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Cancer Stem Cells in Head and Neck Carcinomas: Identification and Possible Therapeutic Implications

  • Elize Wolmarans
  • Sonja C. Boy
  • Sulette Nel
  • Anne E. Mercier
  • Michael Sean Pepper
Conference paper
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1083)

Abstract

The recurrence and/or lack of response of certain tumors to radio- and chemotherapy has been attributed to a small subpopulation of cells termed cancer stem cells (CSCs). CSCs have been identified in many tumors (including solid and hematological tumors). CSCs are characterized by their capacity for self-renewal, their ability to introduce heterogeneity within a tumor mass and its metastases, genomic instability, and their insensitivity to both radiation and chemotherapy. The latter highlights the clinical importance of studying this subpopulation since their resistance to traditional treatments may lead to metastatic disease and/or tumor relapse. Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignancy worldwide with the highest incidence occurring in East Asia and eastern and southern Africa. Several cellular subpopulations believed to have CSC properties have been isolated from HNSCCs, but at present, identification and characterization of CSCs remains an experimental challenge with no established or standardized protocols in place to confirm their identity. In this review we discuss current approaches to the study of CSCs with a focus on HNSCCs, particularly in the context of what this might mean from a therapeutic perspective.

Keywords

Cancer stem cells Head and neck carcinomas 

Abbreviations

ABC

ATP-binding cassette

AKT

Protein kinase B

ALCAM

Activated leukocyte cell adhesion molecule

ALDH

Aldehyde dehydrogenase

ATP

Adenosine triphosphate

BCRP

Breast cancer resistant protein

BMI1

Moloney murine leukemia virus insertion site 1

CD44

Cluster of differentiation

CSC

Cancer stem cell

EMT

Epithelial-mesenchymal transition

ESCC

Esophageal squamous cell carcinoma

FACS

Fluorescence-activated cell sorting

HIF

Hypoxia-inducible factors

HNC

Head and neck carcinoma

HNSCC

Head and neck squamous cell carcinoma

HPV

Human papillomavirus

HSA

Heat stable antigen

ICAM1

Intercellular adhesion molecule 1

MAPK

Mitogen-activated protein kinases

NOD

Nonobese diabetic

Oct3/4

Octamer-binding transcription factor 3/4

OSCC

Oral squamous cell carcinoma

P-gp

P-glycoprotein

PI3K

Phosphatidylinositol-3-kinase

POU

Pit-Oct-Unc

SCC

Squamous cell carcinoma

SCID

Severe combined immunodeficiency

SOX2

Sex-determining region Y-box2

SP

Side population

Notes

Acknowledgements

This research was funded by the South African Medical Research Council in terms of the SAMRC's Flagship Award Project SAMRC-RFA-UFSP-01-2013/STEM CELLS, the SAMRC Extramural Unit for Stem Cell Research and Therapy and the Institute for Cellular and Molecular Medicine of the University of Pretoria.

Conflicts of Interest

The authors have no conflicts of interest to declare.

Author Contribution

MSP conceived the project, EW drafted the first version of the manuscript, and EW, SB, SN, AEM, and MSP provided intellectual input and contributed to the writing of the manuscript. All authors vetted and approved the final version of the manuscript.

References

  1. Albrecht, C., & Viturro, E. (2007). The ABCA subfamily--gene and protein structures, functions and associated hereditary diseases. Pflügers Archiv, 453(5), 581–589.Google Scholar
  2. Allegra, E., & Trapasso, S. (2012). Cancer stem cells in head and neck cancer. Oncotargets and Therapy, 5, 375–583.Google Scholar
  3. Borst, P., Evers, R., Kool, M., et al. (1999). The multidrug resistance protein family. Biochimica et Biophysica Acta, 1461, 347–357.Google Scholar
  4. Bourguignon, L. Y., Wong, G., Earie, C., et al. (2012). Hyaluronan-CD44v3 interaction with Oct4-Sox2-Nanog promotes miR-302 expression leading to self-renewal, clonal formation, and cisplatin resistance in cancer stem cells from head and neck squamous cell carcinoma. The Journal of Biological Chemistry, 287(39), 32800–32824.Google Scholar
  5. Bruni, L., Barrionuevo-Rosas, L., Albero, G. et al. (2017). Human papillomavirus and related diseases in South Africa. Summary Report.Google Scholar
  6. Chen, Y. C., Chen, Y. W., Hsu, H. S., et al. (2009). Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochemical and Biophysical Research Communications, 385(3), 307–313.Google Scholar
  7. Chen, D., Wu, M., Li, Y., et al. (2017). Targeting BMI1 + cancer stem cells overcomes Chemoresistance and inhibits metastases in squamous cell carcinoma. Cell Stem Cell, 20(5), 621–634.Google Scholar
  8. Chiou, S. H., CC, Y., Huang, C. Y., et al. (2008). Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high-grade oral squamous cell carcinoma. Clinical Cancer Research, 14(13), 4085–4095.Google Scholar
  9. Clarke, M., & Fuller, M. (2006). Stem cells and cancer: Two faces of eve. Cell, 124(6), 111–1115.Google Scholar
  10. Clay, M. R., Tabor, M., Owen, J. H., et al. (2010). Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head & Neck, 23(9), 1195–1201.Google Scholar
  11. Dean, M. (2009). ABC transporters, drug resistance, and cancer stem cells. Journal of Mammary Gland Biology and Neoplasia, 14(1), 3–9.Google Scholar
  12. Dean, M., Hamon, Y., & Chimini, G. (2001). The human ATP-binding cassette (ABC) transporter superfamily. Journal of Lipid Research, 42(7), 1007–1017.Google Scholar
  13. Ding, X., Wu, J., & Jiang, C. (2010). ABCG2: A potential marker of stem cells and novel target in stem cell and cancer therapy. Life Sciences, 86(17–18), 631–637.Google Scholar
  14. El-Naggar, A., Chan, J., & Grandis, J. (Eds). (2017). Tumours of the oropharynx (base of tongue, tonsils, adenoids). In WHO Classification of Head and Nect Tumours. IARC.Google Scholar
  15. Erdei, Z., Lőrincz, R., Szebényi, K., et al. (2014). Expression pattern of the human ABC transporters in pluripotent embryonic stem cells and in their derivatives. Cytometry Part B, Clinical Cytometry, 86(5), 299–310.Google Scholar
  16. Eun, K., Ham, S. W., & Kim, H. (2017). Cancer stem cell heterogeneity: Origin and new perspectives on CSC targeting. BMB Reports, 50(3), 117–125.Google Scholar
  17. Eyler, C., & Rich, J. (2008). Survival of the fittest: Cancer stem cells in therapeutic resistance and angiogenesis. Journal of Clinical Oncology, 26(17), 2839–2845.Google Scholar
  18. Fábián, Á., Vereb, G., & Szöllosi, J. (2013). The hitchhikers guide to cancer stem cell theory: Markers, pathways and therapy. Cytometry. Part A, 83(1), 62–71.Google Scholar
  19. Falasca, M., & Linton, K. J. (2012). Investigational ABC transporter inhibitors. Expert Opinion on Investigational Drugs, 21(5), 657–666.Google Scholar
  20. Fan, Z., Li, M., Chen, X., et al. (2017). Prognostic value of cancer stem cell markers in head and neck squamous cell carcinoma: A meta-analysis. Scientific Reports, 7, 1–8.Google Scholar
  21. Gil, J., Stembalska, A., Pesz, K. A., et al. (2008). Cancer stem cells: The theory and perspectives in cancer therapy. Journal of Applied Genetics, 49(2), 193–199.Google Scholar
  22. Golebiewska, A., Brons, N. H., Bjerkvig, R., et al. (2011). Critical appraisal of the side population assay in stem cell and cancer stem cell research. Cell Stem Cell, 8(2), 136–147.Google Scholar
  23. González-Moles, M. A., Scully, C., Ruiz-Ávila, I., et al. (2013). The cancer stem cell hypothesis applied to oral carcinoma. Oral Oncology, 49(8), 738–746.Google Scholar
  24. Goodell, M. A., Brose, K., Paradis, G., et al. (1996). Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo. The Journal of Experimental Medicine, 183, 1797–1806.Google Scholar
  25. Grimm, M., Krimmel, M., Polligkeit, J., et al. (2012). ABCB5 expression and cancer stem cell hypothesis in oral squamous cell carcinoma. European Journal of Cancer, 48(17), 3186–3197.Google Scholar
  26. Han, J., Fujisawa, T., Husain, S. R., et al. (2014). Identification and characterization of cancer stem cells in human head and neck squamous cell carcinoma. BMC Cancer, 14(1), 173–184.Google Scholar
  27. Hang, D., Dong, H. C., Ning, T., et al. (2012). Prognostic value of the stem cell markers CD133 and ABCG2 expression in esophageal squamous cell carcinoma. Diseases of the Esophagus, 25(7), 638–644.Google Scholar
  28. Harper, L. J., Piper, K., Common, J., et al. (2007). Stem cell patterns in cell lines derived from head and neck squamous cell carcinoma. Journal of Oral Pathology & Medicine, 36(10), 594–603.Google Scholar
  29. Heddleston, J. M., Li, Z., Lathia, J. D., et al. (2010). Hypoxia inducible factors in cancer stem cells. British Journal of Cancer, 102(5), 789–795.Google Scholar
  30. Huls, M., Russel, F. G., & Masereeuw, R. (2009). The role of ATP binding cassette transporters in tissue defense and organ regeneration. The Journal of Pharmacology and Experimental Therapeutics, 328(1), 3–9.Google Scholar
  31. Jamal-Hanjani, M., Quezada, S. A., Larkin, J., et al. (2015). Translational implications of tumor heterogeneity. Clinical Cancer Research, 21(6), 1258–1266.Google Scholar
  32. Jemal, A., Bray, F., Center, M. M., et al. (2011). Global cancer statistics. CA: a Cancer Journal for Clinicians, 61(2), 69–90.Google Scholar
  33. Karimnejad, K., Lindquist, N., & Lin, R. (2016). The role of cancer stem cells in head and neck squamous cell carcinoma and its clinical implications. In New aspects in molecular and cellular mechanisms of human carcinogenesis (pp. 97–113).Google Scholar
  34. Kaseb, H. O., Fohrer-Ting, H., Lewis, D. W., et al. (2016). Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas. Experimental Cell Research, 348(1), 75–86.Google Scholar
  35. Koukourakis, M. I., Giatromanolaki, A., Tsakmaki, V., et al. (2012). Cancer stem cell phenotype relates to radio-chemotherapy outcome in locally advanced squamous cell head–neck cancer. British Journal of Cancer, 106(5), 846–853.Google Scholar
  36. Leonard, G. D., Fojo, T., & Bates, S. E. (2003). The role of ABC transporters in clinical practice. The Oncologist, 8(5), 411–424.Google Scholar
  37. Li, H., Gao, Q., Guo, L., et al. (2011). The PTEN/PI3K/Akt pathway regulates stem-like cells in primary esophageal carcinoma cells. Cancer Biology & Therapy, 11(11), 950–958.Google Scholar
  38. Liang, S. B., & Fu, L. W. (2017). Application of single-cell technology in cancer research. Biotechnology Advances, 35(4), 443–449.Google Scholar
  39. Lin, T., Islam, O., & Heese, K. (2006). ABC transporters, neural stem cells and neurogenesis – a different perspective. Cell Research, 16, 857–871.Google Scholar
  40. Mao, Q., & Unadkat, J. D. (2015). Role of the Breast Cancer Resistance Protein (BCRP/ABCG2) in drug transport—An update. The AAPS Journal, 17(1), 65–82.Google Scholar
  41. Mǎrgǎritescu, C., Pirici, D., Simionescu, C., et al. (2012). The utility of CD44, CD117 and CD133 in identification of cancer stem cells (CSC) in oral squamous cell carcinomas (OSCC). Romanian Journal of Morphology and Embryology, 52, 985–993.Google Scholar
  42. Méry, B., Guy, J. B., Espenel, S., et al. (2016). Targeting head and neck tumoral stem cells: From biological aspects to therapeutic perspectives. World J Stem Cells, 8(1), 13–21.Google Scholar
  43. Misra, S., Toole, B. P., & Ghatak, S. (2006). Hyaluronan constitutively regulates activation of multiple receptor tyrosine kinases in epithelial and carcinoma cells. The Journal of Biological Chemistry, 281(46), 34936–34941.Google Scholar
  44. Modur, V., Joshi, P., Nie, D., et al. (2016). CD24 expression may play a role as a predictive indicator and a modulator of cisplatin treatment response in head and neck squamous cellular carcinoma. PLoS One.  https://doi.org/10.1371/journal.pone.0156651.Google Scholar
  45. Noto, Z., Yoshida, T., Okabe, M., et al. (2013). CD44 and SSEA-4 positive cells in an oral cancer cell line HSC-4 possess cancer stem-like cell characteristics. Oral Oncology, 49(8), 787–795.Google Scholar
  46. Okamoto, H., Fujishima, F., Nakamura, Y., et al. (2013). Significance of CD133 expression in esophageal squamous cell carcinoma. World Journal of Surgical Oncology, 11(1), 51–60.Google Scholar
  47. Prince, M. E., Sivanandan, R., Kaczorowski, A., et al. (2007). Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proceedings of the National Academy of Sciences of the United States of America, 104(3), 973–978.Google Scholar
  48. Qian, X., Tan, C., Wang, F., et al. (2016). Esophageal cancer stem cells and implications for future therapeutics. OncoTargets Ther, 9, 2247–2254.Google Scholar
  49. Ren, Z. H., Zhang, C. P., & Ji, T. (2016). Expression of SOX2 in oral squamous cell carcinoma and the association with lymph node metastasis. Oncology Letters, 11(3), 1973–1979.Google Scholar
  50. Saliba, A. E., Westermann, A. J., Gorski, S. A., et al. (2014). Single-cell RNA-seq: Advances and future challenges. Nucleic Acids Research, 42, 8845–8860.Google Scholar
  51. Sato, N., Meijer, L., Skaltsounis, L., et al. (2004). Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nature Medicine, 10(1), 55–63.Google Scholar
  52. Satpute, P. S., Hazarey, V., Ahmed, R., et al. (2013). Cancer stem cells in head and neck squamous cell carcinoma: A review. Asian Pacific Journal of Cancer Prevention, 14(10), 5579–5587.Google Scholar
  53. Spiegelberg, D., Kuku, G., Selvaraju, R., et al. (2014). Characterization of CD44 variant expression in head and neck squamous cell carcinomas. Tumor Biology, 35(3), 2053–2062.Google Scholar
  54. Takahashi-Yanaga, F., & Kahn, M. (2010). Targeting Wnt signaling: Can we safely eradicate cancer stem cells? Clinical Cancer Research, 16(12), 3153–3162.Google Scholar
  55. Toledano, I., Graff, P., Serre, A., et al. (2012). Intensity-modulated radiotherapy in head and neck cancer: Results of the prospective study GORTEC 2004-03. Radiotherapy and Oncology, 103(1), 57–62.Google Scholar
  56. Torre, L. A., Bray, F., Siegel, R. L., et al. (2015). Global cancer statistics, 2012. CA: a Cancer Journal for Clinicians, 65(2), 87–108.Google Scholar
  57. Tsai, L. L., CC, Y., Chang, Y. C., et al. (2011). Markedly increased Oct4 and Nanog expression correlates with cisplatin resistance in oral squamous cell carcinoma. Journal of Oral Pathology & Medicine, 40(8), 621–628.Google Scholar
  58. Tsai, S. T., Wang, P. J., Liou, N. J., et al. (2015). ICAM1 is a potential cancer stem cell marker of esophageal squamous cell carcinoma. PLoS One.  https://doi.org/10.1371/journal.pone.0142834.Google Scholar
  59. Valent, P., Bonnet, D., De Maria, R., et al. (2012). Cancer stem cell definitions and terminology : The devil is in the details. Nature Review Cancer, 12, 767–775.Google Scholar
  60. Vallard, A., Espenel, S., & Guy, J. B. (2016). Targeting stem cells by radiation: From the biological angle to clinical aspects. World Journal Stem Cells, 8(8), 243–250.Google Scholar
  61. Vasiliou, V., Vasiliou, K., & Nebert, D. W. (2009). Human ATP-binding cassette (ABC) transporter family. Human Genomics, 3(3), 281–290.Google Scholar
  62. Vigneswaran, N., & Williams, D. M. (2014). Epidemiological trends in head and neck cancer and aids in diagnosis. Oral and Maxillofacial Surgery Clinics of North America, 26(2), 123–141.Google Scholar
  63. Vissink, A., Mitchell, J. B., Baum, B. J., et al. (2010). Clinical management of salivary gland hypofunction and xerostomia in head and neck cancer patients: Successes and barriers. International Journal of Radiation Oncology, Biology, Physics, 78(4), 983–991.Google Scholar
  64. Visvader, J. E., & Lindeman, G. J. (2012). Perspective cancer stem Cells : Current status and evolving complexities. Cell Stem Cell, 10(6), 717–728.Google Scholar
  65. Vlashi, E., McBride, W., & Pajonk, F. (2009). Radiation responses of cancer stem cells. Journal of Cellular Biochemistry, 108(2), 339–342.Google Scholar
  66. Wang, E., Casciano, C. N., Clement, R. P., et al. (2000). In vitro flow cytometry method to quantitatively assess inhibitors of P-glycoprotein. Drug Metabolism and Disposition, 28(5), 522–528.Google Scholar
  67. Wang, J., Guo, L. P., Chen, L. Z., et al. (2007). Identification of cancer stem cell-like side population cells in human nasopharyngeal carcinoma cell line. Cancer Research, 67(8), 3716–3724.Google Scholar
  68. Wang, S., Wong, G., & de Heer, A. (2009). CD44 variant isoforms in head and neck squamous cell carcinoma progression. Laryngoscope, 119(8), 1518–1530.Google Scholar
  69. Wang, Y., Zhe, H., Zhang, N., et al. (2012). Cancer stem cell marker ALDH1 expression is associated with lymph node metastasis and poor survival in esophageal squamous cell carcinoma: a study from high incidence area of northern China. Diseases of the Esophagus, 25, 560–565.Google Scholar
  70. Wicha, M., Liu, S., & Dontu, G. (2006). Cancer stem cells: An old idea – a paradigm shift. Cancer Research, 66(4), 1883–1890.Google Scholar
  71. Yan, M., Yang, X., Wang, L., et al. (2013). Plasma membrane proteomics of tumor spheres identify CD166 as a novel marker for cancer stem-like cells in head and neck squamous cell carcinoma. Molecular & Cellular Proteomics, 12(11), 3271–3284.Google Scholar
  72. Yang, M. H., Hsu, D. S., Wang, H. W., et al. (2010). Bmi1 is essential in Twist1-induced epithelial-mesenchymal transition. Nature Cell Biology, 12(10), 982–992.Google Scholar
  73. Yaromina, A., Krause, M., Thames, H., et al. (2007). Pre-treatment number of clonogenic cells and their radiosensitivity are major determinants of local tumour control after fractionated irradiation. Radiotherapy and Oncology, 83(3), 304–310.Google Scholar
  74. Yata, K., Beder, L., Tamagawa, S., et al. (2015). MicroRNA expression profiles of cancer stem cells in head and neck squamous cell carcinoma. International Journal of Oncology, 47(4), 1249–1256.Google Scholar
  75. Yu, C., Lo, W., Chen, Y., et al. (2010). Bmi-1 regulates snail expression and promotes metastasis ability in head and neck squamous cancer-derived ALDH1 positive cells. Journal of Oncology, 2011, 1–16.Google Scholar
  76. Zechner, D., Fuijita, Y., Hulsken, J., et al. (2003). Beta-catenin signals regulate cell growth and the balance between progenitor cell expansion and differentiation in the nervous system. Developmental Biology, 258(2), 406–418.Google Scholar
  77. Zhang, P., Zhang, Y., Mao, L., et al. (2009). Side population in oral squamous cell carcinoma possesses tumor stem cell phenotypes. Cancer Letters, 277(2), 227–234.Google Scholar
  78. Zhang, Q., Shi, S., Yen, Y., et al. (2010). A subpopulation of CD133+ cancer stem-like cells characterized in human oral squamous cell carcinoma confer resistance to chemotherapy. Cancer Letters, 289(2), 151–160.Google Scholar
  79. Zhang, G., Ma, L., Xie, Y., et al. (2012a). Esophageal cancer tumorspheres involve cancer stem-like populations with elevated aldehyde dehydrogenase enzymatic activity. Molecular Medicine Reports, 6(3), 519–524.Google Scholar
  80. Zhang, Z., Filho, M. S. A., & Nor, J. E. (2012b). The biology of head and neck cancer stem cells. Oral Oncology, 49(1), 1–9.Google Scholar
  81. Zhu, L., Yuan, L., Wang, H., et al. (2015). A meta-analysis of concurrent chemoradiotherapy for advanced esophageal cancer. PLoS One.  https://doi.org/10.1371/journal.pone.0128616.Google Scholar
  82. Zimmerer, R., Ludwig, N., Kampmann, A., et al. (2017). CD24+ tumor-initiating cells from oral squamous cell carcinoma induce initial angiogenesis in vivo. Microvascular Research, 112, 101–108.Google Scholar
  83. Zscheppang, K., Kurth, I., Wachtel, N., et al. (2016). Efficacy of beta1 integrin and EGFR targeting in sphere-forming human head and neck cancer cells. Journal of Cancer, 7(6), 736–745.Google Scholar

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© Springer International Publishing AG 2017

Authors and Affiliations

  • Elize Wolmarans
    • 1
  • Sonja C. Boy
    • 2
  • Sulette Nel
    • 3
  • Anne E. Mercier
    • 4
  • Michael Sean Pepper
    • 1
  1. 1.Institute for Cellular and Molecular Medicine (ICMM), Department of Immunology, and SAMRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
  2. 2.Department of Oral Pathology, School of Oral Health SciencesSefako Makgatho Health Sciences UniversityPretoriaSouth Africa
  3. 3.Department of Oral Pathology and Oral Biology, School of Dentistry, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa
  4. 4.Department of Physiology, Faculty of Health SciencesUniversity of PretoriaPretoriaSouth Africa

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