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Markers of Cancer Stem Cells and Their Functions

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Trends in Stem Cell Proliferation and Cancer Research

Abstract

Embryonic stem cells are the basis of developing organisms. They posses self-renewal capacity and pluripotency to eventually generate every cell type of the mature body. In the course of development, organs arise through morphogenesis, including the differentiation of tissue progenitor cells into mature cells. Thorough analysis of the composition and the heterogeneity of organs revealed the presence of residual tissue progenitors, which retain the capacity to repopulate organs if necessary, e.g., because of injury. Hence, organs display a hierarchical structure very comparable to the initial structures in the developing embryo, however with a loss of potency. Similarly to healthy organs, tumors have hierarchical structures comprising tumor progenitors, which give rise to the tumor bulk (i.e., more “differentiated” tumor cells). Tumor progenitors are termed cancer stem cells (CSCs) or tumor-initiating cells. In this chapter, we discuss markers commonly used to discriminate CSCs from the tumor bulk and address their functions in the context of tumor development. The main focus is on the structure and function of CD44, CD133, epithelial cell adhesion molecule, CD24, CD166, CD47, leucine-rich-repeat-containing G-protein-coupled receptor 5, and aldehyde dehydrogenase 1 in CSCs. Importantly, the option of substantial plasticity of CSCs is addressed in the light of the functions of CSC markers and their expression pattern.

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References

  • Al Dhaybi R, Sartelet H, Powell J, Kokta V (2010) Expression of CD133+ cancer stem cells in childhood malignant melanoma and its correlation with metastasis. Mod Pathol 23:376–380

    Google Scholar 

  • Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 100:3983–3988

    Article  PubMed  CAS  Google Scholar 

  • Andrews PW, Matin MM, Bahrami AR, Damjanov I, Gokhale P, Draper JS (2005) Embryonic stem (ES) cells and embryonal carcinoma (EC) cells: opposite sides of the same coin. Biochem Soc Trans 33:1526–1530

    Article  PubMed  CAS  Google Scholar 

  • Azvolinsky A (2012) Cancer stem cells: getting to the root of cancer. J Natl Cancer Inst 104:893–895

    Google Scholar 

  • Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H (2007) Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 449:1003–1007

    Article  PubMed  CAS  Google Scholar 

  • Barker N, Ridgway RA, van Es JH, van de Wetering M, Begthel H, van den Born M, Danenberg E, Clarke AR, Sansom OJ, Clevers H (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457:608–611

    Article  PubMed  CAS  Google Scholar 

  • Bauer N, Fonseca AV, Florek M, Freund D, Jaszai J, Bornhauser M, Fargeas CA, Corbeil D (2008) New insights into the cell biology of hematopoietic progenitors by studying prominin-1 (CD133). Cells Tissues Organs 188:127–138

    Article  PubMed  CAS  Google Scholar 

  • Baumann P, Cremers N, Kroese F, Orend G, Chiquet-Ehrismann R, Uede T, Yagita H, Sleeman JP (2005) CD24 expression causes the acquisition of multiple cellular properties associated with tumor growth and metastasis. Cancer Res 65:10783–10793

    Article  PubMed  CAS  Google Scholar 

  • Beier CP, Beier D (2011) CD133 negative cancer stem cells in glioblastoma. Front Biosci (Elite Ed) 3:701–710

    Article  Google Scholar 

  • Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L, Pratesi G, Fabbri A, Andriani F, Tinelli S, Roz E, Caserini R, Lo Vullo S, Camerini T, Mariani L, Delia D, Calabro E, Pastorino U, Sozzi G (2009) Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proc Natl Acad Sci USA 106:16281–16286

    Google Scholar 

  • Biddle A, Liang X, Gammon L, Fazil B, Harper LJ, Emich H, Costea DE, Mackenzie IC (2011) Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res 71:5317–5326

    Article  PubMed  CAS  Google Scholar 

  • Bidlingmaier S, Zhu X, Liu B (2008) The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. J Mol Med (Berl) 86:1025–1032

    Article  CAS  Google Scholar 

  • Bourguignon LY, Spevak CC, Wong G, Xia W, Gilad E (2009a) Hyaluronan-CD44 interaction with protein kinase C(epsilon) promotes oncogenic signaling by the stem cell marker nanog and the production of microRNA-21, leading to down-regulation of the tumor suppressor protein PDCD4, anti-apoptosis, and chemotherapy resistance in breast tumor cells. J Biol Chem 284:26533–26546

    Article  PubMed  CAS  Google Scholar 

  • Bourguignon LY, Xia W, Wong G (2009b) Hyaluronan-mediated CD44 interaction with p300 and SIRT1 regulates beta-catenin signaling and NFkappaB-specific transcription activity leading to MDR1 and Bcl-xL gene expression and chemoresistance in breast tumor cells. J Biol Chem 284:2657–2671

    Article  PubMed  CAS  Google Scholar 

  • Bourguignon LY, Wong G, Earle C, Krueger K, Spevak CC (2010) Hyaluronan-CD44 interaction promotes c-Src-mediated twist signaling, microRNA-10b expression, and RhoA/RhoC up-regulation, leading to rho-kinase-associated cytoskeleton activation and breast tumor cell invasion. J Biol Chem 285:36721–36735

    Article  PubMed  CAS  Google Scholar 

  • Canis M, Lechner A, Mack B, Zengel P, Laubender RP, Koehler U, Heissmeyer V, Gires O (2013) CD133 induces tumour initiating properties in HEK293 cells. Tumour Biol 34:437–443

    Google Scholar 

  • Carmon KS, Lin Q, Gong X, Thomas A, Liu Q (2012) LGR5 interacts and cointernalizes with Wnt receptors to modulate Wnt/beta-catenin signaling. Mol Cell Biol 32:2054–2064

    Google Scholar 

  • Carpentino JE, Hynes MJ, Appelman HD, Zheng T, Steindler DA, Scott EW, Huang EH (2009) Aldehyde dehydrogenase-expressing colon stem cells contribute to tumorigenesis in the transition from colitis to cancer. Cancer Res 69:8208–8215

    Article  PubMed  CAS  Google Scholar 

  • Chaves-Pérez A, Mack B, Maetzel D, Kremling H, Eggert C, Harréus U, Gires O (2013) EpCAM regulates cell cycle progression via control of cyclin D1 expression. Oncogene 32:641–650

    Google Scholar 

  • Chen HF, Chuang CY, Lee WC, Huang HP, Wu HC, Ho HN, Chen YJ, Kuo HC (2011a) Surface marker epithelial cell adhesion molecule and E-cadherin facilitate the identification and selection of induced pluripotent stem cells. Stem Cell Rev 7:722–735

    Google Scholar 

  • Chen YS, Wu MJ, Huang CY, Lin SC, Chuang TH, Yu CC, Lo JF (2011b) CD133/Src axis mediates tumor initiating property and epithelial-mesenchymal transition of head and neck cancer. PLoS One 6:e28053

    Article  PubMed  CAS  Google Scholar 

  • Cho HC, Lai CY, Shao LE, Yu J (2011) Identification of tumorigenic cells in Kras(G12D)-induced lung adenocarcinoma. Cancer Res 71:7250–7258

    Google Scholar 

  • Chong JM, Speicher DW (2001) Determination of disulfide bond assignments and N-glycosylation sites of the human gastrointestinal carcinoma antigen GA733-2 (CO17-1A, EGP, KS1-4, KSA, and Ep-CAM). J Biol Chem 276:5804–5813

    Article  PubMed  CAS  Google Scholar 

  • Cohnheim J (1867) Ueber Entzundung und Eiterung. Pathol Anat Physiol Klin Med 40:1–79

    Google Scholar 

  • Cohnheim V (1875) Congenitales, quergestreiftes Muskelsarkom der Nieren. Virchows Arch Pathol Anat Physiol Klin Med 65:64–69

    Article  Google Scholar 

  • Corbeil D, Roper K, Hellwig A, Tavian M, Miraglia S, Watt SM, Simmons PJ, Peault B, Buck DW, Huttner WB (2000) The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions. J Biol Chem 275:5512–5520

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Curley MD, Therrien VA, Cummings CL, Sergent PA, Koulouris CR, Friel AM, Roberts DJ, Seiden MV, Scadden DT, Rueda BR, Foster R (2009) CD133 expression defines a tumor initiating cell population in primary human ovarian cancer. Stem Cells 27:2875–2883

    PubMed  CAS  Google Scholar 

  • Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW, Hoey T, Gurney A, Huang EH, Simeone DM, Shelton AA, Parmiani G, Castelli C, Clarke MF (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 104:10158–10163

    Article  PubMed  CAS  Google Scholar 

  • de Boer CJ, van Krieken JH, Janssen-van Rhijn CM, Litvinov SV (1999) Expression of Ep-CAM in normal, regenerating, metaplastic, and neoplastic liver. J Pathol 188:201–206

    Google Scholar 

  • Evans MJ, Kaufman MH (1981) Establishment in culture of pluripotential cells from mouse embryos. Nature 292:154–156

    Article  PubMed  CAS  Google Scholar 

  • Fargeas CA, Huttner WB, Corbeil D (2007) Nomenclature of prominin-1 (CD133) splice variants—an update. Tissue Antigens 69:602–606

    Article  PubMed  CAS  Google Scholar 

  • Fargeas CA, Karbanova J, Jaszai J, Corbeil D (2011) CD133 and membrane microdomains: old facets for future hypotheses. World J Gastroenterol 17:4149–4152

    Google Scholar 

  • Fields AL, Keller A, Schwartzberg L, Bernard S, Kardinal C, Cohen A, Schulz J, Eisenberg P, Forster J, Wissel P (2009) Adjuvant therapy with the monoclonal antibody Edrecolomab plus fluorouracil-based therapy does not improve overall survival of patients with stage III colon cancer. J Clin Oncol 27:1941–1947

    Article  PubMed  CAS  Google Scholar 

  • Freund D, Bauer N, Boxberger S, Feldmann S, Streller U, Ehninger G, Werner C, Bornhauser M, Oswald J, Corbeil D (2006) Polarization of human hematopoietic progenitors during contact with multipotent mesenchymal stromal cells: effects on proliferation and clonogenicity. Stem Cells Dev 15:815–829

    Article  PubMed  CAS  Google Scholar 

  • Gao AG, Frazier WA (1994) Identification of a receptor candidate for the carboxyl-terminal cell binding domain of thrombospondins. J Biol Chem 269:29650–29657

    PubMed  CAS  Google Scholar 

  • Gires O (2011) EpCAM in hepatocytes and their progenitors. J Hepatol 56:490–492

    Article  PubMed  CAS  Google Scholar 

  • Gires O, Baeuerle PA (2010) EpCAM as a target in cancer therapy. J Clin Oncol 28:e239–e240

    Google Scholar 

  • Gires O, Klein CA, Baeuerle PA (2009) On the abundance of EpCAM on cancer stem cells. Nat Rev Cancer 9:143; author reply 143

    Google Scholar 

  • Glinka A, Dolde C, Kirsch N, Huang YL, Kazanskaya O, Ingelfinger D, Boutros M, Cruciat CM, Niehrs C (2011) LGR4 and LGR5 are R-spondin receptors mediating Wnt/beta-catenin and Wnt/PCP signalling. EMBO Rep 12:1055–1061

    Google Scholar 

  • Gonzalez B, Denzel S, Mack B, Conrad M, Gires O (2009) EpCAM is involved in maintenance of the murine embryonic stem cell phenotype. Stem Cells 27:1782–1791

    Article  PubMed  CAS  Google Scholar 

  • Gudas LJ, Wagner JA (2011) Retinoids regulate stem cell differentiation. J Cell Physiol 226:322–330

    Article  PubMed  CAS  Google Scholar 

  • Gunthert U, Hofmann M, Rudy W, Reber S, Zoller M, Haussmann I, Matzku S, Wenzel A, Ponta H, Herrlich P (1991) A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell 65:13–24

    Article  PubMed  CAS  Google Scholar 

  • Haegebarth A, Clevers H (2009) Wnt signaling, lgr5, and stem cells in the intestine and skin. Am J Pathol 174:715–721

    Article  PubMed  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  PubMed  CAS  Google Scholar 

  • He TC, Sparks AB, Rago C, Hermeking H, Zawel L, da Costa LT, Morin PJ, Vogelstein B, Kinzler KW (1998) Identification of c-MYC as a target of the APC pathway. Science 281:1509–1512

    Article  PubMed  CAS  Google Scholar 

  • Herlyn D, Herlyn M, Steplewski Z, Koprowski H (1979) Monoclonal antibodies in cell-mediated cytotoxicity against human melanoma and colorectal carcinoma. Eur J Immunol 9:657–659

    Article  PubMed  CAS  Google Scholar 

  • Hermanek P, Hutter RV, Sobin LH, Wittekind C (1999) International union against cancer. Classification of isolated tumor cells and micrometastasis. Cancer 86:2668–2673

    Article  PubMed  CAS  Google Scholar 

  • Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M, Bruns CJ, Heeschen C (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1(3):313–323

    Article  PubMed  CAS  Google Scholar 

  • Horn PA, Tesch H, Staib P, Kube D, Diehl V, Voliotis D (1999) Expression of AC133, a novel hematopoietic precursor antigen, on acute myeloid leukemia cells. Blood 93:1435–1437

    PubMed  CAS  Google Scholar 

  • Horst D, Scheel SK, Liebmann S, Neumann J, Maatz S, Kirchner T, Jung A (2009) The cancer stem cell marker CD133 has high prognostic impact but unknown functional relevance for the metastasis of human colon cancer. J Pathol 219:427–434

    Article  PubMed  CAS  Google Scholar 

  • Jezierska A, Matysiak W, Motyl T (2006) ALCAM/CD166 protects breast cancer cells against apoptosis and autophagy. Med Sci Monit 12:BR263–BR273

    Google Scholar 

  • Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE (2006) Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 12:1167–1174

    Article  PubMed  CAS  Google Scholar 

  • Johannessen M, Moller S, Hansen T, Moens U, Van Ghelue Mc-rp-p (2006) The multifunctional roles of the four-and-a-half-LIM only protein FHL2. Cell Mol Life Sci 63:268–284

    Google Scholar 

  • Kawano T, Nakamura Y, Yanoma S, Kubota A, Furukawa M, Miyagi Y, Tsukuda M (2004) Expression of E-cadherin, and CD44 s and CD44v6 and its association with prognosis in head and neck cancer. Auris Nasus Larynx 31:35–41

    Article  PubMed  Google Scholar 

  • Kay R, Rosten PM, Humphries RK (1991) CD24, a signal transducer modulating B cell activation responses, is a very short peptide with a glycosyl phosphatidylinositol membrane anchor. J Immunol 147:1412–1416

    PubMed  CAS  Google Scholar 

  • Kemper K, Sprick MR, de Bree M, Scopelliti A, Vermeulen L, Hoek M, Zeilstra J, Pals ST, Mehmet H, Stassi G, Medema JP (2010) The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation. Cancer Res 70:719–729

    Article  PubMed  CAS  Google Scholar 

  • Kenny PA (2007) TACE: a new target in epidermal growth factor receptor dependent tumors. Differentiation 75:800–808

    Article  PubMed  CAS  Google Scholar 

  • Kijima N, Hosen N, Kagawa N, Hashimoto N, Nakano A, Fujimoto Y, Kinoshita M, Sugiyama H, Yoshimine T (2012) CD166/Activated leukocyte cell adhesion molecule is expressed on glioblastoma progenitor cells and involved in the regulation of tumor cell invasion. Neuro Oncol 14(10):1254–1264

    Google Scholar 

  • Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE (1994) A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367:645–648

    Article  PubMed  CAS  Google Scholar 

  • Leung EL, Fiscus RR, Tung JW, Tin VP, Cheng LC, Sihoe AD, Fink LM, Ma Y, Wong MP (2010) Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS One 5:e14062

    Article  PubMed  CAS  Google Scholar 

  • Li C, Heidt DG, Dalerba P, Burant CF, Zhang L, Adsay V, Wicha M, Clarke MF, Simeone DM (2007) Identification of pancreatic cancer stem cells. Cancer Res 67:1030–1037

    Article  PubMed  CAS  Google Scholar 

  • Li M, Wang J, Ng SS, Chan CY, Chen AC, Xia HP, Yew DT, Wong BC, Chen Z, Kung HF, Lin MC (2008) The four-and-a-half-LIM protein 2 (FHL2) is overexpressed in gliomas and associated with oncogenic activities. Glia 56:1328–1338

    Article  PubMed  Google Scholar 

  • Lindberg FP, Gresham HD, Schwarz E, Brown EJ (1993) Molecular cloning of integrin-associated protein: an immunoglobulin family member with multiple membrane-spanning domains implicated in alpha v beta 3-dependent ligand binding. J Cell Biol 123:485–496

    Article  PubMed  CAS  Google Scholar 

  • Litvinov SV, Bakker HA, Gourevitch MM, Velders MP, Warnaar SO (1994a) Evidence for a role of the epithelial glycoprotein 40 (Ep-CAM) in epithelial cell-cell adhesion. Cell Adhes Commun 2:417–428

    Article  PubMed  CAS  Google Scholar 

  • Litvinov SV, Velders MP, Bakker HA, Fleuren GJ, Warnaar SO (1994b) Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. J Cell Biol 125:437–446

    Article  PubMed  CAS  Google Scholar 

  • Litvinov SV, van Driel W, van Rhijn CM, Bakker HA, van Krieken H, Fleuren GJ, Warnaar SO (1996) Expression of Ep-CAM in cervical squamous epithelia correlates with an increased proliferation and the disappearance of markers for terminal differentiation. Am J Pathol 148:865–875

    PubMed  CAS  Google Scholar 

  • Litvinov SV, Balzar M, Winter MJ, Bakker HA, Briaire-de Bruijn IH, Prins F, Fleuren GJ, Warnaar SO (1997) Epithelial cell adhesion molecule (Ep-CAM) modulates cell-cell interactions mediated by classic cadherins. J Cell Biol 139:1337–1348

    Google Scholar 

  • Liu Y, Zheng P (2007) CD24: a genetic checkpoint in T cell homeostasis and autoimmune diseases. Trends Immunol 28:315–320

    Article  PubMed  CAS  Google Scholar 

  • Lobo NA, Shimono Y, Qian D, Clarke MF (2007) The biology of cancer stem cells. Annu Rev Cell Dev Biol 23:675–699

    Article  PubMed  CAS  Google Scholar 

  • Lu TY, Lu RM, Liao MY, Yu J, Chung CH, Kao CF, Wu HC (2010) Epithelial cell adhesion molecule regulation is associated with the maintenance of the undifferentiated phenotype of human embryonic stem cells. J Biol Chem 285:8719–8732

    Article  PubMed  CAS  Google Scholar 

  • Ma I, Allan AL (2010) The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev 7:292–306

    Google Scholar 

  • Maaser K, Borlak J (2008) A genome-wide expression analysis identifies a network of EpCAM-induced cell cycle regulators. Br J Cancer 99:1635–1643

    Article  PubMed  CAS  Google Scholar 

  • Mack B, Gires O (2008) CD44 s and CD44v6 expression in head and neck epithelia. PLoS One 3:e3360

    Article  PubMed  CAS  Google Scholar 

  • Maetzel D, Denzel S, Mack B, Canis M, Went P, Benk M, Kieu C, Papior P, Baeuerle PA, Munz M, Gires O (2009) Nuclear signalling by tumour-associated antigen EpCAM. Nat Cell Biol 11:162–171

    Article  PubMed  CAS  Google Scholar 

  • Magee JA, Piskounova E, Morrison SJ (2012) Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21:283–296

    Google Scholar 

  • Martin GR, Evans MJ (1974) The morphology and growth of a pluripotent teratocarcinoma cell line and its derivatives in tissue culture. Cell 2:163–172

    Article  PubMed  CAS  Google Scholar 

  • Martin GR (1981) Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci USA 78:7634–7638

    Article  PubMed  CAS  Google Scholar 

  • Marzesco AM, Janich P, Wilsch-Brauninger M, Dubreuil V, Langenfeld K, Corbeil D, Huttner WB (2005) Release of extracellular membrane particles carrying the stem cell marker prominin-1 (CD133) from neural progenitors and other epithelial cells. J Cell Sci 118:2849–2858

    Article  PubMed  CAS  Google Scholar 

  • Maw MA, Corbeil D, Koch J, Hellwig A, Wilson-Wheeler JC, Bridges RJ, Kumaramanickavel G, John S, Nancarrow D, Roper K, Weigmann A, Huttner WB, Denton MJ (2000) A frameshift mutation in prominin (mouse)-like 1 causes human retinal degeneration. Hum Mol Genet 9:27–34

    Article  PubMed  CAS  Google Scholar 

  • Meirelles K, Benedict LA, Dombkowski D, Pepin D, Preffer FI, Teixeira J, Tanwar PS, Young RH, MacLaughlin DT, Donahoe PK, Wei (2012) X Human ovarian cancer stem/progenitor cells are stimulated by doxorubicin but inhibited by Mullerian inhibiting substance. Proc Natl Acad Sci USA 109:2358–2363

    Google Scholar 

  • Merchant NB, Voskresensky I, Rogers CM, Lafleur B, Dempsey PJ, Graves-Deal R, Revetta F, Foutch AC, Rothenberg ML, Washington MK, Coffey RJ (2008) TACE/ADAM-17: a component of the epidermal growth factor receptor axis and a promising therapeutic target in colorectal cancer. Clin Cancer Res 14:1182–1191

    Article  PubMed  CAS  Google Scholar 

  • Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT, Bray RA, Waller EK, Buck DW (1997) A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 90:5013–5021

    PubMed  CAS  Google Scholar 

  • Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A (2008) Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 3:e2888

    Article  PubMed  CAS  Google Scholar 

  • Munz M, Kieu C, Mack B, Schmitt B, Zeidler R, Gires O (2004) The carcinoma-associated antigen EpCAM upregulates c-myc and induces cell proliferation. Oncogene 23:5748–5758

    Article  PubMed  CAS  Google Scholar 

  • Munz M, Fellinger K, Hofmann T, Schmitt B, Gires O (2008) Glycosylation is crucial for stability of tumour and cancer stem cell antigen EpCAM. Front Biosci 13:5195–5201

    Article  PubMed  CAS  Google Scholar 

  • Nagano O, Saya H (2004) Mechanism and biological significance of CD44 cleavage. Cancer Sci 95:930–935

    Article  PubMed  CAS  Google Scholar 

  • Nagao K, Zhu J, Heneghan MB, Hanson JC, Morasso MI, Tessarollo L, Mackem S, Udey MC (2009) Abnormal placental development and early embryonic lethality in EpCAM-null mice. PLoS One 4:e8543

    Article  PubMed  CAS  Google Scholar 

  • Navarro-Alvarez N, Kondo E, Kawamoto H, Hassan W, Yuasa T, Kubota Y, Seita M, Nakahara H, Hayashi T, Nishikawa Y, Hassan RA, Javed SM, Noguchi H, Matsumoto S, Nakaji S, Tanaka N, Kobayashi N, Soto-Gutierrez A (2010) Isolation and propagation of a human CD133- colon tumor-derived cell line with tumorigenic and angiogenic properties. Cell Transplant 19:865–877

    Article  PubMed  Google Scholar 

  • Ng VY, Ang SN, Chan JX, Choo AB (2010) Characterization of epithelial cell adhesion molecule as a surface marker on undifferentiated human embryonic stem cells. Stem Cells 28:29–35

    Google Scholar 

  • O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445:106–110

    Article  PubMed  CAS  Google Scholar 

  • Ohneda O, Ohneda K, Arai F, Lee J, Miyamoto T, Fukushima Y, Dowbenko D, Lasky LA, Suda T (2001) ALCAM (CD166): its role in hematopoietic and endothelial development. Blood 98:2134–2142

    Article  PubMed  CAS  Google Scholar 

  • Osta WA, Chen Y, Mikhitarian K, Mitas M, Salem M, Hannun YA, Cole DJ, Gillanders WE (2004) EpCAM is overexpressed in breast cancer and is a potential target for breast cancer gene therapy. Cancer Res 64:5818–5824

    Article  PubMed  CAS  Google Scholar 

  • Pauli C, Munz M, Kieu C, Mack B, Breinl P, Wollenberg B, Lang S, Zeidler R, Gires O (2003) Tumor-specific glycosylation of the carcinoma-associated epithelial cell adhesion molecule EpCAM in head and neck carcinomas. Cancer Lett 193:25–32

    Article  PubMed  CAS  Google Scholar 

  • Pelletier L, Guillaumot P, Freche B, Luquain C, Christiansen D, Brugiere S, Garin J, Manie SN (2006) Gamma-secretase-dependent proteolysis of CD44 promotes neoplastic transformation of rat fibroblastic cells. Cancer Res 66:3681–3687

    Article  PubMed  CAS  Google Scholar 

  • Ponta H, Sherman L, Herrlich PA (2003) CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol 4:33–45

    Article  PubMed  CAS  Google Scholar 

  • Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, Dalerba P, Weissman IL, Clarke MF, Ailles LE (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 104:973–978

    Article  PubMed  CAS  Google Scholar 

  • Reya T, Duncan AW, Ailles L, Domen J, Scherer DC, Willert K, Hintz L, Nusse R, Weissman IL (2003) A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423:409–414

    Article  PubMed  CAS  Google Scholar 

  • Reya T, Clevers H (2005) Wnt signalling in stem cells and cancer. Nature 434:843–850

    Article  PubMed  CAS  Google Scholar 

  • Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C, De Maria R (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445:111–115

    Article  PubMed  CAS  Google Scholar 

  • Riethmüller G, Schneider Gadicke E, Schlimok G, Schmiegel W, Raab R, Hoffken K, Gruber R, Pichlmaier H, Hirche H, Pichlmayr R, et al. (1994) Randomised trial of monoclonal antibody for adjuvant therapy of resected Dukes’ C colorectal carcinoma. Lancet 343:1177–1183

    Google Scholar 

  • Riethmüller G, Holz E, Schlimok G, Schmiegel W, Raab R, Hoffken K, Gruber R, Funke I, Pichlmaier H, Hirche H, Buggisch P, Witte J, Pichlmayr R (1998) Monoclonal antibody therapy for resected Dukes’ C colorectal cancer: seven-year outcome of a multicenter randomized trial. J Clin Oncol 16:1788–1794

    PubMed  Google Scholar 

  • Rosso O, Piazza T, Bongarzone I, Rossello A, Mezzanzanica D, Canevari S, Orengo AM, Puppo A, Ferrini S, Fabbi M (2007) The ALCAM shedding by the metalloprotease ADAM17/TACE is involved in motility of ovarian carcinoma cells. Mol Cancer Res 5:1246–1253

    Article  PubMed  CAS  Google Scholar 

  • Ruck P, Wichert G, Handgretinger R, Kaiserling E (2000) Ep-CAM in malignant liver tumours. J Pathol 191:102–103

    Article  PubMed  CAS  Google Scholar 

  • Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, van Es JH, Abo A, Kujala P, Peters PJ, Clevers H (2009) Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature 459:262–265

    Article  PubMed  CAS  Google Scholar 

  • Schmoll HJ, Arnold D (2009) When wishful thinking leads to a misty-eyed appraisal: the story of the adjuvant colon cancer trials with edrecolomab. J Clin Oncol 27:1926–1929

    Article  PubMed  Google Scholar 

  • Selkoe DJ, Wolfe MS (2007) Presenilin: running with scissors in the membrane. Cell 131:215–221

    Article  PubMed  CAS  Google Scholar 

  • Shi C, Tian R, Wang M, Wang X, Jiang J, Zhang Z, Li X, He Z, Gong W, Qin R (2010) CD44+ CD133+ population exhibits cancer stem cell-like characteristics in human gallbladder carcinoma. Cancer Biol Ther 10(11):1182–1190

    Google Scholar 

  • Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T, St Clair R, Baljevic M, White I, Jin DK, Chadburn A, Murphy AJ, Valenzuela DM, Gale NW, Thurston G, Yancopoulos GD, D’Angelica M, Kemeny N, Lyden D, Rafii S (2008) CD133 expression is not restricted to stem cells, and both CD133 and CD133 metastatic colon cancer cells initiate tumors. J Clin Invest 118:2111–2120

    Google Scholar 

  • Shtutman M, Zhurinsky J, Simcha I, Albanese C, D’Amico M, Pestell R, Ben-Ze’ev A (1999) The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci USA 96:5522–5527

    Article  PubMed  CAS  Google Scholar 

  • Sick E, Boukhari A, Deramaudt T, Ronde P, Bucher B, Andre P, Gies JP, Takeda K (2011) Activation of CD47 receptors causes proliferation of human astrocytoma but not normal astrocytes via an Akt-dependent pathway. Glia 59:308–319

    Article  PubMed  Google Scholar 

  • Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB (2004) Identification of human brain tumour initiating cells. Nature 432:396–401

    Article  PubMed  CAS  Google Scholar 

  • Southam CM, Brunschwig A (1960) Quantitative studies of autotransplantation of human cancer. Cancer 14:971–978

    Article  Google Scholar 

  • Suva ML, Riggi N, Stehle JC, Baumer K, Tercier S, Joseph JM, Suva D, Clement V, Provero P, Cironi L, Osterheld MC, Guillou L, Stamenkovic I (2009) Identification of cancer stem cells in Ewing’s sarcoma. Cancer Res 69:1776–1781

    Article  PubMed  CAS  Google Scholar 

  • Swart GW (2002) Activated leukocyte cell adhesion molecule (CD166/ALCAM): developmental and mechanistic aspects of cell clustering and cell migration. Eur J Cell Biol 81:313–321

    Article  PubMed  CAS  Google Scholar 

  • Takenobu H, Shimozato O, Nakamura T, Ochiai H, Yamaguchi Y, Ohira M, Nakagawara A, Kamijo T (2011) CD133 suppresses neuroblastoma cell differentiation via signal pathway modification. Oncogene 30:97–105

    Google Scholar 

  • Terris B, Cavard C, Perret C (2010) EpCAM, a new marker for cancer stem cells in hepatocellular carcinoma. J Hepatol 52:280–281

    Google Scholar 

  • Till JE, Mc CE (1961) A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 14:213–222

    Article  PubMed  CAS  Google Scholar 

  • Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV, Tsukamoto AS, Gage FH, Weissman IL (2000) Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 97:14720–14725

    Article  PubMed  CAS  Google Scholar 

  • Van der Flier LG, Sabates-Bellver J, Oving I, Haegebarth A, De Palo M, Anti M, Van Gijn ME, Suijkerbuijk S, Van de Wetering M, Marra G, Clevers H (2007) The intestinal Wnt/TCF signature. Gastroenterology 132:628–632

    Article  PubMed  CAS  Google Scholar 

  • Visvader JE, Lindeman GJ (2008) Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8:755–768

    Article  PubMed  CAS  Google Scholar 

  • Wang J, Yang Y, Xia HH, Gu Q, Lin MC, Jiang B, Peng Y, Li G, An X, Zhang Y, Zhuang Z, Zhang Z, Kung HF, Wong BC (2007) Suppression of FHL2 expression induces cell differentiation and inhibits gastric and colon carcinogenesis. Gastroenterology 132:1066–1076

    Article  PubMed  CAS  Google Scholar 

  • Wang M, Xiao J, Shen M, Yahong Y, Tian R, Zhu F, Jiang J, Du Z, Hu J, Liu W, Qin R (2011) Isolation and characterization of tumorigenic extrahepatic cholangiocarcinoma cells with stem cell-like properties. Int J Cancer 128:72–81

    Google Scholar 

  • Weidle UH, Eggle D, Klostermann S, Swart GW (2010) ALCAM/CD166: cancer-related issues. Cancer Genomics Proteomics 7:231–243

    PubMed  CAS  Google Scholar 

  • Wielenga VJ, Smits R, Korinek V, Smit L, Kielman M, Fodde R, Clevers H, Pals ST (1999) Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway. Am J Pathol 154:515–523

    Article  PubMed  CAS  Google Scholar 

  • Wong DJ, Liu H, Ridky TW, Cassarino D, Segal E, Chang HY (2008) Module map of stem cell genes guides creation of epithelial cancer stem cells. Cell Stem Cell 2:333–344

    Article  PubMed  CAS  Google Scholar 

  • Yamashita T, Budhu A, Forgues M, Wang XW (2007) Activation of hepatic stem cell marker EpCAM by Wnt-beta-catenin signaling in hepatocellular carcinoma. Cancer Res 67:10831–10839

    Article  PubMed  CAS  Google Scholar 

  • Yamashita T, Ji J, Budhu A, Forgues M, Yang W, Wang HY, Jia H, Ye Q, Qin LX, Wauthier E, Reid LM, Minato H, Honda M, Kaneko S, Tang ZY, Wang XW (2009) EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 136:1012–1024

    Google Scholar 

  • Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG, Olweus J, Kearney J, Buck DW (1997) AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 90:5002–5012

    PubMed  CAS  Google Scholar 

  • Yoon SM, Gerasimidou D, Kuwahara R, Hytiroglou P, Yoo JE, Park YN, Theise ND (2011) Epithelial cell adhesion molecule (EpCAM) marks hepatocytes newly derived from stem/progenitor cells in humans. Hepatology 53:964–973

    Google Scholar 

  • Yu Y, Flint A, Dvorin EL, Bischoff J (2002) AC133-2, a novel isoform of human AC133 stem cell antigen. J Biol Chem 277:20711–20716

    Article  PubMed  CAS  Google Scholar 

  • Zeilstra J, Joosten SP, Dokter M, Verwiel E, Spaargaren M, Pals ST (2008) Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis. Cancer Res 68:3655–3661

    Article  PubMed  CAS  Google Scholar 

  • Zhang M, Shoeb M, Goswamy J, Liu P, Xiao TL, Hogan D, Campbell GA, Ansari NH (2010) Overexpression of aldehyde dehydrogenase 1A1 reduces oxidation-induced toxicity in SH-SY5Y neuroblastoma cells. J Neurosci Res 88:686–694

    Article  PubMed  CAS  Google Scholar 

  • Zhu L, Gibson P, Currle DS, Tong Y, Richardson RJ, Bayazitov IT, Poppleton H, Zakharenko S, Ellison DW, Gilbertson RJ (2009) Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation. Nature 457:603–607

    Article  PubMed  CAS  Google Scholar 

  • Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, Li J (2010) Cancer stem/progenitor cells are highly enriched in CD133+ CD44+ population in hepatocellular carcinoma. Int J Cancer 126:2067–2078

    Article  PubMed  CAS  Google Scholar 

  • Zoller M (2011) CD44: can a cancer-initiating cell profit from an abundantly expressed molecule? Nat Rev Cancer 11:254–267

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Otorhinolaryngology, Head and Neck Surgery, Grosshadern Medical Center, Ludwig Maximilian University of Munich, Marchioninistr. 15, 81377, Munich, Germany

    Olivier Gires

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  1. Instituto de Ciências Biológicas, Departamento de Bioquímica, Universidade Federal de Minas Gerais, Belo Horizonte, São Paulo, Brazil

    Rodrigo R. Resende

  2. Depto. Bioquímica, Universidade de São Paulo Inst. Química, São Paulo, São Paulo, Brazil

    Henning Ulrich

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Gires, O. (2013). Markers of Cancer Stem Cells and Their Functions. In: Resende, R., Ulrich, H. (eds) Trends in Stem Cell Proliferation and Cancer Research. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6211-4_20

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