Skip to main content

Advertisement

SpringerLink
Log in

Targeting cancer stem cell-specific markers and/or associated signaling pathways for overcoming cancer drug resistance

  • Review
  • Published:
Tumor Biology

Abstract

Cancer stem cells (CSCs) are a small subpopulation of tumor cells with capabilities of self-renewal, dedifferentiation, tumorigenicity, and inherent chemo-and-radio therapy resistance. Tumor resistance is believed to be caused by CSCs that are intrinsically challenging to common treatments. A number of CSC markers including CD44, CD133, receptor tyrosine kinase, aldehyde dehydrogenases, epithelial cell adhesion molecule/epithelial specific antigen, and ATP-binding cassette subfamily G member 2 have been proved as the useful targets for defining CSC population in solid tumors. Furthermore, targeting CSC markers through new therapeutic strategies will ultimately improve treatments and overcome cancer drug resistance. Therefore, the identification of novel strategies to increase sensitivity of CSC markers has major clinical implications. This review will focus on the innovative treatment methods such as nano-, immuno-, gene-, and chemotherapy approaches for targeting CSC-specific markers and/or their associated signaling pathways.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

Abbreviations

ABCG2:

ATP-binding cassette subfamily G member 2

ABCB5:

ATP-binding cassette transporter B5

ADR:

Adriamycin

ALDH1:

Aldehyde dehydrogenase 1

AML:

Acute myeloid leukemia

ANT2:

Adenine nucleotide translocase 2

ATRA:

All-trans retinoic acid

AuNRs:

Gold nanorods

BRAC1:

Breast cancer type 1

CAF:

Carcinoma-associated fibroblast

Chk1:

Checkpoint kinase

CSF-1:

Colony stimulating factor 1

CSCs:

Cancer stem cells

dCD133KDEL:

Deimmunized Pseudomonas exotoxin fused to anti-CD133 scFv with a KDEL terminus

DEAB:

4-(Diethylamino)benzaldehyde

DLBCL:

Diffuse large B cell lymphoma

DNR:

Daunorubicin

DPAGT1:

Dolichyl-phosphate N-acetylglucosamine phosphotransferase 1

DOX:

Doxorubicin

EGFR:

Epidermal growth factor receptor

EpCAM:

Epithelial cell adhesion molecule

ERK:

Extracellular-signal-regulated kinases

ESA:

Epithelial specific antigen

FA:

Folate

FAHAC18:

Folate hyaluronic acidoctadecyl

FLT3:

FMS-like receptor tyrosine kinase 3

GBM:

Glioblastoma multiforme

GRP78:

78 kDa glucose-regulated protein

GSK3β:

Glycogen synthase kinase 3 beta

HA:

Hyaluronan

HAC18:

Hyaluronic acidoctadecyl

HAPEI/HA:

HA poly(ethyleneimine)/HA

Hh:

Hedgehog

ISL:

Isoliquiritigenin

PEG:

Poly(ethylene glycol)

HDAC6:

Histone deacetylase 6

HER2:

Human epidermal growth factor receptor 2

HGF:

Hepatocyte growth factor

HSP90:

Heat shock protein 90

JAK:

Janus family kinases

JNK:

Jun N-terminal kinase

LA:

Lipoic acid

pDNA:

Plasmid DNA

MAPK:

Mitogen-activated protein kinase

METF:

Metformin

mAb:

Monoclonal antibody

MDR1:

Multidrug resistance protein 1

MM:

Multiple myeloma

mPEG-PLGA-PLL, PEAL:

Monomethoxy polyethylene glycol–polylactic acid/glycolic acid–poly(l-lysine) triblock copolymer

MT:

Microtubules

NPs:

Nanoparticles

NSCLC:

Non-small cell lung cancer

PEG:

Poly(ethylene glycol)

PEO:

Poly(ethylene oxide)

PDGF:

Platelet-derived growth factor

PI3:

Phosphoinositide 3

PPI:

Polypropylenimine

PTEN:

Phosphatase and tensin homologue deleted on chromosome 10

PTPRK:

Receptor-type protein tyrosine phosphatase k

PTX:

Paclitaxel

P-gp:

Permeability glycoprotein

PZ-39:

N-(4-chlorophenyl)-2-[(6-{[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl] amino}-1,3-benzothiazol-2-yl; sulfanyl]acetamide)

ROR1:

Type I receptor tyrosine kinase-like orphan receptor

RTK:

Receptor tyrosine kinase

SAL:

Salinomycin

SCF:

Stem cell factor

shRNA:

Short hairpin RNA

STAT:

Signal transducers and activators of transcription

SSCs:

Somatic stem cells

TKI:

Tyrosine kinase inhibitors

Topo:

Topoisomerase

References

  1. Johari-Ahar M, Barar J, Alizadeh AM, Davaran S, Omidi Y, Rashidi M-R. Methotrexate-conjugated quantum dots: synthesis, characterisation and cytotoxicity in drug resistant cancer cells. J Drug Target. 2016;24(2):120–33.

    Article  CAS  PubMed  Google Scholar 

  2. Vinogradov S, Wei X. Cancer stem cells and drug resistance: the potential of nanomedicine. Nanomed. 2012;7(4):597–615.

    Article  CAS  Google Scholar 

  3. Andrews TE, Wang D, Harki DA. Cell surface markers of cancer stem cells: diagnostic macromolecules and targets for drug delivery. Drug Deliv Transl Res. 2013;3(2):121–42.

    Article  CAS  PubMed  Google Scholar 

  4. Xue X, Liang X-J. Overcoming drug efflux-based multidrug resistance in cancer with nanotechnology. Chin J Cancer. 2012;31(2):100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Farsinejad S, Gheisary Z, Samani SE, Alizadeh AM. Mitochondrial targeted peptides for cancer therapy. Tumor Biol. 2015;36(8):5715–25.

    Article  CAS  Google Scholar 

  6. Vaz AP, Ponnusamy MP, Batra SK. Cancer stem cells and therapeutic targets: an emerging field for cancer treatment. Drug Deliv Transl Res. 2013;3(2):113–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Alama A, Orengo AM, Ferrini S, Gangemi R. Targeting cancer-initiating cell drug-resistance: a roadmap to a new-generation of cancer therapies? Drug Discov Today. 2012;17(9):435–42.

    Article  CAS  PubMed  Google Scholar 

  8. Mimeault M, Batra SK. Novel biomarkers and therapeutic targets for optimizing the therapeutic management of melanomas. World J Clin Oncol. 2012;3(3):32–42.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Shapira A, Livney YD, Broxterman HJ, Assaraf YG. Nanomedicine for targeted cancer therapy: towards the overcoming of drug resistance. Drug Resist Updat. 2011;14(3):150–63.

    Article  CAS  PubMed  Google Scholar 

  10. Shigdar S, Lin J, Yu Y, Pastuovic M, Wei M, Duan W. RNA aptamer against a cancer stem cell marker epithelial cell adhesion molecule. Cancer Sci. 2011;102(5):991–8.

    Article  CAS  PubMed  Google Scholar 

  11. Ranji P, Heydari Z, Alizadeh AM. Nanobiotechnological approaches to overcome drug resistance in breast cancer. Curr Cancer Drug Targets. 2015;15(7):544–62.

    Article  CAS  PubMed  Google Scholar 

  12. Clevers H. The cancer stem cell: premises, promises and challenges. Nature Med. 2011;313–9.

  13. Chen L, Bourguignon LY. Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells. Mol Cancer. 2014;13(1):1.

    Article  CAS  Google Scholar 

  14. Gu J, Fang X, Hao J, Sha X. Reversal of P-glycoprotein-mediated multidrug resistance by CD44 antibody-targeted nanocomplexes for short hairpin RNA-encoding plasmid DNA delivery. Biomaterials. 2015;45:99–114.

    Article  CAS  PubMed  Google Scholar 

  15. Ebben JD, Treisman DM, Zorniak M, Kutty RG, Clark PA, Kuo JS. The cancer stem cell paradigm: a new understanding of tumor development and treatment. Expert Opin Ther Targets. 2010;14(6):621–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Aguilar-Gallardo C, Rutledge EC, Martínez-Arroyo AM, Hidalgo JJ, Domingo S, Simón C. Overcoming challenges of ovarian cancer stem cells: novel therapeutic approaches. Stem Cell Rev. 2012;8(3):994–1010.

    Article  CAS  PubMed  Google Scholar 

  17. Bourguignon LY, Earle C, Wong G, Spevak CC, Krueger K. Stem cell marker (Nanog) and Stat-3 signaling promote microRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene. 2012;31(2):149–60.

    Article  CAS  PubMed  Google Scholar 

  18. Thomas ML, Coyle KM, Sultan M, Vaghar-Kashani A, Marcato P. Chemoresistance in cancer stem cells and strategies to overcome resistance. Chemotherapy: Open Access. 2014;2014.

  19. Jordan AR, Racine RR, Hennig MJ, Lokeshwar VB. The role of CD44 in disease pathophysiology and targeted treatment. Frontiers In Immunol. 2015;6.

  20. Hong SP, Wen J, Bang S, Park S, Song SY. CD44-positive cells are responsible for gemcitabine resistance in pancreatic cancer cells. Inter J Cancer. 2009;125(10):2323–31.

    Article  CAS  Google Scholar 

  21. Miletti-González KE, Chen S, Muthukumaran N, Saglimbeni GN, Wu X, Yang J, et al. The CD44 receptor interacts with P-glycoprotein to promote cell migration and invasion in cancer. Cancer Res. 2005;65(15):6660–7.

    Article  PubMed  Google Scholar 

  22. Bourguignon LY, Peyrollier K, Xia W, Gilad E. Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J Biol Chem. 2008;283(25):17635–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yang X, Singh A, Choy E, Hornicek FJ, Amiji MM, Duan Z. MDR1 siRNA loaded hyaluronic acid-based CD44 targeted nanoparticle systems circumvent paclitaxel resistance in ovarian cancer. Sci Rep. 2015;5.

  24. Zhong Y, Zhang J, Cheng R, Deng C, Meng F, Xie F, et al. Reversibly crosslinked hyaluronic acid nanoparticles for active targeting and intelligent delivery of doxorubicin to drug resistant CD44+ human breast tumor xenografts. J Control Release. 2015;205:144–54.

    Article  CAS  PubMed  Google Scholar 

  25. Liu Y, Sun J, Lian H, Cao W, Wang Y, He Z. Folate and CD44 receptors dual-targeting hydrophobized hyaluronic acid paclitaxel-loaded polymeric micelles for overcoming multidrug resistance and improving tumor distribution. J Pharm Sci. 2014;103(5):1538–47.

    Article  CAS  PubMed  Google Scholar 

  26. Liu YP, Liu CF, Ma DX, Lu F, Zhang JJ, Kong HL. [Effect of CD44 gene silence on multi-drug resistance reversal and biologic activity in K562/A02 cells]. Zhongguo ShiYan Xue Ye Xue Za Zhi. 2010;18(2):335–9.

  27. Opyrchal M, Salisbury JL, Iankov I, Goetz MP, McCubrey J, Gambino MW, et al. Inhibition of Cdk2 kinase activity selectively targets the CD44+/CD24−/low stem-like subpopulation and restores chemosensitivity of SUM149PT triple-negative breast cancer cells. Inter j Oncol. 2014;45(3):1193–9.

    CAS  Google Scholar 

  28. Ahmadipour F, Noordin MI, Mohan S, Arya A, Paydar M, Looi CY, et al. Koenimbin, a natural dietary compound of Murraya koenigii (L) Spreng: inhibition of MCF7 breast cancer cells and targeting of derived MCF7 breast cancer stem cells (CD44+/CD24−/low): an in vitro study. Drug Des Dev Ther. 2015;9:1193.

    Google Scholar 

  29. Fargeas CA, Florek M, Huttner WB, Corbeil D. Characterization of prominin-2, a new member of the prominin family of pentaspan membrane glycoproteins. J Biol Chem. 2003;278(10):8586–96.

    Article  CAS  PubMed  Google Scholar 

  30. Dubreuil V, Marzesco A-M, Corbeil D, Huttner WB, Wilsch-Bräuninger M. Midbody and primary cilium of neural progenitors release extracellular membrane particles enriched in the stem cell marker prominin-1. J Cell Biol. 2007;176(4):483–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT, et al. A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood. 1997;90(12):5013–21.

    CAS  PubMed  Google Scholar 

  32. Grosse-Gehling P, Fargeas CA, Dittfeld C, Garbe Y, Alison MR, Corbeil D, et al. CD133 as a biomarker for putative cancer stem cells in solid tumours: limitations, problems and challenges. J Pathol. 2013;229(3):355–78.

    Article  CAS  PubMed  Google Scholar 

  33. Corbeil D, Röper K, Fargeas CA, Joester A, Huttner WB. Prominin: a story of cholesterol, plasma membrane protrusions and human pathology. Traffic. 2001;2(2):82–91.

    Article  CAS  PubMed  Google Scholar 

  34. Weigmann A, Corbeil D, Hellwig A, Huttner WB. Prominin, a novel microvilli-specific polytopic membrane protein of the apical surface of epithelial cells, is targeted to plasmalemmal protrusions of non-epithelial cells. P Natl Acad Sci. 1997;94(23):12425–30.

    Article  CAS  Google Scholar 

  35. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, et al. Identification of human brain tumour initiating cells. Nature. 2004;432(7015):396–401.

    Article  CAS  PubMed  Google Scholar 

  36. Mak AB, Nixon AM, Kittanakom S, Stewart JM, Chen GI, Curak J, et al. Regulation of CD133 by HDAC6 promotes β-catenin signaling to suppress cancer cell differentiation. Cell Rep. 2012;2(4):951–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Chao C, Carmical JR, Ives KL, Wood TG, Aronson JF, Gomez GA, et al. CD133+ colon cancer cells are more interactive with the tumor microenvironment than CD133- cells. Lab Investig. 2012;92(3):420–36.

    Article  CAS  PubMed  Google Scholar 

  38. Shimozato O, Waraya M, Nakashima K, Souda H, Takiguchi N, Yamamoto H, et al. Receptor-type protein tyrosine phosphatase k directly dephosphorylates CD133 and regulates downstream AKT activation. Oncogene. 2015;34(15):1949–60.

  39. Wei Y, Jiang Y, Zou F, Liu Y, Wang S, Xu N, et al. Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells. P Natl Acad Sci. 2013;110(17):6829–34.

    Article  CAS  Google Scholar 

  40. Barr MP, Gray SG, Hoffmann AC, Hilger RA, Thomale J, O’Flaherty JD, et al. Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature. PLoS One. 2013;8(1):e54193.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Liu Y-P, Yang C-J, Huang M-S, Yeh C-T, Wu AT, Lee Y-C, et al. Cisplatin selects for multidrug-resistant CD133+ cells in lung adenocarcinoma by activating notch signaling. Cancer Res. 2013;73(1):406–16.

    Article  CAS  PubMed  Google Scholar 

  42. Bolderson E, Richard DJ, Zhou B-BS, Khanna KK. Recent advances in cancer therapy targeting proteins involved in DNA double-strand break repair. Clin Cancer Res. 2009;15(20):6314–20.

    Article  CAS  PubMed  Google Scholar 

  43. Gallmeier E, Hermann PC, Mueller MT, Machado JG, Ziesch A, De Toni EN, et al. Inhibition of ataxia telangiectasia-and Rad3-related function abrogates the in vitro and in vivo tumorigenicity of human colon cancer cells through depletion of the CD133+ tumor-initiating cell fraction. Stem Cells. 2011;29(3):418–29.

    Article  CAS  PubMed  Google Scholar 

  44. Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, AB H, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444(7120):756–60.

    Article  CAS  PubMed  Google Scholar 

  45. Yeh C-T, Wu AT, Chang PM-H, Chen K-Y, Yang C-N, Yang S-C, et al. Trifluoperazine, an antipsychotic agent, inhibits cancer stem cell growth and overcomes drug resistance of lung cancer. A J Res Crit Care Medicine. 2012;186(11):1180–8.

    Article  CAS  Google Scholar 

  46. Skubitz AP, Taras EP, Boylan KL, Waldron NN, Oh S, Panoskaltsis-Mortari A, et al. Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression. Gynecolo Oncol. 2013;130(3):579–87.

    Article  CAS  Google Scholar 

  47. Fan X, Matsui W, Khaki L, Stearns D, Chun J, Li Y-M, et al. Notch pathway inhibition depletes stem-like cells and blocks engraftment in embryonal brain tumors. Cancer Res. 2006;66(15):7445–52.

    Article  CAS  PubMed  Google Scholar 

  48. Zhao L, Yang Y, Zhou P, Ma H, Zhao X, He X, et al. Targeting CD133high colorectal cancer cells in vitro and in vivo with an asymmetric bispecific antibody. J Immunother. 2015;38(6):217–28.

    Article  CAS  PubMed  Google Scholar 

  49. Di Cristofori A, Ferrero S, Bertolini I, Gaudioso G, MV R, Berno V, et al. The vacuolar H+ ATPase is a novel therapeutic target for glioblastoma. Oncotarget. 2015;6(19):17514–31.

  50. Lin F, Yan W, Wen T, Wu G. [Metformin induces apoptosis in hepatocellular carcinoma Huh-7 cells in vitro and its mechanism]. Zhonghua zhong liu za zhi [Chinese Journal of Oncology]. 2013;35(10):742–6.

    CAS  Google Scholar 

  51. Kiyoi H, Naoe T. Biology, clinical relevance, and molecularly targeted therapy in acute leukemia with FLT3 mutation. Inter J hematol. 2006;83(4):301–8.

    Article  CAS  Google Scholar 

  52. Linnekin D, Mou S, Deberry CS, Weiler SR, Keller JR, Ruscetti FW, et al. Stem cell factor, the JAK-STAT pathway and signal transduction. Leukemia & lymphoma. 1997;27(5–6):439–44.

    Article  CAS  Google Scholar 

  53. Awad AJ, Burns TC, Zhang Y, Abounader R. Targeting MET for glioma therapy. Neurosurg Focus. 2014;37(6):E10.

    Article  PubMed  Google Scholar 

  54. Schmoll H-J, Cunningham D, Sobrero A, Karapetis CS, Rougier P, Koski SL, et al. Cediranib with mFOLFOX6 versus bevacizumab with mFOLFOX6 as first-line treatment for patients with advanced colorectal cancer: a double-blind, randomized phase III study (HORIZON III). J Clin Oncol. 2012;30(29):3588–95.

    Article  CAS  PubMed  Google Scholar 

  55. Heinrich MC, Griffith D, McKinley A, Patterson J, Presnell A, Ramachandran A, et al. Crenolanib inhibits the drug-resistant PDGFRA D842V mutation associated with imatinib-resistant gastrointestinal stromal tumors. Clin Cancer Res. 2012;18(16):4375–84.

    Article  CAS  PubMed  Google Scholar 

  56. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Gene Dev. 2008;22(10):1276–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hojjat-Farsangi M. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Inter J Mol Sci. 2014;15(8):13768–801.

    Article  CAS  Google Scholar 

  58. Xiao Z, Sperl B, Ullrich A, Knyazev P. Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status. Oncotarget. 2014;5(24):12877.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Deng R, Wang X, Liu Y, Yan M, Hanada S, Xu Q, et al. A new gamboge derivative compound 2 inhibits cancer stem-like cells via suppressing EGFR tyrosine phosphorylation in head and neck squamous cell carcinoma. J Cell Mol Med. 2013;17(11):1422–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Dos Santos C, McDonald T, Ho YW, Liu H, Lin A, Forman SJ, et al. The Src and c-Kit kinase inhibitor dasatinib enhances p53-mediated targeting of human acute myeloid leukemia stem cells by chemotherapeutic agents. Blood. 2013;122(11):1900–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. O’Farrell AM, Yuen HA, Smolich B, Hannah AL, Louie SG, Hong W, et al. Effects of SU5416, a small molecule tyrosine kinase receptor inhibitor, on FLT3 expression and phosphorylation in patients with refractory acute myeloid leukemia. Leuk Res. 2004;28(7):679–89. doi:10.1016/j.leukres.2003.11.004.

    Article  PubMed  CAS  Google Scholar 

  62. Zhang S, Cui B, Lai H, Liu G, Ghia EM, Widhopf GF, et al. Ovarian cancer stem cells express ROR1, which can be targeted for anti–cancer-stem-cell therapy. P Natl Acad Sci. 2014;111(48):17266–71.

    Article  CAS  Google Scholar 

  63. Lebron MB, Brennan L, Damoci CB, Prewett MC, O’Mahony M, Duignan IJ, et al. A human monoclonal antibody targeting the stem cell factor receptor (c-Kit) blocks tumor cell signaling and inhibits tumor growth. Cancer Biol & Ther. 2014;15(9):1208–18.

    Article  CAS  Google Scholar 

  64. Srikanth M, Das S, Berns EJ, Kim J, Stupp SI, Kessler JA. Nanofiber-mediated inhibition of focal adhesion kinase sensitizes glioma stemlike cells to epidermal growth factor receptor inhibition. Neuro-oncol. 2013;15(3):319–29.

  65. Padhye SS, Guin S, Yao H-P, Zhou Y-Q, Zhang R, Wang M-H. Sustained expression of the RON receptor tyrosine kinase by pancreatic cancer stem cells as a potential targeting moiety for antibody-directed chemotherapeutics. Mol Pharma. 2011;8(6):2310–9.

    Article  CAS  Google Scholar 

  66. Rath P, Lal B, Ajala O, Li Y, Xia S, Kim J, et al. In vivo c-Met pathway inhibition depletes human glioma xenografts of tumor-propagating stem-like cells. Transl Oncol. 2013;6(2):104–IN1.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Giles FJ, Cooper MA, Silverman L, Karp JE, Lancet JE, Zangari M, et al. Phase II study of SU5416–a small-molecule, vascular endothelial growth factor tyrosine-kinase receptor inhibitor–in patients with refractory myeloproliferative diseases. Cancer. 2003;97(8):1920–8. doi:10.1002/cncr.11315.

    Article  CAS  PubMed  Google Scholar 

  68. Stacchiotti S, Negri T, Palassini E, Conca E, Gronchi A, Morosi C, et al. Sunitinib malate and figitumumab in solitary fibrous tumor: patterns and molecular bases of tumor response. Mol Cancer Ther. 2010;9(5):1286–97. doi:10.1158/1535-7163.mct-09-1205.

    Article  CAS  PubMed  Google Scholar 

  69. Boumendjel A, Macalou S, Valdameri G, Pozza A, Gauthier C, Arnaud O, et al. Targeting the multidrug ABCG2 transporter with flavonoidic inhibitors: in vitro optimization and in vivo validation. Curr Med Chem. 2011;18(22):3387–401.

    Article  CAS  PubMed  Google Scholar 

  70. Bhatia A, Schäfer H-J, Hrycyna CA. Oligomerization of the human ABC transporter ABCG2: evaluation of the native protein and chimeric dimers. Biochem. 2005;44(32):10893–904.

    Article  CAS  Google Scholar 

  71. Robey RW, Polgar O, Deeken J, To KW, Bates SE. ABCG2: determining its relevance in clinical drug resistance. Cancer and Metastasis Rev. 2007;26(1):39–57.

    Article  CAS  Google Scholar 

  72. Diestra JE, Scheffer GL, Catala I, Maliepaard M, Schellens JH, Scheper RJ, et al. Frequent expression of the multi-drug resistance-associated protein BCRP/MXR/ABCP/ABCG2 in human tumours detected by the BXP-21 monoclonal antibody in paraffin-embedded material. J Pathol. 2002;198(2):213–9.

    Article  CAS  PubMed  Google Scholar 

  73. Raaijmakers MH, de Grouw EP, Heuver LH, van der Reijden BA, Jansen JH, Scheffer G, et al. Impaired breast cancer resistance protein mediated drug transport in plasma cells in multiple myeloma. Leukemia Res. 2005;29(12):1455–8.

    Article  CAS  Google Scholar 

  74. Turner JG, Gump JL, Zhang C, Cook JM, Marchion D, Hazlehurst L, et al. ABCG2 expression, function, and promoter methylation in human multiple myeloma. Blood. 2006;108(12):3881–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Dou J, Jiang C, Wang J, Zhang X, Zhao F, Hu W, et al. Using ABCG2-molecule-expressing side population cells to identify cancer stem-like cells in a human ovarian cell line. Cell Biol Int. 2011;35(3):227–34.

    Article  CAS  PubMed  Google Scholar 

  76. To KK, Tomlinson B. Targeting the ABCG2-overexpressing multidrug resistant (MDR) cancer cells by PPARγ agonists. Br J Pharmacol. 2013;170(5):1137–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Wang N, Wang Z, Peng C, You J, Shen J, Han S, et al. Dietary compound isoliquiritigenin targets GRP78 to chemosensitize breast cancer stem cells via β-catenin/ABCG2 signaling. Carcinogenesis. 2014;35(11):2544–54.

  78. Sims-Mourtada J, Izzo J, Ajani J, Chao K. Sonic hedgehog promotes multiple drug resistance by regulation of drug transport. Oncogene. 2007;26(38):5674–9.

    Article  CAS  PubMed  Google Scholar 

  79. Kim JE, Singh RR, Cho-Vega JH, Drakos E, Davuluri Y, Khokhar FA, et al. Sonic hedgehog signaling proteins and ATP-binding cassette G2 are aberrantly expressed in diffuse large B-cell lymphoma. Mod Pathol. 2009;22(10):1312–20.

    Article  CAS  PubMed  Google Scholar 

  80. Singh RR, Kunkalla K, Qu C, Schlette E, Neelapu SS, Samaniego F, et al. ABCG2 is a direct transcriptional target of hedgehog signaling and involved in stroma-induced drug tolerance in diffuse large B-cell lymphoma. Oncogene. 2011;30(49):4874–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Eng C. PTEN: one gene, many syndromes. Hum Mutat. 2003;22(3):183–98.

    Article  CAS  PubMed  Google Scholar 

  82. Jang J-Y, Jeon Y-K, Kim C-W. Degradation of HER2/neu by ANT2 shRNA suppresses migration and invasiveness of breast cancer cells. BMC Cancer. 2010;10(1):391.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Jang J-Y, Kim M-K, Jeon Y-K, Joung Y-K, Park K-D, Kim C-W. Adenovirus adenine nucleotide translocator-2 shRNA effectively induces apoptosis and enhances chemosensitivity by the down-regulation of ABCG2 in breast cancer stem-like cells. Exp Mol Med. 2012;44(4):251–9.

    Article  CAS  PubMed  Google Scholar 

  84. Yang C, Xiong F, Dou J, Xue J, Zhan X, Shi F, et al. Target therapy of multiple myeloma by PTX-NPs and ABCG2 antibody in a mouse xenograft model. Oncotarget. 2015;6(29):27714–24.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Peng H, Dong Z, Qi J, Yang Y, Liu Y, Li Z, et al. A novel two mode-acting inhibitor of ABCG2-mediated multidrug transport and resistance in cancer chemotherapy. PLoS One. 2009;4(5):e5676.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Li YT, Chua MJ, Kunnath AP, Chowdhury EH. Reversing multidrug resistance in breast cancer cells by silencing ABC transporter genes with nanoparticle-facilitated delivery of target siRNAs. Int J Nanomedicine. 2012;7:2473.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Teng Y, Bai M, Sun Y, Wang Q, Li F, Xing J, et al. Enhanced delivery of PEAL nanoparticles with ultrasound targeted microbubble destruction mediated siRNA transfection in human MCF-7/S and MCF-7/ADR cells in vitro. Int J Nanomedicine. 2015;10:5447.

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Wei Y, Ma Y, Zhao Q, Ren Z, Li Y, Hou T, et al. New use for an old drug: inhibiting ABCG2 with sorafenib. Mol Cancer Ther. 2012;11(8):1693–702.

    Article  CAS  PubMed  Google Scholar 

  89. Hou H, Sun H, Lu P, Ge C, Zhang L, Li H, et al. Tunicamycin potentiates cisplatin anticancer efficacy through the DPAGT1/Akt/ABCG2 pathway in mouse xenograft models of human hepatocellular carcinoma. Mol Cancer Ther. 2013;12(12):2874–84.

    Article  CAS  PubMed  Google Scholar 

  90. Vogt T, Hafner C, Bross K, Bataille F, Jauch KW, Berand A, et al. Antiangiogenetic therapy with pioglitazone, rofecoxib, and metronomic trofosfamide in patients with advanced malignant vascular tumors. Cancer. 2003;98(10):2251–6. doi:10.1002/cncr.11775.

    Article  CAS  PubMed  Google Scholar 

  91. Thiessen B, Stewart C, Tsao M, Kamel-Reid S, Schaiquevich P, Mason W, et al. A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics and molecular correlation. Cancer Chemother Pharmacol. 2010;65(2):353–61. doi:10.1007/s00280-009-1041-6.

    Article  CAS  PubMed  Google Scholar 

  92. Sladek NE. Human aldehyde dehydrogenases: potential pathological, pharmacological, and toxicological impact. J Biochem Mol Toxicol. 2003;17(1):7–23.

    Article  CAS  PubMed  Google Scholar 

  93. Black WJ, Stagos D, Marchitti SA, Nebert DW, Tipton KF, Bairoch A, et al. Human aldehyde dehydrogenase genes: alternatively-spliced transcriptional variants and their suggested nomenclature. Pharmacogenet Genom. 2009;19(11):893.

    Article  CAS  Google Scholar 

  94. Ma I, Allan AL. The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev. 2011;7(2):292–306.

    Article  CAS  PubMed  Google Scholar 

  95. Tanei T, Morimoto K, Shimazu K, Kim SJ, Tanji Y, Taguchi T, et al. Association of breast cancer stem cells identified by aldehyde dehydrogenase 1 expression with resistance to sequential paclitaxel and epirubicin-based chemotherapy for breast cancers. Clin Cancer Res. 2009;15(12):4234–41.

    Article  CAS  PubMed  Google Scholar 

  96. Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell. 2007;1(5):555–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Moreb JS, Muhoczy D, Ostmark B, Zucali JR. RNAi-mediated knockdown of aldehyde dehydrogenase class-1A1 and class-3A1 is specific and reveals that each contributes equally to the resistance against 4-hydroperoxycyclophosphamide. Cancer Chemother Pharmacol. 2007;59(1):127–36.

    Article  CAS  PubMed  Google Scholar 

  98. Marchitti SA, Brocker C, Stagos D, Vasiliou V. Non-P450 aldehyde oxidizing enzymes: the aldehyde dehydrogenase superfamily. Expert Opin Drug Metab Toxicol. 2008;4(6):697–720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Krause U, Ryan D, Clough B, Gregory C. An unexpected role for a Wnt-inhibitor: Dickkopf-1 triggers a novel cancer survival mechanism through modulation of aldehyde-dehydrogenase-1 activity. Cell Death Dis. 2014;5(2):e1093.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Golubovskaya V, O’Brien S, Ho B, Heffler M, Conroy J, Hu Q, et al. Down-regulation of ALDH1A3, CD44 or MDR1 sensitizes resistant cancer cells to FAK autophosphorylation inhibitor Y15. J Cancer Res Clin Oncol. 2015;1–19.

  101. Li S-Y, Sun R, Wang H-X, Shen S, Liu Y, Du X-J, et al. Combination therapy with epigenetic-targeted and chemotherapeutic drugs delivered by nanoparticles to enhance the chemotherapy response and overcome resistance by breast cancer stem cells. J Control Release. 2015;205:7–14.

    Article  CAS  PubMed  Google Scholar 

  102. Bertrand G, Maalouf M, Boivin A, Battiston-Montagne P, Beuve M, Levy A, et al. Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation. Stem Cell Rev. 2014;10(1):114–26.

    Article  CAS  PubMed  Google Scholar 

  103. Xu Y, Wang J, Li X, Liu Y, Dai L, Wu X, et al. Selective inhibition of breast cancer stem cells by gold nanorods mediated plasmonic hyperthermia. Biomaterials. 2014;35(16):4667–77.

    Article  CAS  PubMed  Google Scholar 

  104. Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, et al. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997;337(15):1021–8.

    Article  CAS  PubMed  Google Scholar 

  105. Budd GT, Adamson PC, Gupta M, Homayoun P, Sandstrom SK, Murphy RF, et al. Phase I/II trial of all-trans retinoic acid and tamoxifen in patients with advanced breast cancer. Clin Cancer Res. 1998;4(3):635–42.

    CAS  PubMed  Google Scholar 

  106. An H, Kim JY, Lee N, Cho Y, Oh E, Seo JH. Salinomycin possesses anti-tumor activity and inhibits breast cancer stem-like cells via an apoptosis-independent pathway. Biochem Biophys Res Commun. 2015;466(4):696–703.

    Article  CAS  PubMed  Google Scholar 

  107. Kubo M, Kanaya N, Petrossian K, Ye J, Warden C, Liu Z, et al. Inhibition of the proliferation of acquired aromatase inhibitor-resistant breast cancer cells by histone deacetylase inhibitor LBH589 (panobinostat). Breast Cancer Res Treat. 2013;137(1):93–107.

    Article  CAS  PubMed  Google Scholar 

  108. Pandrangi SL, Chikati R, Chauhan PS, Kumar CS, Banarji A, Saxena S. Effects of ellipticine on ALDH1A1-expressing breast cancer stem cells—an in vitro and in silico study. Tumor Biol. 2014;35(1):723–37.

    Article  CAS  Google Scholar 

  109. Jokinen E, Laurila N, Koivunen P, Koivunen JP. Combining targeted drugs to overcome and prevent resistance of solid cancers with some stem-like cell features. Oncotarget. 2014;5(19):9295–307.

    Article  PubMed  PubMed Central  Google Scholar 

  110. Grishina O, Schmoor C, Dohner K, Hackanson B, Lubrich B, May AM, et al. DECIDER: prospective randomized multicenter phase II trial of low-dose decitabine (DAC) administered alone or in combination with the histone deacetylase inhibitor valproic acid (VPA) and all-trans retinoic acid (ATRA) in patients >60 years with acute myeloid leukemia who are ineligible for induction chemotherapy. BMC Cancer. 2015;15:430. doi:10.1186/s12885-015-1432-5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Munz M, Baeuerle PA, Gires O. The emerging role of EpCAM in cancer and stem cell signaling. Cancer Res. 2009;69(14):5627–9.

    Article  CAS  PubMed  Google Scholar 

  112. Baeuerle P, Gires O. EpCAM (CD326) finding its role in cancer. Br J Cancer. 2007;96(3):417–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. van der Gun BT, Melchers LJ, Ruiters MH, de Leij LF, McLaughlin PM, Rots MG. EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinog. 2010;31(11):1913–21.

    Article  CAS  Google Scholar 

  114. Maetzel D, Denzel S, Mack B, Canis M, Went P, Benk M, et al. Nuclear signalling by tumour-associated antigen EpCAM. Nature cell Biol. 2009;11(2):162–71.

    Article  CAS  PubMed  Google Scholar 

  115. Schnell U, Kuipers J, Giepmans BN. EpCAM proteolysis: new fragments with distinct functions? Biosci Rep. 2013;33(2):e00030.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Lu T-Y, Lu R-M, Liao M-Y, Yu J, Chung C-H, Kao C-F, et al. Epithelial cell adhesion molecule regulation is associated with the maintenance of the undifferentiated phenotype of human embryonic stem cells. J Biol Chemist. 2010;285(12):8719–32.

    Article  CAS  Google Scholar 

  117. Münz M, Murr A, Kvesic M, Rau D, Mangold S, Pflanz S, et al. Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies. Cancer Cell Int. 2010;10(1):1.

    Article  CAS  Google Scholar 

  118. Lund K, Bostad M, Skarpen E, Braunagel M, Kiprijanov S, Krauss S, et al. The novel EpCAM-targeting monoclonal antibody 3–17I linked to saporin is highly cytotoxic after photochemical internalization in breast, pancreas and colon cancer cell lines. MAbs. 2014;6(4):1038–50.

  119. Salnikov AV, Groth A, Apel A, Kallifatidis G, Beckermann BM, Khamidjanov A, et al. Targeting of cancer stem cell marker EpCAM by bispecific antibody EpCAMxCD3 inhibits pancreatic carcinoma. J Cell Mol Med. 2009;13(9b):4023–33.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Simon M, Stefan N, Plückthun A, Zangemeister-Wittke U. Epithelial cell adhesion molecule-targeted drug delivery for cancer therapy. Expert Opin Drug Deliv. 2013;10(4):451–68.

    Article  CAS  PubMed  Google Scholar 

  121. Song K-M, Lee S, Ban C. Aptamers and their biological applications. Sensors. 2012;12(1):612–31.

    Article  PubMed  PubMed Central  Google Scholar 

  122. Subramanian N, Kanwar JR, Kanwar RK, Sreemanthula J, Biswas J, Khetan V, et al. EpCAM aptamer-siRNA chimera targets and regress epithelial cancer. PLoS One. 2015;10(7):e0132407.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Wang T, Gantier MP, Xiang D, Bean AG, Bruce M, Zhou S-F, et al. EpCAM aptamer-mediated survivin silencing sensitized cancer stem cells to doxorubicin in a breast cancer model. Theranostics. 2015;5(12):1456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhan Q, Wang C, Ngai S. Ovarian cancer stem cells: a new target for cancer therapy. BioMed Res Int. 2013;2013.

  125. Alizadeh AM, Shiri S, Farsinejad S. Metastasis review: from bench to bedside. Tumor Biol. 2014;35(9):8483–523.

    Article  Google Scholar 

Download references

Acknowledgments

This study was founded by Tehran University of Medical Sciences (Grant Number 26012).

Author information

Authors and Affiliations

  1. Cancer Research Center, Tehran University of Medical Sciences, Tehran, Iran

    Peyman Ranji, Tayyebali Salmani Kesejini, Sara Saeedikhoo & Ali Mohammad Alizadeh

Authors
  1. Peyman Ranji
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tayyebali Salmani Kesejini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sara Saeedikhoo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ali Mohammad Alizadeh
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ali Mohammad Alizadeh.

Ethics declarations

Conflicts of interest

The author(s) report no conflicts of interest and are responsible for the content of the paper.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ranji, P., Salmani Kesejini, T., Saeedikhoo, S. et al. Targeting cancer stem cell-specific markers and/or associated signaling pathways for overcoming cancer drug resistance. Tumor Biol. 37, 13059–13075 (2016). https://doi.org/10.1007/s13277-016-5294-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13277-016-5294-5

Keywords

Search

Navigation