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Is CD44 a Marker for Cancer Stem Cells?

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Stem Cells and Cancer Stem Cells, Volume 9

Part of the book series: Stem Cells and Cancer Stem Cells ((STEM,volume 9))

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Abstract

CD44 is a cell surface transmembrane glycoprotein involved in cell adhesion and migration, and also the regulation of numerous intracellular signalling events. As well as the ubiquitously expressed standard form, alternative splicing and post-translational modification give rise to numerous variant isoforms. Altered expression of CD44 occurs in cancer, particularly in association with invasion and metastasis. More recently the molecule has received considerable attention as a potential marker of cancer stem cells (CSC). The CD44+ fraction of numerous tumours has been reported to demonstrate enhanced tumourigenic potential and the ability to recapitulate the parental tumour. Blockade of CD44 may therefore represent a means of eliminating the putative tumour-propagating CSC fraction of some tumours.

However, CD44 is not a universal marker of CSC. More fundamentally, some evidence suggests that the CD44+ CSC phenotype could be unstable, or even acquired by cells within the CD44− fraction, questioning the concept of CD44+ cancer cells existing at the apex of a unidirectional developmental hierarchy. Moreover, any notion of targetting CD44 will be complicated by its widespread expression on normal cells. Thus, although many features of CD44 make it an attractive candidate as a CSC marker, there is need for a greater understanding of the significance of expression, and in particular the expression of variant isoforms, in the context of putative cellular hierarchies in cancer.

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References

  • Abraham BK, Fritz P, Mcclellan M, Hauptvogel P, Athelogou M, Brauch H (2005) Prevalence of CD44+/CD24−/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clin Cancer Res 11:1154–1159

    PubMed  CAS  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 

  • Alho AM, Underhill CB (1989) The hyaluronate receptor is preferentially expressed on proliferating epithelial cells. J Cell Biol 108:1557–1565

    Article  PubMed  CAS  Google Scholar 

  • Balic M, Lin H, Young L, Hawes D, Giuliano A, Mcnamara G, Datar RH, Cote RJ (2006) Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 12:5615–5621

    Article  PubMed  CAS  Google Scholar 

  • Barabe F, Kennedy JA, Hope KJ, Dick JE (2007) Modeling the initiation and progression of human acute leukemia in mice. Science 316:600–604

    Article  PubMed  CAS  Google Scholar 

  • Blacking TM, Waterfall M, Argyle DJ (2011) CD44 is associated with proliferation, rather than a specific cancer stem cell population, in cultured canine cancer cells. Vet Immunol Immunopathol 141:46–57

    Article  PubMed  CAS  Google Scholar 

  • Bourguignon LY, Xia W, Wong G (2009) 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 

  • Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO, Brooks M, Reinhardt F, Su Y, Polyak K, Arendt LM, Kuperwasser C, Bierie B, Weinberg RA (2011) Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA 108:7950–7955

    Article  PubMed  CAS  Google Scholar 

  • Dimitroff CJ, Lee JY, Rafii S, Fuhlbrigge RC, Sackstein R (2001) CD44 is a major E-selectin ligand on human hematopoietic progenitor cells. J Cell Biol 153:1277–1286

    Article  PubMed  CAS  Google Scholar 

  • Draffin JE, Mcfarlane S, Hill A, Johnston PG, Waugh DJ (2004) CD44 potentiates the adherence of metastatic prostate and breast cancer cells to bone marrow endothelial cells. Cancer Res 64:5702–5711

    Article  PubMed  CAS  Google Scholar 

  • Driessens MH, Stroeken PJ, Rodriguez Erena NF, Van Der Valk MA, Van Rijthoven EA, Roos E (1995) Targeted disruption of CD44 in MDAY-D2 lymphosarcoma cells has no effect on subcutaneous growth or metastatic capacity. J Cell Biol 131:1849–1855

    Article  PubMed  CAS  Google Scholar 

  • Filippov V, Filippova M, Duerksen-Hughes PJ (2007) The early response to DNA damage can lead to activation of alternative splicing activity resulting in CD44 splice pattern changes. Cancer Res 67:7621–7630

    Article  PubMed  CAS  Google Scholar 

  • Fox SB, Fawcett J, Jackson DG, Collins I, Gatter KC, Harris AL, Gearing A, Simmons DL (1994) Normal human tissues, in addition to some tumors, express multiple different CD44 isoforms. Cancer Res 54:4539–4546

    PubMed  CAS  Google Scholar 

  • Godar S, Ince TA, Bell GW, Feldser D, Donaher JL, Bergh J, Liu A, Miu K, Watnick RS, Reinhardt F, Mcallister SS, Jacks T, Weinberg RA (2008) Growth-inhibitory and tumor- suppressive functions of p53 depend on its repression of CD44 expression. Cell 134:62–73

    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 

  • Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C, Lander ES (2011) Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146:633–644

    Article  PubMed  CAS  Google Scholar 

  • Haegel H, Dierich A, Ceredig R (1994) CD44 in differentiated embryonic stem cells: surface expression and transcripts encoding multiple variants. Dev Immunol 3:239–246

    Article  PubMed  CAS  Google Scholar 

  • Harper LJ, Costea DE, Gammon L, Fazil B, Biddle A, Mackenzie IC (2010) Normal and malignant epithelial cells with stem-like properties have an extended G2 cell cycle phase that is associated with apoptotic resistance. BMC Cancer 10:166

    Article  PubMed  Google Scholar 

  • Hart IR, Birch M, Marshall JF (1991) Cell adhesion receptor expression during melanoma progression and metastasis. Cancer Metastasis Rev 10:115–128

    Article  PubMed  CAS  Google Scholar 

  • Hebbard L, Steffen A, Zawadzki V, Fieber C, Howells N, Moll J, Ponta H, Hofmann M, Sleeman J (2000) CD44 expression and regulation during mammary gland development and function. J Cell Sci 113(Pt 14):2619–2630

    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 1:313–323

    Article  PubMed  CAS  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  Google Scholar 

  • Jung T, Castellana D, Klingbeil P, Cuesta Hernandez I, Vitacolonna M, Orlicky DJ, Roffler SR, Brodt P, Zoller M (2009) CD44v6 dependence of premetastatic niche preparation by exosomes. Neoplasia 11:1093–1105

    PubMed  CAS  Google Scholar 

  • Khaldoyanidi S, Denzel A, Zoller M (1996) Requirement for CD44 in proliferation and homing of hematopoietic precursor cells. J Leukoc Biol 60:579–592

    PubMed  CAS  Google Scholar 

  • Kondo K, Miyoshi T, Hino N, Shimizu E, Masuda N, Takada M, Uyama T, Monden Y (1998) High frequency expressions of CD44 standard and variant forms in non-small cell lung cancers, but not in small cell lung cancers. J Surg Oncol 69:128–136

    Article  PubMed  CAS  Google Scholar 

  • Lee HE, Kim JH, Kim YJ, Choi SY, Kim SW, Kang E, Chung IY, Kim IA, Kim EJ, Choi Y, Ryu HS, Park SY (2011) An increase in cancer stem cell population after primary systemic therapy is a poor prognostic factor in breast cancer. Br J Cancer 104:1730–1738

    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 

  • Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY, Brooks M, Reinhard F, Zhang CC, Shipitsin M, Campbell LL, Polyak K, Brisken C, Yang J, Weinberg RA (2008) The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133:704–715

    Article  PubMed  CAS  Google Scholar 

  • Marhaba R, Zoller M (2004) CD44 in cancer progression: adhesion, migration and growth regulation. J Mol Histol 35:211–231

    Article  PubMed  CAS  Google Scholar 

  • Misra S, Ghatak S, Toole BP (2005) Regulation of MDR1 expression and drug resistance by a positive feedback loop involving hyaluronan, phosphoinositide 3-kinase, and ErbB2. J Biol Chem 280:20310–20315

    Article  PubMed  CAS  Google Scholar 

  • Miyake K, Medina KL, Hayashi S, Ono S, Hamaoka T, Kincade PW (1990) Monoclonal antibodies to Pgp-1/CD44 block lympho-hemopoiesis in long-term bone marrow cultures. J Exp Med 171:477–488

    Article  PubMed  CAS  Google Scholar 

  • Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194:23–28

    Article  PubMed  CAS  Google Scholar 

  • Oertl A, Castein J, Engl T, Beecken WD, Jonas D, Melamed R, Blaheta RA (2005) Endothelial adhesion of synchronized gastric tumor cells changes during cell cycle transit and correlates with the expression level of CD44 splice variants. World J Gastroenterol 11:6243–6248

    PubMed  CAS  Google Scholar 

  • Olsson E, Honeth G, Bendahl PO, Saal LH, Gruvberger-Saal S, Ringner M, Vallon-Christersson J, Jonsson G, Holm K, Lovgren K, Ferno M, Grabau D, Borg A, Hegardt C (2011) CD44 isoforms are heterogeneously expressed in breast cancer and correlate with tumor subtypes and cancer stem cell markers. BMC Cancer 11:418

    Article  PubMed  CAS  Google Scholar 

  • Protin U, Schweighoffer T, Jochum W, Hilberg F (1999) CD44-deficient mice develop normally with changes in subpopulations and recirculation of lymphocyte subsets. J Immunol 163:4917–4923

    PubMed  CAS  Google Scholar 

  • Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ (2008) Efficient tumour formation by single human melanoma cells. Nature 456:593–598

    Article  PubMed  CAS  Google Scholar 

  • Seiter S, Arch R, Reber S, Komitowski D, Hofmann M, Ponta H, Herrlich P, Matzku S, Zoller M (1993) Prevention of tumor metastasis formation by anti-variant CD44. J Exp Med 177:443–455

    Article  PubMed  CAS  Google Scholar 

  • Sherman L, Wainwright D, Ponta H, Herrlich P (1998) A splice variant of CD44 expressed in the apical ectodermal ridge presents fibroblast growth factors to limb mesenchyme and is required for limb outgrowth. Genes Dev 12:1058–1071

    Article  PubMed  CAS  Google Scholar 

  • Shipitsin M, Campbell LL, Argani P, Weremowicz S, Bloushtain-Qimron N, Yao J, Nikolskaya T, Serebryiskaya T, Beroukhim R, Hu M, Halushka MK, Sukumar S, Parker LM, Anderson KS, Harris LN, Garber JE, Richardson AL, Schnitt SJ, Nikolsky Y, Gelman RS, Polyak K (2007) Molecular definition of breast tumor heterogeneity. Cancer Cell 11:259–273

    Article  PubMed  CAS  Google Scholar 

  • Stamenkovic I, Aruffo A, Amiot M, Seed B (1991) The hematopoietic and epithelial forms of CD44 are distinct polypeptides with different adhesion potentials for hyaluronate-bearing cells. EMBO J 10:343–348

    PubMed  CAS  Google Scholar 

  • Sugino T, Gorham H, Yoshida K, Bolodeoku J, Nargund V, Cranston D, Goodison S, Tarin D (1996) Progressive loss of CD44 gene expression in invasive bladder cancer. Am J Pathol 149:873–882

    PubMed  CAS  Google Scholar 

  • Sy MS, Guo YJ, Stamenkovic I (1991) Distinct effects of two CD44 isoforms on tumor growth in vivo. J Exp Med 174:859–866

    Article  PubMed  CAS  Google Scholar 

  • Thiery JP (2002) Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer 2:442–454

    Article  PubMed  CAS  Google Scholar 

  • Thomas L, Byers HR, Vink J, Stamenkovic I (1992) CD44H regulates tumor cell migration on hyaluronate-coated substrate. J Cell Biol 118:971–977

    Article  PubMed  CAS  Google Scholar 

  • Vermeulen L, Todaro M, De Sousa Mello F, Sprick MR, Kemper K, Perez Alea M, Richel DJ, Stassi G, Medema JP (2008) Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci USA 105:13427–13432

    Article  PubMed  CAS  Google Scholar 

  • Weber GF, Bronson RT, Ilagan J, Cantor H, Schmits R, Mak TW (2002) Absence of the CD44 gene prevents sarcoma metastasis. Cancer Res 62:2281–2286

    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 

  • Yu Q, Toole BP, Stamenkovic I (1997) Induction of apoptosis of metastatic mammary carcinoma cells in vivo by disruption of tumor cell surface CD44 function. J Exp Med 186:1985–1996

    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 

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

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Comparative Oncology and Stem Cell Research Group, The Royal (Dick) School of Veterinary Studies and Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK

    Thalia Blacking

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  1. Thalia Blacking
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Correspondence to Thalia Blacking .

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  1. , Kean University, Room 213, Library building, Morris Avenue 1000, Union, 07083, New Jersey, USA

    M.A. Hayat

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Blacking, T. (2013). Is CD44 a Marker for Cancer Stem Cells?. In: Hayat, M. (eds) Stem Cells and Cancer Stem Cells, Volume 9. Stem Cells and Cancer Stem Cells, vol 9. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5645-8_23

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