Drug and apoptosis resistance in cancer stem cells: a puzzle with many pieces

Abstract

Resistance to anticancer agents and apoptosis results in cancer relapse and is associated with cancer mortality. Substantial data have provided convincing evidence establishing that human cancers emerge from cancer stem cells (CSCs), which display self-renewal and are resistant to anticancer drugs, radiation, and apoptosis, and express enhanced epithelial to mesenchymal progression. CSCs represent a heterogeneous tumor cell population and lack specific cellular targets, which makes it a great challenge to target and eradicate them. Similarly, their close relationship with the tumor microenvironment creates greater complexity in developing novel treatment strategies targeting CSCs. Several mechanisms participate in the drug and apoptosis resistance phenotype in CSCs in various cancers. These include enhanced expression of ATP-binding cassette membrane transporters, activation of various cytoprotective and survival signaling pathways, dysregulation of stemness signaling pathways, aberrant DNA repair mechanisms, increased quiescence, autophagy, increased immune evasion, deficiency of mitochondrial-mediated apoptosis, upregulation of anti-apoptotic proteins including c-FLIP [cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein], Bcl-2 family members, inhibitors of apoptosis proteins, and PI3K/AKT signaling. Studying such mechanisms not only provides mechanistic insights into these cells that are unresponsive to drugs, but may lead to the development of targeted and effective therapeutics to eradicate CSCs. Several studies have identified promising strategies to target CSCs. These emerging strategies may help target CSC-associated drug resistance and metastasis in clinical settings. This article will review the CSCs drug and apoptosis resistance mechanisms and how to target CSCs.

Keywords

Cancer stem cells (CSCs) / apoptosis / drug resistance / death receptor pathways / anti-apoptotic proteins / Bcl-2 family / c-FLIP

References

[1] Lapidot T,Vormoor J.A cell initiating human acute myeloid leukaemia after transplantation into SCID mice.Nature1994;367:645-8

[2] Turdo A,Gaggianesi M.Meeting the challenge of targeting cancer stem cells.Front Cell Dev Biol2019;7:16 PMCID:PMC6387961

[3] Ben-Porath I,Carey VJ.An embryonic stem cell-like gene expression signature in poorly differentiated aggressive human tumors.Nat Genet2008;40:499-507 PMCID:PMC2912221

[4] Morgan RG,Williams AC.Targeting LGR5 in colorectal cancer: therapeutic gold or too plastic?.Br J Cancer2018;118:1410-8 PMCID:PMC5988707

[5] Wang Q,Hu X.Tumor evolution of glioma-intrinsic gene expression subtypes associates with immunological changes in the microenvironment.Cancer Cell2017;32:42-56.e6 PMCID:PMC5599156

[6] Wang X,Wan F.AMPK promotes SPOP-mediated NANOG degradation to regulate prostate cancer cell stemness.Dev Cell2019;48:345-360.e7 PMCID:PMC7523188

[7] Wei Y,Zou F.Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells.Proc Natl Acad Sci USA2013;110:6829-34 PMCID:PMC3637720

[8] Zhang J,Zhu Y.SPOP promotes nanog destruction to suppress stem cell traits and prostate cancer progression.Dev Cell2019;48:329-344.e5 PMCID:PMC6462403

[9] Katoh M.Canonical and non-canonical WNT signaling in cancer stem cells and their niches: cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity (review).Int J Oncol2017;51:1357-69 PMCID:PMC5642388

[10] Han B,Jin Y.FOXC1 activates smoothened-independent hedgehog signaling in basal-like breast cancer.Cell Rep2015;13:1046-58 PMCID:PMC4806384

[11] Hirata N,Shoda T,Sekino Y.Sphingosine-1-phosphate promotes expansion of cancer stem cells via S1PR3 by a ligand-independent Notch activation.Nat Commun2014;5:4806

[12] Zhang H,Wei Y.CD44 splice isoform switching determines breast cancer stem cell state.Genes Dev2019;33:166-79 PMCID:PMC6362815

[13] Chen P,Han J,DePinho RA.Cancer stemness meets immunity: from mechanism to therapy.Cell Rep2021;34:108597 PMCID:PMC7839836

[14] Nimmakayala RK,Ponnusamy MP.Unraveling the journey of cancer stem cells from origin to metastasis.Biochim Biophys Acta Rev Cancer2019;1871:50-63 PMCID:PMC6347501

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

[16] Nowell PC.The clonal evolution of tumor cell populations.Science1976;194:23-8

[17] Safa AR,Cohen-Gadol AA,Bijangi-Vishehsaraei K.Glioblastoma stem cells (GSCs) epigenetic plasticity and interconversion between differentiated non-GSCs and GSCs.Genes Dis2015;2:152-63 PMCID:PMC4484766

[18] Safa AR.Epithelial-mesenchymal transition: a hallmark in pancreatic cancer stem cell migration, metastasis formation, and drug resistance.J Cancer Metastasis Treat2020;6:36 PMCID:PMC8623975

[19] Aderetti DA,Molenaar RJ.The hypoxic peri-arteriolar glioma stem cell niche, an integrated concept of five types of niches in human glioblastoma.Biochim Biophys Acta Rev Cancer2018;1869:346-54

[20] Lee TK,Ma S.Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications.Nat Rev Gastroenterol Hepatol2022;19:26-44

[21] Prasetyanti PR.Intra-tumor heterogeneity from a cancer stem cell perspective.Mol Cancer2017;16:41 PMCID:PMC5314464

[22] Cortes-Dericks L.Impact of cancer stem cells and cancer stem cell-driven drug resiliency in lung tumor: options in sight.Cancers (Basel)2022;14:267 PMCID:PMC8773978

[23] Eun K,Kim H.Cancer stem cell heterogeneity: origin and new perspectives on CSC targeting.BMB Rep2017;50:117-25 PMCID:PMC5422023

[24] O’Connor ML,Shigdar S.Cancer stem cells: a contentious hypothesis now moving forward.Cancer Lett2014;344:180-7

[25] Holohan C,Longley DB.Cancer drug resistance: an evolving paradigm.Nat Rev Cancer2013;13:714-26

[26] Bajaj J,Reya TJ.Stem cells in cancer initiation and progression.Cell Biol2020;219:e201911053 PMCID:PMC7039188

[27] Chatterjee N.Polytherapy and targeted cancer drug resistance.Trends Cancer2019;5:170-82 PMCID:PMC6446041

[28] Safa AR.Resistance to cell death and its modulation in cancer stem cells.Crit Rev Oncog2016;21:203-19 PMCID:PMC5356509

[29] Senthebane DA,Rowe A.The role of tumor microenvironment in chemoresistance: 3D extracellular matrices as accomplices.Int J Mol Sci2018;19:2861 PMCID:PMC6213202

[30] Tang KD.Targeting drug-resistant prostate cancer with dual PI3K/mTOR inhibition.Curr Med Chem2014;21:3048-56

[31] Koff JL,Bernal-Mizrachi L.A time to kill: targeting apoptosis in cancer.Int J Mol Sci2015;16:2942-55 PMCID:PMC4346874

[32] Pfeffer CM.Apoptosis: a target for anticancer therapy.Int J Mol Sci2018;19:448 PMCID:PMC5855670

[33] Zang F,Leng X,Sun B.C-FLIP(L) contributes to TRAIL resistance in HER2-positive breast cancer.Biochem Biophys Res Commun2014;450:267-73

[34] Safa AR.Targeting the anti-apoptotic protein c-FLIP for cancer therapy.Cancers (Basel)2011;3:1639-71 PMCID:PMC3281420

[35] Naik PP,Parida R.Metabostemness in cancer: linking metaboloepigenetics and mitophagy in remodeling cancer stem cells.Stem Cell Rev Rep2022;18:198-213

[36] Zhou Y,Luo H,Chen M.Wnt signaling pathway in cancer immunotherapy.Cancer Lett2022;525:84-96

[37] Thomas S.Signaling network regulating osteogenesis in mesenchymal stem cells.J Cell Commun Signal2022;16:47-61 PMCID:PMC8688675

[38] Buyuk B,Ye K.Epithelial-to-mesenchymal transition signaling pathways responsible for breast cancer metastasis.Cell Mol Bioeng2022;15:1-13 PMCID:PMC8761190

[39] Zhou S,Xiao L.TRIM25 regulates oxaliplatin resistance in colorectal cancer by promoting EZH2 stability.Cell Death Dis2021;12:463 PMCID:PMC8106682

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

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

[42] Takeishi S.To wake up cancer stem cells, or to let them sleep, that is the question.Cancer Sci2016;107:875-81 PMCID:PMC4946711

[43] Vassalli G.Aldehyde dehydrogenases: not just markers, but functional regulators of stem cells.Stem Cells Int2019;2019:3904645 PMCID:PMC6348814

[44] Najafi M,Mortezaee K.Cancer stem cells (CSCs) in cancer progression and therapy.J Cell Physiol2019;234:8381-95

[45] Wang R,Wang P.Notch and Wnt/β-catenin signaling pathway play important roles in activating liver cancer stem cells.Oncotarget2016;7:5754-68 PMCID:PMC4868719

[46] Safa AR,Cohen-Gadol AA,Bijangi-Vishehsaraei K.Emerging targets for glioblastoma stem cell therapy.J Biomed Res2016;30:19-31 PMCID:PMC4726830

[47] Fang P,Lim LY,Yuan ZX.Targeting strategies for renal cancer stem cell therapy.Curr Pharm Des2020;26:1964-78

[48] Luo M.Targeting cancer stem cell redox metabolism to enhance therapy responses.Semin Radiat Oncol2019;29:42-54 PMCID:PMC6614864

[49] Snyder V,Arnold L,Anant S.Cancer stem cell metabolism and potential therapeutic targets.Front Oncol2018;8:203 PMCID:PMC5996058

[50] Somasagara RR,Tripathi K.RAD6 promotes DNA repair and stem cell signaling in ovarian cancer and is a promising therapeutic target to prevent and treat acquired chemoresistance.Oncogene2017;36:6680-90 PMCID:PMC5709226

[51] Macha MA,Qazi AK.Afatinib radiosensitizes head and neck squamous cell carcinoma cells by targeting cancer stem cells.Oncotarget2017;8:20961-73 PMCID:PMC5400558

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

[53] Prieto-Vila M,Usuba W,Ochiya T.Drug resistance driven by cancer stem cells and their niche.Int J Mol Sci2017;18:2574 PMCID:PMC5751177

[54] Yeldag G,Del Río Hernández A.Chemoresistance and the self-maintaining tumor microenvironment.Cancers (Basel)2018;10:471 PMCID:PMC6315745

[55] Dey P,De A.Targeting stem cells in the realm of drug-resistant breast cancer.Breast Cancer (Dove Med Press)2019;11:115-35 PMCID:PMC6410754

[56] Suresh R,Ahmad A,Sarkar FH.The role of cancer stem cells in recurrent and drug-resistant lung cancer. In: Ahmad A, Gadgeel SM, editors. Lung cancer and personalized medicine: novel therapies and clinical management. Cham: Springer International Publishing; 2016. pp. 57-74.

[57] Toledo-Guzmán ME,Ibáñez Hernández M.Cancer stem cell impact on clinical oncology.World J Stem Cells2018;10:183-95 PMCID:PMC6306557

[58] Sharifzad F,Verdi J.Glioblastoma cancer stem cell biology: Potential theranostic targets.Drug Resist Updat2019;42:35-45

[59] Wong ALA,Hirpara JL.Understanding the cancer stem cell phenotype: a step forward in the therapeutic management of cancer.Biochem Pharmacol2019;162:79-88

[60] Ajani JA,Hochster HS.Cancer stem cells: the promise and the potential.Semin Oncol2015;42 Suppl 1:S3-17

[61] Jhanwar-Uniyal M,Cooper JB,Schmidt MH.Discrete signaling mechanisms of mTORC1 and mTORC2: connected yet apart in cellular and molecular aspects.Adv Biol Regul2017;64:39-48

[62] Wang YH.Harnessing the apoptotic programs in cancer stem-like cells.EMBO Rep2015;16:1084-98 PMCID:PMC4576979

[63] Saeg F.Breast cancer stem cells and the challenges of eradication: a review of novel therapies.Stem Cell Investig2018;5:39 PMCID:PMC6232051

[64] Wen Y,Hou Y,Wang Z.Role of EZH2 in cancer stem cells: from biological insight to a therapeutic target.Oncotarget2017;8:37974-90 PMCID:PMC5514966

[65] Cai MH,Yan SL.Depletion of HDAC1, 7 and 8 by histone deacetylase inhibition confers elimination of pancreatic cancer stem cells in combination with gemcitabine.Sci Rep2018;8:1621 PMCID:PMC5786009

[66] Yang W,Gao R,Sun T.HDAC6 inhibition induces glioma stem cells differentiation and enhances cellular radiation sensitivity through the SHH/Gli1 signaling pathway.Cancer Lett2018;415:164-76

[67] Iriondo O,Domenici G.Distinct breast cancer stem/progenitor cell populations require either HIF1α or loss of PHD3 to expand under hypoxic conditions.Oncotarget2015;6:31721-39 PMCID:PMC4741635

[68] Lee G,Guo D.Dedifferentiation of glioma cells to glioma stem-like cells by therapeutic stress-induced HIF signaling in the recurrent GBM model.Mol Cancer Ther2016;15:3064-76 PMCID:PMC5298928

[69] Axelson H,Ovenberger M,Påhlman S.Hypoxia-induced dedifferentiation of tumor cells--a mechanism behind heterogeneity and aggressiveness of solid tumors.Semin Cell Dev Biol2005;16:554-63

[70] Del Vecchio CA,Sokol ES.De-differentiation confers multidrug resistance via noncanonical PERK-Nrf2 signaling.PLoS Biol2014;12:e1001945 PMCID:PMC4159113

[71] Ganguly R,Thiel J,Beullens M.MELK-a conserved kinase: functions, signaling, cancer, and controversy.Clin Transl Med2015;4:11 PMCID:PMC4385133

[72] Kim SH,Ezhilarasan R.EZH2 protects glioma stem cells from radiation-induced cell death in a MELK/FOXM1-dependent manner.Stem Cell Reports2015;4:226-38 PMCID:PMC4325196

[73] Inoue H,Olugbile S.Effective growth-suppressive activity of maternal embryonic leucine-zipper kinase (MELK) inhibitor against small cell lung cancer.Oncotarget2016;7:13621-33. PMCID:PMC4924666

[74] Zhang X,Wang Q.EZH2 targeting to improve the sensitivity of acquired radio-resistance bladder cancer cells.Transl Oncol2022;16:101316 PMCID:PMC8695351

[75] Neophytou CM,Erin N.Apoptosis deregulation and the development of cancer multi-drug resistance.Cancers (Basel)2021;13:4363 PMCID:PMC8430856

[76] Gregory CD.An apoptosis-driven “onco-regenerative niche”: roles of tumour-associated macrophages and extracellular vesicles.Philos Trans R Soc Lond B Biol Sci2018;373:20170003 PMCID:PMC5717442

[77] Godwin I,Bava SV,Jinesh GG.Targeting K-Ras and apoptosis-driven cellular transformation in cancer.Cell Death Discov2021;7:80 PMCID:PMC8047025

[78] Boumahdi S.The great escape: tumour cell plasticity in resistance to targeted therapy.Nat Rev Drug Discov2020;19:39-56

[79] Liao TT.Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness.Mol Oncol2017;11:792-804 PMCID:PMC5496497

[80] Babaei G,Jaghi NZZ.EMT, cancer stem cells and autophagy; the three main axes of metastasis.Biomed Pharmacother2021;133:110909

[81] Singh A.EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer.Oncogene2010;29:4741-51 PMCID:PMC3176718

[82] Cao Z,Kyprianou N.Anoikis and EMT: Lethal “liaisons” during cancer progression.Crit Rev Oncog2016;21:155-68 PMCID:PMC5451151

[83] Fattahi S,Tabaripour R,Akhavan-Niaki H.PI3K/AKT/mTOR signaling in gastric cancer: epigenetics and beyond.Life Sci2020;262:118513

[84] Lee S,Kolch W.Targeting MAPK signaling in cancer: mechanisms of drug resistance and sensitivity.Int J Mol Sci2020;21:1102 PMCID:PMC7037308

[85] Robak P,Szemraj J.Drug resistance in multiple myeloma.Cancer Treat Rev2018;70:199-208

[86] Comaills V,Morris R.Genomic instability is induced by persistent proliferation of cells undergoing epithelial-to-mesenchymal transition.Cell Rep2016;17:2632-47 PMCID:PMC5320932

[87] Huang T,Xu D.Stem cell programs in cancer initiation, progression, and therapy resistance.Theranostics2020;10:8721-43 PMCID:PMC7392012

[88] Topper MJ,Marrone KA,Baylin SB.The emerging role of epigenetic therapeutics in immuno-oncology.Nat Rev Clin Oncol2020;17:75-90 PMCID:PMC7254932

[89] Li F,Chen J.Apoptotic cells activate the “phoenix rising” pathway to promote wound healing and tissue regeneration.Sci Signal2010;3:ra13 PMCID:PMC2905599

[90] Shalini S,Dawar S.Old, new and emerging functions of caspases.Cell Death Differ2015;22:526-39 PMCID:PMC4356345

[91] Cadamuro M,Spirli C,Strazzabosco M.Autocrine and paracrine mechanisms promoting chemoresistance in cholangiocarcinoma.Int J Mol Sci2017;18:149 PMCID:PMC5297782

[92] Kološa K,Herold-Mende C,Lah TT.Paracrine effects of mesenchymal stem cells induce senescence and differentiation of glioblastoma stem-like cells.Cell Transplant2015;24:631-44

[93] Ingangi V,Ragone C,Carriero MV.Role of microenvironment on the fate of disseminating cancer stem cells.Front Oncol2019;9:82 PMCID:PMC6393337

[94] Perusina Lanfranca M,Bednar F.Metabolism and epigenetics of pancreatic cancer stem cells.Semin Cancer Biol2019;57:19-26 PMCID:PMC6438777

[95] Pires BR,Souza LD,Mencalha AL.Targeting cellular signaling pathways in breast cancer stem cells and its implication for cancer treatment.Anticancer Res2016;36:5681-91

[96] Giamogante F,Barazzuol L,Calì T.Apoptotic signals at the endoplasmic reticulum-mitochondria interface. apoptosis in health and disease - part B. Elsevier; 2021. pp. 307-43.

[97] Yadav N,O'Malley J.Molecular insights on cytochrome c and nucleotide regulation of apoptosome function and its implication in cancer.Biochim Biophys Acta Mol Cell Res2020;1867:118573 PMCID:PMC7733678

[98] Singh R,Sarosiek K.Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins.Nat Rev Mol Cell Biol2019;20:175-93 PMCID:PMC7325303

[99] Aouacheria A,Lamb HM,Pineda FJ.Connecting mitochondrial dynamics and life-or-death events via Bcl-2 family proteins.Neurochem Int2017;109:141-61 PMCID:PMC5641228

[100] Vela L.Bcl-2 family of proteins as drug targets for cancer chemotherapy: the long way of BH3 mimetics from bench to bedside.Curr Opin Pharmacol2015;23:74-81

[101] Correia C,Meng XW.Emerging understanding of Bcl-2 biology: Implications for neoplastic progression and treatment.Biochim Biophys Acta2015;1853:1658-71 PMCID:PMC4429517

[102] Krammer PH,Kiessling M.No life without death.Adv Cancer Res2007;97:111-38.

[103] Lavrik IN.Regulation of CD95/Fas signaling at the DISC.Cell Death Differ2012;19:36-41 PMCID:PMC3252827

[104] Lavrik I,Krammer PH.Death receptor signaling.J Cell Sci2005;118:265-7

[105] Leonard BC.Signaling by cell surface death receptors: alterations in head and neck cancer.Adv Biol Regul2018;67:170-8 PMCID:PMC5854325

[106] Redza-Dutordoir M.Activation of apoptosis signalling pathways by reactive oxygen species.Biochim Biophys Acta2016;1863:2977-92

[107] Zhang Z,Zhou L,Zhang Y.Redox signaling and unfolded protein response coordinate cell fate decisions under ER stress.Redox Biol2019;25:101047 PMCID:PMC6859529

[108] Bahar E,Yoon H.Chemotherapy resistance explained through endoplasmic reticulum stress-dependent signaling.Cancers (Basel)2019;11:338 PMCID:PMC6468910

[109] Mohamed MS,Almutairi FM.Inhibitors of apoptosis: clinical implications in cancer.Apoptosis2017;22:1487-509

[110] Mukherjee N,Fujita M,Shellman YG.Alternative treatments for melanoma: targeting BCL-2 family members to de-bulk and kill cancer stem cells.J Invest Dermatol2015;135:2155-61 PMCID:PMC4537369

[111] French R,Jones S,Clarkson R.Cytoplasmic levels of cFLIP determine a broad susceptibility of breast cancer stem/progenitor-like cells to TRAIL.Mol Cancer2015;14:209 PMCID:PMC4678708

[112] Fulda S.Regulation of apoptosis pathways in cancer stem cells.Cancer Lett2013;338:168-73

[113] Robey RW,Hall MD,Bates SE.Revisiting the role of ABC transporters in multidrug-resistant cancer.Nat Rev Cancer2018;18:452-64 PMCID:PMC6622180

[114] Lu JF,Bebawy M.MRP1 and its role in anticancer drug resistance.Drug Metab Rev2015;47:406-19

[115] Jaramillo AC,Lemos C.Ex vivo resistance in childhood acute lymphoblastic leukemia: correlations between BCRP, MRP1, MRP4 and MRP5 ABC transporter expression and intracellular methotrexate polyglutamate accumulation.Leuk Res2019;79:45-51

[116] Wilson BJ,Ma J.ABCB5 maintains melanoma-initiating cells through a proinflammatory cytokine signaling circuit.Cancer Res2014;74:4196-207 PMCID:PMC4119553

[117] Speigl L,Weide B,Shipp C.Prognostic impact of the putative cancer stem cell markers ABCG2, CD133, ALDH1A1 and CD44V7/8 in metastatic melanoma.Br J Dermatol2017;177:1447-9

[118] Wang D,Zhu Y.Retraction notice to “CD133+/CD44+/Oct4+/Nestin+ stem-like cells isolated from Panc-1 cell line may contribute to multi-resistance and metastasis of pancreatic cancer” [Acta Histochemica 115 (2013) 349-356].Acta Histochem2018;120:302

[119] Xie CR,Zhang N,Zheng XS.Epigallocatechin gallate preferentially inhibits O⁶-methylguanine DNA-methyltransferase expression in glioblastoma cells rather than in nontumor glial cells.Nutr Cancer2018;70:1339-47

[120] Guo Q,Gonzalez G.ATP-binding cassette member B5 (ABCB5) promotes tumor cell invasiveness in human colorectal cancer.J Biol Chem2018;293:11166-78 PMCID:PMC6052213

[121] Xia P.PI3K/Akt/mTOR signaling pathway in cancer stem cells: from basic research to clinical application.Am J Cancer Res2015;5:1602-9 PMCID:PMC4497429

[122] Yang Q,Hou P.Emerging role of PI3K/AKT in tumor-related epigenetic regulation.Semin Cancer Biol2019;59:112-24

[123] Noorolyai S,Baghbani E,Baradaran B.The relation between PI3K/AKT signalling pathway and cancer.Gene2019;698:120-8

[124] Yang SH,Lu G.Metformin treatment reduces temozolomide resistance of glioblastoma cells.Oncotarget2016;7:78787-803 PMCID:PMC5346677

[125] Aldea MD,Soritau O.Metformin plus sorafenib highly impacts temozolomide resistant glioblastoma stem-like cells.J BUON2014;19:502-11.

[126] Mayer MJ,Venkateswaran V.Metformin and prostate cancer stem cells: a novel therapeutic target.Prostate Cancer Prostatic Dis2015;18:303-9

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

[128] Sun W,Du F.Targeted drug delivery to cancer stem cells through nanotechnological approaches.Curr Stem Cell Res Ther2021;16:367-84.

[129] Hata AN,Faber AC.The BCL2 family: key mediators of the apoptotic response to targeted anticancer therapeutics.Cancer Discov2015;5:475-87 PMCID:PMC4727530

[130] Knight T,Edwards H,Ge Y.A delicate balance - the BCL-2 family and its role in apoptosis, oncogenesis, and cancer therapeutics.Biochem Pharmacol2019;162:250-61

[131] Hu Y,Zhao J.Sabutoclax, pan-active BCL-2 protein family antagonist, overcomes drug resistance and eliminates cancer stem cells in breast cancer.Cancer Lett2018;423:47-59

[132] Zhang L,Chen K.The pan-Bcl2 inhibitor AT101 activates the intrinsic apoptotic pathway and causes DNA damage in acute myeloid leukemia stem-like cells.Target Oncol2017;12:677-87

[133] Ryoo IG,Kwak MK.Redox modulating NRF2: a potential mediator of cancer stem cell resistance.Oxid Med Cell Longev2016;2016:2428153 PMCID:PMC4670665

[134] Wajant H.TNFR1-induced activation of the classical NF-κB pathway.FEBS J2011;278:862-76

[135] Chakraborty S,Tang H.Cytoplasmic TRADD confers a worse prognosis in glioblastoma.Neoplasia2013;15:888-97 PMCID:PMC3730041

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

[137] Fu ZH,Qin MB.NIK- and IKKβ-binding protein contributes to gastric cancer chemoresistance by promoting epithelial-mesenchymal transition through the NF-κB signaling pathway.Oncol Rep2018;39:2721-30

[138] Zhou J,Gu P,Margolick JB.NF-kappaB pathway inhibitors preferentially inhibit breast cancer stem-like cells.Breast Cancer Res Treat2008;111:419-27 PMCID:PMC3320112

[139] Lee MR,Mia-Jan K.Chemoresistance of CD133(+) colon cancer may be related with increased survivin expression.Biochem Biophys Res Commun2015;463:229-34

[140] Chen SM,Tu CH.Blockade of inhibitors of apoptosis proteins in combination with conventional chemotherapy leads to synergistic antitumor activity in medulloblastoma and cancer stem-like cells.PLoS One2016;11:e0161299 PMCID:PMC4990200

[141] Evans MK,Geradts J.XIAP regulation by MNK links MAPK and NFκB signaling to determine an aggressive breast cancer phenotype.Cancer Res2018;78:1726-38 PMCID:PMC7724565

[142] Ji J,Li ZL.XIAP Limits autophagic degradation of Sox2 and is a therapeutic target in nasopharyngeal carcinoma stem cells.Theranostics2018;8:1494-510 PMCID:PMC5858163

[143] Janzen DM,Salehi JA.An apoptosis-enhancing drug overcomes platinum resistance in a tumour-initiating subpopulation of ovarian cancer. Nat Commun 2015;6:7956. PMCID: PMC4532886

[144] Safa AR.Roles of c-FLIP in apoptosis, necroptosis, and autophagy.J Carcinog Mutagen2013;Suppl 6:003 PMCID:PMC4219646

[145] Ivanisenko NV,Hillert-Richter LK.Regulation of extrinsic apoptotic signaling by c-FLIP: towards targeting cancer networks.Trends Cancer2022;8:190-209

[146] Yoon MJ,Kim IY.Monensin, a polyether ionophore antibiotic, overcomes TRAIL resistance in glioma cells via endoplasmic reticulum stress, DR5 upregulation and c-FLIP downregulation.Carcinogenesis2013;34:1918-28

[147] Ding L,Wei F.Cisplatin restores TRAIL apoptotic pathway in glioblastoma-derived stem cells through up-regulation of DR5 and down-regulation of c-FLIP.Cancer Invest2011;29:511-20 PMCID:PMC3255792

[148] Zobalova R,Prokopova K,Neuzil J.Cancer cells with high expression of CD133 exert FLIP upregulation and resistance to TRAIL-induced apoptosis.Biofactors2008;34:231-5

[149] Behrooz A, Syahir A, Ahmad S. CD133: beyond a cancer stem cell biomarker.J Drug Target2019;27:257-69

[150] Toledo-Guzmán ME,Gómez-Gallegos ÁA.ALDH as a stem cell marker in solid tumors.Curr Stem Cell Res Ther2019;14:375-88

[151] 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

[152] Tomita H,Tanaka T.Aldehyde dehydrogenase 1A1 in stem cells and cancer.Oncotarget2016;7:11018-32 PMCID:PMC4905455

[153] Roy M,Al-Niaimi A,Mahajan A.Aldehyde dehydrogenase 1A1 (ALDH1A1) expression by immunohistochemistry is associated with chemo-refractoriness in patients with high-grade ovarian serous carcinoma.Hum Pathol2018;73:1-6

[154] Moreb JS.Aldehyde dehydrogenase as a marker for stem cells.Curr Stem Cell Res Ther2008;3:237-46

[155] Manic G,Corradi F,De Maria R.Replication stress response in cancer stem cells as a target for chemotherapy.Semin Cancer Biol2018;53:31-41

[156] Ding S,Cheng N,Xu X.Redox regulation in cancer stem cells.Oxid Med Cell Longev2015;2015:750798 PMCID:PMC4529979

[157] Maugeri-Saccà M,De Maria R.DNA damage repair pathways in cancer stem cells.Mol Cancer Ther2012;11:1627-36

[158] Coudre C,Ritchie W,Sola B.HIF-1α and rapamycin act as gerosuppressant in multiple myeloma cells upon genotoxic stress.Cell Cycle2016;15:2174-82 PMCID:PMC4993538

[159] Ronco C,Demange L.ATM, ATR, CHK1, CHK2 and WEE1 inhibitors in cancer and cancer stem cells.Medchemcomm2017;8:295-319 PMCID:PMC6072143

[160] Fang DD,Jani JP.Combined gemcitabine and CHK1 inhibitor treatment induces apoptosis resistance in cancer stem cell-like cells enriched with tumor spheroids from a non-small cell lung cancer cell line.Front Med2013;7:462-76

[161] Levine B.Autophagy in the pathogenesis of disease. Cell 2008;132:27-42.

[162] Ariosa AR,Lei Y.A perspective on the role of autophagy in cancer.Biochim Biophys Acta Mol Basis Dis2021;1867:166262 PMCID:PMC8488024

[163] Smith AG.Autophagy, cancer stem cells and drug resistance.J Pathol2019;247:708-18 PMCID:PMC6668344

[164] Rothe K,Jiang X.Current outlook on autophagy in human leukemia: foe in cancer stem cells and drug resistance, friend in new therapeutic interventions.Int J Mol Sci2019;20:461 PMCID:PMC6387281

[165] Nazio F,Cianfanelli V,Cecconi F.Autophagy and cancer stem cells: molecular mechanisms and therapeutic applications.Cell Death Differ2019;26:690-702 PMCID:PMC6460398

[166] Rebecca T Marquez 1.Bcl-2: Beclin 1 complex: multiple, mechanisms regulating autophagy/apoptosis toggle switch.Am J Cancer Res2012;2:214-21. PMCID:PMC3304572

[167] Davis JE,Ji Y.Tumor Dormancy and slow-cycling cancer cells. In: Rhim JS, Dritschilo A, Kremer R, editors. Human cell transformation. Cham: Springer International Publishing; 2019. pp. 199-206. PMCID:PMC8025565

[168] Nik Nabil WN,Song Z.Towards a framework for better understanding of quiescent cancer cells.Cells2021;10:562 PMCID:PMC7999675

[169] Talukdar S,Emdad L,Sarkar D.Dormancy and cancer stem cells: an enigma for cancer therapeutic targeting. Cancer stem cells. Adv Cancer Res 2019;141:43-84.

[170] Basu S,Kumar R,Tang DG.Slow-cycling (dormant) cancer cells in therapy resistance, cancer relapse and metastasis.Semin Cancer Biol2022;78:90-103 PMCID:PMC8576068

[171] Hen O.Dormant disseminated tumor cells and cancer stem/progenitor-like cells: similarities and opportunities.Semin Cancer Biol2020;60:157-65

[172] Chen X,Zhao B.Dormancy activation mechanism of oral cavity cancer stem cells.Tumour Biol2015;36:5551-9

[173] Brown Y,Tanwar PS.Extracellular matrix-mediated regulation of cancer stem cells and chemoresistance.Int J Biochem Cell Biol2019;109:90-104

[174] Neal ME, Brenner JC, Prince MEP, Chinn SB. Advancement in cancer stem cell biology and precision medicine-review article head and neck cancer stem cell plasticity and the tumor microenvironment.Front Cell Dev Biol2021;9:660210 PMCID:PMC8762309

[175] Oskarsson T,Massagué J.Metastatic stem cells: sources, niches, and vital pathways.Cell Stem Cell2014;14:306-21 PMCID:PMC3998185

[176] Gupta R,Johnston TP.Colon cancer stem cells: potential target for the treatment of colorectal cancer.Cancer Biol Ther2019;20:1068-82 PMCID:PMC6606008

[177] Chang HH,Wu CY.Hedgehog overexpression leads to the formation of prostate cancer stem cells with metastatic property irrespective of androgen receptor expression in the mouse model.J Biomed Sci2011;18:6 PMCID:PMC3025942

[178] Xiao W,Zhang R.Bioengineered scaffolds for 3D culture demonstrate extracellular matrix-mediated mechanisms of chemotherapy resistance in glioblastoma.Matrix Biol2020;85-86:128-46 PMCID:PMC6813884

[179] Li Y,Ajani JA.Drug resistance and cancer stem cells.Cell Commun Signal2021;19:19 PMCID:PMC7885480

[180] Fu Y,Zhao J,Qin Y.Gastric cancer stem cells: mechanisms and therapeutic approaches.Yonsei Med J2018;59:1150-8 PMCID:PMC6240570

[181] Duchartre Y,Kahn M.The Wnt signaling pathway in cancer.Crit Rev Oncol Hematol2016;99:141-9 PMCID:PMC5853106

[182] Cui X,Duan L,Zhang Q.CAR-T therapy: prospects in targeting cancer stem cells.J Cell Mol Med2021;25:9891-904 PMCID:PMC8572776

[183] Hsieh HL,Cheng LC,Tsai MM.Molecular mechanism of therapeutic approaches for human gastric cancer stem cells.World J Stem Cells2022;14:76-91 PMCID:PMC8788185

[184] Oliveira LFS,Borges HL.Therapeutic potential of naturally occurring small molecules to target the Wnt/β-catenin signaling pathway in colorectal cancer.Cancers (Basel)2022;14:403 PMCID:PMC8774030

[185] Chan MH,Huang CF,Liu RS.Integrated therapy platform of exosomal system: hybrid inorganic/organic nanoparticles with exosomes for cancer treatment.Nanoscale Horiz2022;7:352-67

[186] Deng J,Feng X.Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression.BMC Cancer2019;19:618 PMCID:PMC6591840

[187] Croker AK.Inhibition of aldehyde dehydrogenase (ALDH) activity reduces chemotherapy and radiation resistance of stem-like ALDHhiCD44⁺ human breast cancer cells.Breast Cancer Res Treat2012;133:75-87

[188] Saneja A,Kumar R,Panda AK.CD44 targeted PLGA nanomedicines for cancer chemotherapy.Eur J Pharm Sci2018;121:47-58

[189] Basu SM,Singh R.Lipid nanocapsules co-encapsulating paclitaxel and salinomycin for eradicating breast cancer and cancer stem cells.Colloids Surf B Biointerfaces2021;204:111775

[190] Zhang C,Li Q.Salinomycin suppresses TGF-β1-induced epithelial-to-mesenchymal transition in MCF-7 human breast cancer cells.Chem Biol Interact2016;248:74-81

[191] Wang H,Zhu Y,Cui C.Anticancer mechanisms of salinomycin in breast cancer and its clinical applications.Front Oncol2021;11:654428 PMCID:PMC8350729

[192] Muntimadugu E,Saladi S,Khan W.CD44 targeted chemotherapy for co-eradication of breast cancer stem cells and cancer cells using polymeric nanoparticles of salinomycin and paclitaxel.Colloids Surf B2016;143:532-46

[193] Han NK,Kim JS,Jang CY.Hyaluronan-conjugated liposomes encapsulating gemcitabine for breast cancer stem cells.Int J Nanomedicine2016;11:1413-25 PMCID:PMC4827594

[194] Diebolder P,Scott J.Preclinical evaluation of an engineered single-chain fragment variable-fragment crystallizable targeting human CD44.J Nucl Med2021;62:137-43

[195] Bijangi-Vishehsaraei K,Wang H.Sulforaphane suppresses the growth of glioblastoma cells, glioblastoma stem cell-like spheroids, and tumor xenografts through multiple cell signaling pathways.J Neurosurg2017;127:1219-30 PMCID:PMC6086125

[196] Naujokat C.The “big five” phytochemicals targeting cancer stem cells: curcumin, EGCG, sulforaphane, resveratrol and genistein.Curr Med Chem2021;28:4321-42

[197] Dandawate PR,Jensen RA.Targeting cancer stem cells and signaling pathways by phytochemicals: novel approach for breast cancer therapy.Semin Cancer Biol2016;40-41:192-208 PMCID:PMC5565737

[198] Bhaskara VK,Mysorekar VV,Simal-Gandara J.Resveratrol, cancer and cancer stem cells: a review on past to future.Curr Res Food Sci2020;3:284-95 PMCID:PMC7718213

[199] Li Y,Schwartz SJ.Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds.J Nutr Biochem2011;22:799-806 PMCID:PMC3248810

[200] Li Y.Targeting cancer stem cells by curcumin and clinical applications.Cancer Lett2014;346:197-205

[201] Pollyea DA,Jones CL.Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia.Nat Med2018;24:1859-66 PMCID:PMC7001730

[202] Niu X,Chen M.Targeting AXL kinase sensitizes leukemic stem and progenitor cells to venetoclax treatment in acute myeloid leukemia.Blood2021;137:3641-55 PMCID:PMC8462401

[203] Song S,Li Y.Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma.Gut2021;70:2238-48

[204] Wang D,Liu B.IL6 blockade potentiates the anti-tumor effects of γ-secretase inhibitors in Notch3-expressing breast cancer.Cell Death Differ2018;25:330-9 PMCID:PMC5762847

[205] Hossain F,Ucar DA.Notch signaling regulates mitochondrial metabolism and NF-κB activity in triple-negative breast cancer cells via IKKα-dependent non-canonical pathways.Front Oncol2018;8:575 PMCID:PMC6289043

[206] McKeage MJ,Markman B.Phase IB trial of the anti-cancer stem cell DLL4-binding agent demcizumab with pemetrexed and carboplatin as first-line treatment of metastatic non-squamous NSCLC. Targ Oncol 2018;13:89-98/

[207] McKeage MJ,Markman B.Phase IB trial of the anti-cancer stem cell DLL4-binding agent demcizumab with pemetrexed and carboplatin as first-line treatment of metastatic non-squamous NSCLC.Target Oncol2018;13:89-98

[208] Szaryńska M,Kobiela J,Kmieć Z.Therapeutic strategies against cancer stem cells in human colorectal cancer.Oncol Lett2017;14:7653-68 PMCID:PMC5727596

[209] Cortes JE,Fiedler W.Survival outcomes and clinical benefit in patients with acute myeloid leukemia treated with glasdegib and low-dose cytarabine according to response to therapy.J Hematol Oncol2020;13:92 PMCID:PMC7362563

[210] Li JJ.Prostate stem cells and cancer stem cells.Cold Spring Harb Perspect Med2019;9:a030395 PMCID:PMC6546034

[211] Eckerdt F,Bell JB.Pharmacological mTOR targeting enhances the antineoplastic effects of selective PI3Kα inhibition in medulloblastoma.Sci Rep2019;9:12822 PMCID:PMC6731286

[212] Calvani M,Taddei ML.Etoposide-Bevacizumab a new strategy against human melanoma cells expressing stem-like traits.Oncotarget2016;7:51138-49 PMCID:PMC5239464

[213] Heckmann D,Laufs S.CXCR4 expression and treatment with SDF-1α or plerixafor modulate proliferation and chemosensitivity of colon cancer cells. Transl Oncol 2013;6:124-32. PMCID:PMC3610551

[214] Navas T,Colantonio S.Novel antibody reagents for characterization of drug- and tumor microenvironment-induced changes in epithelial-mesenchymal transition and cancer stem cells.PLoS One2018;13:e0199361 PMCID:PMC6013203

[215] Katayama R,Sato S,Tsuruo T.Dofequidar fumarate sensitizes cancer stem-like side population cells to chemotherapeutic drugs by inhibiting ABCG2/BCRP-mediated drug export.Cancer Sci2009;100:2060-8

[216] Umebayashi M,Koya N.An epithelial cell adhesion molecule- and CD3-bispecific antibody plus activated T-cells can eradicate chemoresistant cancer stem-like pancreatic carcinoma cells in vitro.Anticancer Res2014;34:4509-4519

[217] Fong D,Chan MM.Targeting cancer stem cells with repurposed drugs to improve current therapies.Recent Pat Anticancer Drug Discov2021;16:136-60