quackenbush KE,Magee JF,Golobi M.Neuroblastoma involvement of the falx cerebri..Pediatr Blood Cancer2009;53:1337-9

[41] Emery LG,Shah NR.Neuroblastoma associated with beckwith-wiedemann syndrome..Cancer1983;52:176-9

[42] Kenny FM,Voorhess ML.Cushing’s syndrome associated with an adrenal neuroblastoma: a case in an infant with clinical, pathological, and adrenal cortical and medullary hormone excretion studies..Am J Dis Child1967;113:611-5

[43] Arnesen MA,Freeman S.Cushing’s syndrome secondary to olfactory neuroblastoma..Ultrastruct Pathol1994;18:61-8

[44] Kinney H,Brazy J.The fetal alcohol syndrome and neuroblastoma..Pediatrics1980;66:130-2

[45] Yang Q,Bondy ML,Pollock BH.Parental smoking and alcohol consumption and risk of neuroblastoma..Cancer Epidemiol Biomarkers Prev2000;9:967-72

[46] Schüz J,Meinert R,Spix C.Risk factors for neuroblastoma at different stages of disease. Results from a population-based case-control study in Germany..J Clin Epidemiol2001;54:702-9

[47] Al-Shammri S,Hsu E.Neuroblastoma and fetal exposure to phenytoin in a child without dysmorphic features..Can J Neurol Sci1992;19:243-5

[48] Ehrenbard L.Cancer in the fetal hydantoin syndrome..The Lancet1981;318:97

[49] Dragu DL,Bleotu C,Chivu-Economescu M.Therapies targeting cancer stem cells: Current trends and future challenges..World J Stem Cells2015;7:1185-201 PMCID:PMC4620424

[50] Li C,Dalerba P,Zhang L.Identification of pancreatic cancer stem cells..Cancer Res2007;130:194-5

[51] Yamashita T.Cancer stem cells in the development of liver cancer..J Clin Invest2013;123:1911-8 PMCID:PMC3635728

[52] Wang Y,Du Y,Huang G.The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling..Cell Stem Cell2015;16:413-25

[53] Alamgeer M,Matsui W,Watkins DN.Cancer stem cells in lung cancer: evidence and controversies..Respirology2013;18:757-64 PMCID:PMC3991120

[54] Al-Hajj M,Benito-Hernandez A,Clarke MF.Prospective identification of tumorigenic breast cancer cells..Proc Natl Acad Sci U S A2003;100:3983-8 PMCID:PMC153034

[55] Han J,Husain SR.Identification and characterization of cancer stem cells in human head and neck squamous cell carcinoma..BMC cancer2014;14:173 PMCID:PMC4008349

[56] Dalerba P,Park IK,Wang X.Phenotypic characterization of human colorectal cancer stem cells..Proc Natl Acad Sci U S A2007;104:10158-63 PMCID:PMC1891215

[57] Ricci-Vitiani L,Pilozzi E,Todaro M.Identification and expansion of human colon-cancer-initiating cells..Nature2007;445:111-5

[58] Singh SK,Clarke ID,Bayani J.Identification of human brain tumour initiating cells..Nature2004;432:396-401

[59] Bonnet D.Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell..Nat Med1997;3:730-7

[60] Hansford LM,Zhang L,Gerstle JT.Neuroblastoma cells isolated from bone marrow metastases contain a naturally enriched tumor-initiating cell..Cancer Res2007;67:11234-43

[61] Mahller YY,Baird WH,Grossheim J.Neuroblastoma cell lines contain pluripotent tumor initiating cells that are susceptible to a targeted oncolytic virus..PLoS One2009;4:e4235 PMCID:PMC2626279

[62] Peiris-Pages M,Pestell RG,Lisanti MP.Cancer stem cell metabolism..Breast Cancer Res2016;18:55 PMCID:PMC4879746

[63] Prieto-Vila M,Usuba W,Ochiya T.Drug resistance driven by cancer stem cells and their niche..Int J Mol Sci2017;18:E2574 PMCID:PMC5751177

[64] Zhu P.Cancer stem cells and tumorigenesis..Biophys Rep2018;4:178-88 PMCID:PMC6153490

[65] Dean M.Cancer stem cells: Implications for cancer causation and therapy resistance..Discov Med2005;5:278-82

[66] Khalil MA,Cipro S,Vicha A.Neuroblastoma stem cells - mechanisms of chemoresistance and histone deacetylase inhibitors..Neoplasma2012;59:737-46

[67] Naiditch JA,Lautz TB,Clark S.Mesenchymal change and drug resistance in neuroblastoma..J Surg Res2015;193:279-88

[68] Biedler JL,Spengler BA.Morphology and growth, tumorigenicity, and cytogenetics of human neuroblastoma cells in continuous culture..Cancer Res1973;33:2643-52

[69] Ross RA,Domenech C,Rettig WJ.Human neuroblastoma I-type cells are malignant neural crest stem cells..Cell Growth Differ1995;6:449-56

[70] Walton JD,Thomas SK,Guo HF.Characteristics of stem cells from human neuroblastoma cell lines and in tumors..Neoplasia2004;6:838-45 PMCID:PMC1531688

[71] Ross RA,Han D,Cheung NK.A distinct gene expression signature characterizes human neuroblastoma cancer stem cells..Stem Cell Res2015;15:419-26 PMCID:PMC4601571

[72] Buhagiar A.Chemoresistance, cancer stem cells, and miRNA influences: the case for neuroblastoma..Anal Cell Pathol (Amst)2015;2015:150634 PMCID:PMC4516851

[73] Oh L,Hainaut P.P53, stem cell biology and childhood blastomas..Curr Opin Oncol2019;31:84-91

[74] Friedman GK.Cancer stem cells and pediatric solid tumors..Cancers (Basel)2011;3:298-318 PMCID:PMC3050504

[75] Garner EF.Cancer stem cells and their interaction with the tumor microenvironment in neuroblastoma..Cancers (Basel)2015;8:e5 PMCID:PMC4728452

[76] Li Z.CD133: a stem cell biomarker and beyond..Exp Hematol Oncol2013;2:17 PMCID:PMC3701589

[77] Phi LTH,Yang YG,Jun N.Cancer stem cells (CSCs) in drug resistance and their therapeutic implications in cancer treatment..Stem Cells Int2018;2018:5416923 PMCID:PMC5850899

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

[79] Dawood S,Cristofanilli M.Cancer stem cells: implications for cancer therapy..Oncology2014;28:1101

[80] Kim WT.Cancer stem cell surface markers on normal stem cells..BMB Rep2017;50:285-98 PMCID:PMC5498139

[81] Matsui WH.Cancer stem cell signaling pathways..Medicine (Baltimore)2016;95:S8-19 PMCID:PMC5599211

[82] Nassar D.Cancer stem cells: basic concepts and therapeutic implications..Annu Rev Pathol2016;11:47-76

[83] Frank NY,Frank MH.The therapeutic promise of the cancer stem cell concept..J Clin Invest2010;120:41-50 PMCID:PMC2798700

[84] Poggi A,Zocchi MR.How to hit mesenchymal stromal cells and make the tumor microenvironment immunostimulant rather than immunosuppressive..Front Immunol2018;9:262 PMCID:PMC5825917

[85] Ishiguro T,Sato A,Enomoto T.Tumor-derived spheroids: Relevance to cancer stem cells and clinical applications..Cancer Sci2017;108:283-9 PMCID:PMC5378268

[86] Yoshida GJ.Therapeutic strategies targeting cancer stem cells..Cancer Sci2016;107:5-11 PMCID:PMC4724810

[87] Trosko JE.Stem cell theory of carcinogenesis..Toxicol Lett1990;49:283-95

[88] Newton TC,Roberts SS.Comparison of the side populations in pretreatment and postrelapse neuroblastoma cell lines..Transl Oncol2010;3:246-51 PMCID:PMC2915416

[89] Hirschmann-Jax C,Wulf GG,Jax TW.A distinct “side population” of cells with high drug efflux capacity in human tumor cells..Proc Natl Acad Sci U S A2004;101:14228-33 PMCID:PMC521140

[90] Islam MO,Tajria J,Kobayashi S.Functional expression of ABCG2 transporter in human neural stem/progenitor cells..Neurosci Res2005;52:75-82

[91] Neradil J.Nestin as a marker of cancer stem cells..Cancer Sci2015;106:803-11 PMCID:PMC4520630

[92] Xing LL,Wu YM,Zhang M.Preliminary analysis of stem cell-like cells in human neuroblastoma..World J Pediatr2015;11:54-60

[93] Shohet JM,Coarfa C,Benham AL.A genome-wide search for promoters that respond to increased MYCN reveals both new oncogenic and tumor suppressor microRNAs associated with aggressive neuroblastoma..Cancer Res2011;71:3841-51

[94] Cournoyer S,Addioui A,Beaunoyer M.Genotype analysis of tumor-initiating cells expressing CD133 in neuroblastoma..Genes Chromosomes Cancer2012;51:792-804

[95] Tong QS,Tang ST,Liu Y.Expression and clinical significance of stem cell marker CD133 in human neuroblastoma..World J Pediatr2008;4:58-62

[96] Sartelet H,Nyalendo C,Annabi B.CD133 expression is associated with poor outcome in neuroblastoma via chemoresistance mediated by the AKT pathway..Histopathology2012;60:1144-55

[97] Takenobu H,Nakamura T,Yamaguchi Y.CD133 suppresses neuroblastoma cell differentiation via signal pathway modification..Oncogene2011;30:97-105

[98] Khalil MA,Groh T,Doktorova H.Valproic acid increases CD133 positive cells that show low sensitivity to cytostatics in neuroblastoma..PLoS One2016;11:e0162916 PMCID:PMC5023141

[99] Vangipuram SD,Lyman WD.Resistance of stem-like cells from neuroblastoma cell lines to commonly used chemotherapeutic agents..Pediatr Blood Cancer2010;54:361-8

[100] Ohmichi M,Tasaka K,Murata Y.Mechanisms of platinum drug resistance..Trends Pharmacol Sci2005;26:113-6

[101] Cipro S,Hrabeta J,Eckschlager T.Valproic acid overcomes hypoxia-induced resistance to apoptosis..Oncol Rep2012;27:1219-26 PMCID:PMC3583540

[102] Cantilena S,Pezzolo A,Pistoia V.Frizzled receptor 6 marks rare, highly tumourigenic stem-like cells in mouse and human neuroblastomas..Oncotarget2011;2:976-83 PMCID:PMC3282103

[103] Vieira GC,Melegh Z,Malik S.LGR5 regulates pro-survival MEK/ERK and proliferative Wnt/beta-catenin signalling in neuroblastoma..Oncotarget2015;6:40053-67 PMCID:PMC4741879

[104] Forgham H,Carter N,Carr-Wilkinson J.Stem cell markers in neuroblastoma - an emerging role for LGR5..Front Cell Dev Biol2015;3:77 PMCID:PMC4667032

[105] Marcato P,Giacomantonio CA.Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform..Cell Cycle2011;10:1378-84

[106] Hartomo TB,Yamamoto N,Hasegawa D.Involvement of aldehyde dehydrogenase 1A2 in the regulation of cancer stem cell properties in neuroblastoma..Int J Oncol2015;46:1089-98

[107] Flahaut M,Chevalier N,Balmas Bourloud K.Aldehyde dehydrogenase activity plays a key role in the aggressive phenotype of neuroblastoma..BMC Cancer2016;16:781 PMCID:PMC5057398

[108] Kuo YT,Adebayo BO,Lee WH.JARID1B expression plays a critical role in chemoresistance and stem cell-like phenotype of neuroblastoma cells..PLoS One2015;10:e0125343 PMCID:PMC4423965

[109] Hsu DM,Benham A,Trahan DN.G-CSF receptor positive neuroblastoma subpopulations are enriched in chemotherapy-resistant or relapsed tumors and are highly tumorigenic..Cancer Res2013;73:4134-46 PMCID:PMC4298227

[110] Agarwal S,Chen Z,Metelitsa LS.G-CSF promotes neuroblastoma tumorigenicity and metastasis via STAT3-dependent cancer stem cell activation..Cancer Res2015;75:2566-79 PMCID:PMC4470771

[111] Baggiolini A,Mateos JM,John N.Premigratory and migratory neural crest cells are multipotent in vivo..Cell Stem Cell2015;16:314-22

[112] Kirsch F,Schneider A.The receptor for granulocyte-colony stimulating factor (G-CSF) is expressed in radial glia during development of the nervous system..BMC Dev Biol2008;8:32 PMCID:PMC2329616

[113] Schneider A,Steigleder T,Pitzer C.The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis..J Clin Invest2005;115:2083-98 PMCID:PMC1172228

[114] Chikaraishi K,Sugino RP,Akter J.CFC1 is a cancer stemness-regulating factor in neuroblastoma..Oncotarget2017;8:45046-59 PMCID:PMC5542166

[115] Cui H,Li T,Alam G.Bmi-1 is essential for the tumorigenicity of neuroblastoma cells..Am J Pathol2007;170:1370-8 PMCID:PMC1829469

[116] Cui H,Ding J,Alam G.Bmi-1 regulates the differentiation and clonogenic self-renewal of I-type neuroblastoma cells in a concentration-dependent manner..J Biol Chem2006;281:34696-704

[117] Nowak K,Fehr D,Gessner C.BMI1 is a target gene of E2F-1 and is strongly expressed in primary neuroblastomas..Nucleic Acids Res2006;34:1745-54 PMCID:PMC1421501

[118] Kamijo T.Role of stemness-related molecules in neuroblastoma..Pediatr Res2012;71:511-5

[119] Ochiai H,Nakagawa A,Kimura M.Bmi1 is a MYCN target gene that regulates tumorigenesis through repression of KIF1Bbeta and TSLC1 in neuroblastoma..Oncogene2010;29:2681-90

[120] Mao L,Perdue A,Zha Y.Cyclin E1 is a common target of BMI1 and MYCN and a prognostic marker for neuroblastoma progression..Oncogene2012;31:3785-95 PMCID:PMC3290747

[121] Melone MA,Squillaro T,Casale F.Genes involved in regulation of stem cell properties: studies on their expression in a small cohort of neuroblastoma patients..Cancer Biol Ther2009;8:1300-6

[122] Chen D,Li Y,Yuan Q.Targeting BMI1+ cancer stem cells overcomes chemoresistance and inhibits metastases in squamous cell carcinoma..Cell Stem Cell2017;20:621-34 PMCID:PMC5419860

[123] Ren H,Ge Z,Ding D.TWIST1 and BMI1 in cancer metastasis and chemoresistance..J Cancer2016;7:1074-80 PMCID:PMC4911874

[124] Yin T,Cao B,Shi P.Bmi1 inhibition enhances the sensitivity of pancreatic cancer cells to gemcitabine..Oncotarget2016;7:37192-204 PMCID:PMC5095068

[125] Siddique HR.Role of BMI1, a stem cell factor, in cancer recurrence and chemoresistance: preclinical and clinical evidences..Stem Cells2012;30:372-8

[126] Yang XX,Sang MX,Liu ZK.BMI-1 suppression increases the radiosensitivity of oesophageal carcinoma via the PI3K/Akt signaling pathway..Oncol Rep2018;39:667-78

[127] Yan Y,Zhao P,Hu Z.BMI-1 promotes self-renewal of radio- and temozolomide (TMZ)-resistant breast cancer cells..Reprod Sci2017;24:1620-9

[128] Facchino S,Chatoo W.BMI1 confers radioresistance to normal and cancerous neural stem cells through recruitment of the DNA damage response machinery..J Neurosci2010;30:10096-111 PMCID:PMC6633363

[129] Jandial R,Chen MY.Cancer stem cells can arise from differentiated neoplastic cells..Neurosurgery2011;69:N22

[130] Friedmann-Morvinski D,Ke E,Marumoto T.Dedifferentiation of neurons and astrocytes by oncogenes can induce gliomas in mice..Science2012;338:1080-4 PMCID:PMC3595315

[131] Nishi M,Akutsu H,Quinn G.Induction of cells with cancer stem cell properties from nontumorigenic human mammary epithelial cells by defined reprogramming factors..Oncogene2014;33:643-52 PMCID:PMC4697746

[132] Scaffidi P.In vitro generation of human cells with cancer stem cell properties..Nat Cell Biol2011;13:1051-61 PMCID:PMC3166977

[133] Vares G,Wang B,Nenoi M.Generation of breast cancer stem cells by steroid hormones in irradiated human mammary cell lines..PLoS One2013;8:e77124 PMCID:PMC3797732

[134] Kang SK,Cha SH.Multipotent, dedifferentiated cancer stem-like cells from brain gliomas..Stem Cells Dev2006;15:423-35

[135] Oshima N,Nagayama S,Hasegawa S.Induction of cancer stem cell properties in colon cancer cells by defined factors..PLoS One2014;9:e101735 PMCID:PMC4090165

[136] Shi L,Sun G,Wan Y.Hypothermia stimulates glioma stem spheres to spontaneously dedifferentiate adjacent non-stem glioma cells..Cell Mol Neurobiol2015;35:217-30

[137] Jeon HM,Lee JS,Sohn YW.Inhibitor of differentiation 4 drives brain tumor-initiating cell genesis through cyclin E and notch signaling..Genes Dev2008;22:2028-33 PMCID:PMC2492750

[138] Iliopoulos D,Wang G.Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion..Proc Natl Acad Sci U S A2011;108:1397-402 PMCID:PMC3029760

[139] Ikegaki N,Fox AM,Jacobs JR.Transient treatment with epigenetic modifiers yields stable neuroblastoma stem cells resembling aggressive large-cell neuroblastomas..Proc Natl Acad Sci U S A2013;110:6097-102 PMCID:PMC3625318

[140] Colak S.Cancer stem cells - important players in tumor therapy resistance..FEBS J2014;281:4779-91

[141] Schatton T,Frank NY,Waaga-Gasser AM.Identification of cells initiating human melanomas..Nature2008;451:345-9 PMCID:PMC3660705

[142] Fillmore CM.Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy..Breast Cancer Res2008;10:R25 PMCID:PMC2397524

[143] Hashimoto N,Yoshimura K,Hazama S.Cancer stem-like sphere cells induced from de-differentiated hepatocellular carcinoma-derived cell lines possess the resistance to anti-cancer drugs..BMC Cancer2014;14:722 PMCID:PMC4190290

[144] Chen X,Li D.Induced cancer stem cells generated by radiochemotherapy and their therapeutic implications..Oncotarget2017;8:17301-12 PMCID:PMC5370042

[145] Seo Y,Lee KE,Kim Y.Anti-cancer stemness and anti-invasive activity of bitter taste receptors, TAS2R8 and TAS2R10, in human neuroblastoma cells..PLoS One2017;12:e0176851 PMCID:PMC5414998

[146] Farace C,Melguizo C,Bandiera P.Microenvironmental modulation of decorin and lumican in temozolomide-resistant glioblastoma and neuroblastoma cancer stem-like cells..PLoS One2015;10:e0134111 PMCID:PMC4521885

[147] Diaz-Carballo D,Bardenheuer W,Malak S.Identification of compounds that selectively target highly chemotherapy refractory neuroblastoma cancer stem cells..Int J Clin Pharmacol Ther2014;52:787-801

[148] Prokocimer M,Nissim-Rafinia M,Bar DZ.Nuclear lamins: key regulators of nuclear structure and activities..J Cell Mol Med2009;13:1059-85 PMCID:PMC4496104

[149] Wu Z,Weng D,Geng J.Reduced expression of lamin A/C correlates with poor histological differentiation and prognosis in primary gastric carcinoma..J Exp Clin Cancer Res2009;28:8 PMCID:PMC2632624

[150] Nardella M,Musa C,Maresca G.Down-regulation of the Lamin A/C in neuroblastoma triggers the expansion of tumor initiating cells..Oncotarget2015;6:32821-40 PMCID:PMC4741732

[151] Kamachi Y,Kondoh H.Pairing SOX off: with partners in the regulation of embryonic development..Trends Genet2000;16:182-7

[152] Fang X,Li L,Zhao N.ChIP-seq and functional analysis of the SOX2 gene in colorectal cancers..OMICS2010;14:369-84

[153] Gen Y,Zen Y,Dohi O.SOX2 identified as a target gene for the amplification at 3q26 that is frequently detected in esophageal squamous cell carcinoma..Cancer Genet Cytogenet2010;202:82-93

[154] Ji J.Expression of Sox2 in human cervical carcinogenesis..Hum Pathol2010;41:1438-47

[155] Nakatsugawa M,Hirohashi Y,Inoda S.SOX2 is overexpressed in stem-like cells of human lung adenocarcinoma and augments the tumorigenicity..Lab Invest2011;91:1796-804

[156] Xiang R,Cheng T,Shi Q.Downregulation of transcription factor SOX2 in cancer stem cells suppresses growth and metastasis of lung cancer..Br J Cancer2011;104:1410-7 PMCID:PMC3101944

[157] Yang S,Ma Y,Xu T.Oct4 and Sox2 are overexpressed in human neuroblastoma and inhibited by chemotherapy..Oncol Rep2012;28:186-92

[158] Yang S,Xiao X,Tang W.SOX2 promotes tumorigenicity and inhibits the differentiation of I-type neuroblastoma cells..Int J Oncol2015;46:317-23

[159] Shi Y,Taupin P,Ray J.Expression and function of orphan nuclear receptor TLX in adult neural stem cells..Nature2004;427:78-83

[160] Chavali PL,Zhai Q,Venkatabalasubramanian S.TLX activates MMP-2, promotes self-renewal of tumor spheres in neuroblastoma and correlates with poor patient survival..Cell Death Dis2014;5:e1502 PMCID:PMC4237266

[161] Fuchs E,Guasch G.Socializing with the neighbors: stem cells and their niche..Cell2004;116:769-78

[162] Ye J,Wu P,Huang J.The cancer stem cell niche: cross talk between cancer stem cells and their microenvironment..Tumour Biol2014;35:3945-51

[163] Jögi A,Nilsson H,Makino Y.Hypoxia alters gene expression in human neuroblastoma cells toward an immature and neural crest-like phenotype..Proc Natl Acad Sci U S A2002;99:7021-6 PMCID:PMC124521

[164] Holmquist-Mengelbier L,Lofstedt T,Navarro S.Recruitment of HIF-1alpha and HIF-2alpha to common target genes is differentially regulated in neuroblastoma: HIF-2alpha promotes an aggressive phenotype..Cancer Cell2006;10:413-23

[165] Asgharzadeh S,Ji L,Fischer M.Clinical significance of tumor-associated inflammatory cells in metastatic neuroblastoma..J Clin Oncol2012;30:3525-32 PMCID:PMC3675667

[166] Borriello L,Sheard MA,Sposto R.Cancer-associated fibroblasts share characteristics and protumorigenic activity with mesenchymal stromal cells..Cancer Res2017;77:5142-57 PMCID:PMC5600847

[167] Yin AH,Zanjani ED,Ogawa M.AC133, a novel marker for human hematopoietic stem and progenitor cells..Blood1997;90:5002-12

[168] Hämmerle B,Palanca S,Burks DJ.Targeting neuroblastoma stem cells with retinoic acid and proteasome inhibitor..PLoS One2013;8:e76761 PMCID:PMC3792090

[169] Smith KM,Fujitani M,Zhang L.Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens..EMBO Mol Med2010;2:371-84 PMCID:PMC3377336

[170] Bahmad HF,Chalhoub RM,Araji T.The Akt/mTOR pathway in cancer stem/progenitor cells is a potential therapeutic target for glioblastoma and neuroblastoma..Oncotarget2018;9:33549-61 PMCID:PMC6173359

[171] Castelo-Branco P,Lipman T,Hansford L.Neural tumor-initiating cells have distinct telomere maintenance and can be safely targeted for telomerase inhibition..Clin Cancer Res2011;17:111-21

[172] Zheng X,Czurylo M,Lautz T.Differential effect of long-term drug selection with doxorubicin and vorinostat on neuroblastoma cells with cancer stem cell characteristics..Cell Death Dis2013;4:e740 PMCID:PMC3730434

[173] Zaatiti H,Nasr Z,Sandler A.Tumorigenic proteins upregulated in the MYCN-amplified IMR-32 human neuroblastoma cells promote proliferation and migration..Int J Oncol2018;52:787-803 PMCID:PMC5807036

[174] Bao S,Li Z,Wang H.Targeting cancer stem cells through L1CAM suppresses glioma growth..Cancer Res2008;68:6043-8 PMCID:PMC2739001

[175] Hong H,Brown C,Ostberg JR.Diverse solid tumors expressing a restricted epitope of L1-CAM can be targeted by chimeric antigen receptor redirected T lymphocytes..J Immunother2014;37:93-104

[176] Kunkele A,Finn LS,Berger C.Preclinical assessment of CD171-directed CAR T-cell adoptive therapy for childhood neuroblastoma: CE7 epitope target safety and product manufacturing feasibility..Clin Cancer Res2017;23:466-77

[177] Grinshtein N,Fujitani M,Prakesch M.Small molecule kinase inhibitor screen identifies polo-like kinase 1 as a target for neuroblastoma tumor-initiating cells..Cancer Res2011;71:1385-95

[178] Pajtler KW,Ackermann S,Schönbeck K.The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models..Oncotarget2017;8:6730-41 PMCID:PMC5351666

[179] Naveen CR,Agrawal-Rajput R.Berberine induces neuronal differentiation through inhibition of cancer stemness and epithelial-mesenchymal transition in neuroblastoma cells..Phytomedicine2016;23:736-44

[180] Kim DW,Kim TY.Enhancement of arsenic trioxide [As(2)O(3)]-mediated apoptosis using berberine in human neuroblastoma SH-SY5Y cells..J Korean Neurosurg Soc2007;42:392-9 PMCID:PMC2588187

[181] Choi MS,Oh JH,Han SB.Berberine inhibits human neuroblastoma cell growth through induction of p53-dependent apoptosis..Anticancer Res2008;28:3777-84

[182] Li J,Zhang H,Tian D.Berberine represses DAXX gene transcription and induces cancer cell apoptosis..Lab Invest2013;93:354-64 PMCID:PMC3961588

[183] Tian X,Bai S,Tong H.XAV939 inhibits the stemness and migration of neuroblastoma cancer stem cells via repression of tankyrase 1..Int J Oncol2014;45:121-8

[184] Schiapparelli P,Enguita-Germán M,Kogner P.Inhibition of the sonic hedgehog pathway by cyplopamine reduces the CD133+/CD15+ cell compartment and the in vitro tumorigenic capability of neuroblastoma cells..Cancer Lett2011;310:222-31

[185] Goel A.Curcumin, the golden spice from Indian saffron, is a chemosensitizer and radiosensitizer for tumors and chemoprotector and radioprotector for normal organs..Nutr Cancer2010;62:919-30

[186] Gheeya JS,Benjamin CD,Tsang P.Screening a panel of drugs with diverse mechanisms of action yields potential therapeutic agents against neuroblastoma..Cancer Biol Ther2009;8:2386-95 PMCID:PMC2829338

[187] Prasad R.Honokiol, an active compound of magnolia plant, inhibits growth, and progression of cancers of different organs..Adv Exp Med Biol2016;928:245-65

[188] Marcucci F,Lefoulon F.Anti-cancer stem-like cell compounds in clinical development - an overview and critical appraisal..Front Oncol2016;6:115 PMCID:PMC4861739

[189] Mishra R.Tinospora cordifolia induces differentiation and senescence pathways in neuroblastoma cells..Mol Neurobiol2015;52:719-33

[190] Pozzoli G,Navarra P,Cenciarelli C.Aspirin inhibits proliferation and promotes differentiation of neuroblastoma cells via p21(Waf1) protein up-regulation and Rb1 pathway modulation..J Cell Mol Med2019;23:7078-87 PMCID:PMC6787451

[191] Farabegoli F,Spisni E.Epigallocatechin-3-gallate and 6-OH-11-O-Hydroxyphenanthrene limit BE(2)-C neuroblastoma cell growth and neurosphere formation in vitro..Nutrients2018;10:1141 PMCID:PMC6164794

[192] Matthay KK,Seeger RC,Harris RE.Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children’s Cancer Group..N Engl J Med1999;341:1165-73

[193] Frappaz D,Coze C,Plouvier E.LMCE3 treatment strategy: results in 99 consecutively diagnosed stage 4 neuroblastomas in children older than 1 year at diagnosis..J Clin Oncol2000;18:468-76

[194] George RE,Medeiros-Nancarrow C,Marcus K.High-risk neuroblastoma treated with tandem autologous peripheral-blood stem cell-supported transplantation: long-term survival update..J Clin Oncol2006;24:2891-6

[195] Kletzel M,Haut PR,Morgan E.Treatment of high-risk neuroblastoma with triple-tandem high-dose therapy and stem-cell rescue: results of the Chicago Pilot II Study..J Clin Oncol2002;20:2284-92

[196] Moss TJ,Santana VM,Hurvitz C.Clonogenicity of circulating neuroblastoma cells: implications regarding peripheral blood stem cell transplantation..Blood1994;83:3085-9

[197] Rill DR,Roberts WM,Bowman LC.Direct demonstration that autologous bone marrow transplantation for solid tumors can return a multiplicity of tumorigenic cells..Blood1994;84:380-3

[198] Yalcin B,van Dalen EC.High-dose chemotherapy and autologous haematopoietic stem cell rescue for children with high-risk neuroblastoma..Cochrane Database Syst Rev2013;CD006301

[199] Kaffenberger J,Ioffreda M.Autologous graft-versus-host disease in a child with stage IV neuroblastoma..Pediatr Dermatol2015;32:276-9

[200] Grupp SA,Yanik GA.Neuroblastoma: issues in transplantation..Biol Blood Marrow Transplant2012;18:S92-100 PMCID:PMC3260463

[201] Fish JD.Stem cell transplantation for neuroblastoma..Bone Marrow Transplant2008;41:159-65 PMCID:PMC2892221

[202] Kumar L.Haematopoietic stem cell transplantation: current status..Natl Med J India2007;20:128-37