Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma: A Review

  • Satpute, Pranali Shirish (Department of Oral and Maxillofacial Pathology, Government Dental College and Hospital) ;
  • Hazarey, Vinay (Department of Oral and Maxillofacial Pathology, Government Dental College and Hospital) ;
  • Ahmed, Riyaz (Department of Dentistry, Government Medical College and Hospital) ;
  • Yadav, Lalita (Department of Oral and Maxillofacial Pathology, Kalka Dental College and Hospital)
  • Published : 2013.10.30


Research indicates that a small population of cancer cells is highly tumorigenic, endowed with the capacity for self-renewal, and has the ability to differentiate into cells that constitute the bulk of tumors. These cells are considered the "drivers" of the tumorigenic process in some tumor types, and have been named cancer stem cells (CSC). Epithelial-mesenchymal transition (EMT) appears to be involved in the process leading to the acquisition of stemness by epithelial tumor cells. Through this process, cells acquire an invasive phenotype that may contribute to tumor recurrence and metastasis. CSC have been identified in human head and neck squamous cell carcinomas (HNSCC) using markers such as CD133 and CD44 expression, and aldehyde dehydrogenase (ALDH) activity. Head and neck cancer stem cells reside primarily in perivascular niches in the invasive fronts where endothelial-cell initiated events contribute to their survival and function. Clinically, CSC enrichment has been shown to be enhanced in recurrent disease, treatment failure and metastasis. CSC represent a novel target of study given their slow growth and innate mechanisms conferring treatment resistance. Further understanding of their unique phenotype may reveal potential molecular targets to improve therapeutic and survival outcomes in patients with HNSCC. Here, we discuss the state-of-the-knowledge on the pathobiology of cancer stem cells, with a focus on the impact of these cells on head and neck tumor progression, metastasis and recurrence due to treatment failure.


Cancer stem cells;epithelial-mesenchymal transition;head and neck squamous cell carcinoma


  1. Allegra E, Baudi F, La Boria A, et al (2009). Multiple head and neck tumours and their genetic relationship. Acta Otorhinolaryngol Ital, 29, 237-41.
  2. Al-Hajj M, Wicha M, Benito-Hernandez A, et al (2003). Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA, 100, 3983-8.
  3. Allegra E, Garozzo A, Lombardo N, et al (2006). Mutations and polymorphisms in mitochondrial DNA in head and neck cancer cell lines. Acta Otorhinolaryngol Ital, 26, 185-90.
  4. Allegra E, Trapasso S (2012). Cancer stem cells in head and neck cancer. Onco Targets and Therapy, 5, 375-83.
  5. Batlle E, Sancho E, Franci C, et al (2000). The transcription factor snail is a repressor of E-cadherin gene expression in the epithelial tumour cells. Nat Cell Biol, 2, 84-9.
  6. Bosron W, Lumeng L, Li T (1988). Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease. Mol Aspects Med, 10, 147-58.
  7. Baumann M, Krause M (2010). CD44: a cancer stem cell-related biomarker with predictive potential for radiotherapy. Clin Cancer Res, 16, 5091-3.
  8. Bonnet D, Dick J (1997). Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med, 3, 730-7.
  9. Borovski T, De Souza E, Melo F, et al (2011). Cancer stem cell niche: the place to be. Cancer Res, 71, 634-9.
  10. Braakhuis B, Tabor M, Leemans C, et al (2002). Second primary tumors and field cancerization in oral and oropharyngeal cancer: molecular techniques provide new insights and definitions. Head Neck, 24, 198-206.
  11. Braakhuis B, Leemans C, Brakenhoff RH, et al (2005). Expanding fields of genetically altered cells in head and neck squamous carcinogenesis. Semin Cancer Biol, 15, 113-20.
  12. Califano J, Westra W, Meininger G, et al (2000). Genetic progression and clonal relationship of recurrent premalignant head and neck lesions. Clin Cancer Res, 2, 347-52.
  13. Cano A, Perez-Moreno M, Rodrigo I, et al (2000). The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol, 2, 76-83.
  14. Carvalho A, Nishimoto I, Califano J, et al (2005). Trends in incidence and prognosis for head and neck cancer in the United States: a site-specific analysis of the SEER database. Int J Cancer, 114, 806-16.
  15. Chikamatsu K, Ishii H, Takahashi G, et al (2012). Resistance to apoptosis-inducing stimuli in CD44+ head and neck squamous cell carcinoma cells. Head Neck, 34, 336-43.
  16. Chen C, Wei Y ,Hummel M, et al (2011). Evidence for epithelial- mesenchymal transition in cancer stem cells of head and neck squamous cell carcinoma. PLoS One, 6, 16466.
  17. Chen Y, Chen Y, Hsu H, et al (2009). Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem Biophys Res Commun, 385, 307-13.
  18. Cheng G, Chan J, Wang Q, et al (2007). Twist transcriptionally up-regulates AKT2 in breast cancer cells leading to increased migration, invasion and resistance to paclitaxel. Cancer Res, 67, 1979-87.
  19. Chiou S, Yu C, Huang Y, et al (2008). Positive correlations of Oct-4 and Nanog in oral cancer stem-like cells and high grade oral squamous cell carcinoma. Clin Cancer Res, 14, 4085-95.
  20. Clarke M, Dick J, Dirks P, et al (2006). Cancer stem cells: Perspectives on current status and future directions: AACR workshop on cancer stem cells. Cancer Res, 66, 9339-44.
  21. Cohnheim J (1875). Congenitales, quergestreiftes muskelsarkon der nireren. Virchows Arch, 65, 64.
  22. Collins A, Berry P, Hyde C, et al (2005). Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res, 65, 10946-51.
  23. Dalerba P, Dylla S, Park I, et al (2007). Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA, 104, 10158-63.
  24. Davis S, Divi V, Owen J, et al (2010). Metastatic potential of cancer stem cells in head and neck squamous cell carcinoma. arch otolaryngol. Head Neck Surg, 136, 1260-6.
  25. Fuchs E, Tumbar T, Guasch G (2004). Socializing with the neighbours: stem cells and their niche. Cell, 116, 769-78.
  26. Durante F (1874). Nessus pathophysiological between the flaw structure of the mother and the genesis of some malignant tumors. Arch Memor Observ Chir Prat, 111, 217.
  27. Eramo A, Lotti F, Sette G, et al (2008). Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ, 15, 504-14.
  28. Fang D, Nguyen T, Leishear K, et al (2005). A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res, 65, 9328-37.
  29. Garozzo A, Cutrona D, Palmeri S, et al (1999). The role of p53 tumor suppressor gene as prognostic factor in laryngeal squamous cell carcinoma. Acta Otorhinolaryngol Ital, 19, 342-7.
  30. Ginestier C, Hur M, Charafe-Jauffret E, et al (2007). ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell, 1, 555-67.
  31. Hermann P, Huber S, Herrler T, et al (2007). Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell, 1, 313-23.
  32. Hirschmann-Jax C, Foster A, Wulf G, et al (2004). A distinct "side population" of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA, 101, 14228-33.
  33. Isacke C, Yarwood H (2002). The hyaluronan receptor, CD44. Int J Biochem Cell Biol, 34, 718-21.
  34. Iwatsuki M, Mimori K, Yokobori T, et al (2010). Epithelial-mesenchymal transition in cancer development and its clinical significance. Cancer Sci, 101, 293-9.
  35. Kalluri R, Neilson E (2003). Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest, 112, 1776-84.
  36. Jemal A, Bray F, Center M, et al (2011). Global cancer statistics. CA Cancer J Clin, 61, 69-90.
  37. Joshua B, Kaplan M, Doweck I, et al (2012). Frequency of cells expressing CD44,ahead and neck cancer stem cell marker: correlation with tumor aggressiveness. Head Neck, 34, 42-9.
  38. Kajita M, Itoh Y, Chiba T, et al (2001). Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J Cell Biol, 153, 893-904.
  39. Kalluri R, Weinberg R (2009). The basics of epithelial-mesenchymal transition. J Clin Invest, 119, 1420-8.
  40. Koukourakis MI, Giatromanolaki A, Tsakmaki V, et al (2012). Cancer stem cell phenotype relates to radiochemotherapy out come in locally advanced squamous cell head-neck cancer. Br J Cancer, 106, 846-53.
  41. Krishnamurthy S, Dong Z, Vodopyanov D, et al (2010). Endothelial cell-initiated signalling promotes the survival and self renewal of cancer stem cells. Cancer Res, 70, 9969-78.
  42. Krishnamurthy S, Nor J (2012). Head and neck cancer stem cells. J Dent Res, 91, 334-40.
  43. Kuhn N, Tuan R (2010). Regulation of stemness and stem cell niche of mesenchymal stem cells: implications in tumorigenesis and metastasis. J Cell Physiol, 222, 268-77.
  44. Li Q, Xu J, Wang W, et al (2009). Twist1-mediated adriamycin-induced epithelial-mesenchymal transition relates to multidrug resistance and invasive potential in breast cancer cells. Clin Cancer Res, 15, 2657-65.
  45. Morel A, Lievre M, Thomas C, et al (2008). Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One, 3, 2888.
  46. Lim S, Oh S (2005). The role of CD24 in various human epithelial neoplasias. Pathol Res Pract, 201, 479-86.
  47. Lim Y, Oh S, Cha Y, et al (2011). Cancer stem cell traits in squamospheres derived from primary head and neck squamous cell carcinomas. Oral Oncol, 47, 83-91.
  48. Mani S, Guo W, Liao M, et al (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133, 704-15.
  49. Moreno-Bueno G, Portillo F, Cano A (2008). Transcriptional regulation of cell polarity in EMT and cancer. Oncogene, 27, 6958-69.
  50. Morrison S, Spradling A (2008). Stem cells and niches: Mechanisms that promote stem cell maintenance throughout life. Cell, 132, 598-611.
  51. Neiva K, Zhang Z, Miyazawa M, et al (2009). Crosstalk initiated by endothelial cells enhances migration and inhibits anoikis of squamous cell carcinoma cells through STAT/Akt/ERK signaling. Neoplasia, 11, 583-93.
  52. Nor J, Peters M, Christensen J, et al (2001). Engineering and characterization of functional human microvessels in immunodeficient mice. Lab Invest, 81, 453-63.
  53. Nowell P (1976). The clonal evolution of tumor cell populations. Science, 194, 23-8
  54. Okamoto A, Chikamatsu K, Sakakura K, et al (2009). Expansion and characterization of cancer stem-like cells in squamous cell carcinoma of the head and neck. Oral Oncol, 45, 633-9.
  55. Park I, Morrison S, Clarke M (2004). Bmi-1, stem cells, and senescence regulation. J Clin Invest, 113, 175-9.
  56. Prince M, 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. Proc Natl Acad Sci USA, 104, 973-8.
  57. Perl A, Wilgenbus P, Dahl U, et al (1998). A causal role for Ecadherin in the transition from adenoma to carcinoma. Nature, 392, 190-3.
  58. Pierce G, Dixon F, Verney E (1960). Teratocarcinogenic and tissue forming potentials of the cell types comprising neoplastic embryoid bodies. Lab Invest, 9, 583-602.
  59. Prince M, Ailles L (2008). Cancer stem cells in head and neck squamous cell cancer. J Clin Oncol, 26, 2871-5.
  60. Reya T, Morrison S, Clarke M, et al (2001). Stem cells, cancer, and cancer stem cells. Nature, 414, 105-11.
  61. Radisky D, LaBarge M (2008). Epithelial-mesenchymal transition and the stem cell phenotype. Cell Stem Cell, 2, 511-2.
  62. Rasper M, Schafer A, Piontek G, et al (2010). Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity. Neuro Oncol, 12, 1024-33.
  63. Sanchez-Tillo E, Lazaro A, Torrent R, et al (2010). ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/ SNF chromatin-remodeling protein BRG1. Oncogene, 29, 3490-500.
  64. Singh S, Hawkins C, Clarke I, et al (2004). Identification of human brain tumour initiating cells. Nature, 432, 396-401.
  65. Shook D, Keller R (2003). Mechanisms, mechanics and function of epithelialmesenchymal transition in early development. Mech Dev, 120, 1351-83.
  66. Spivakov M, Fisher A (2007). Epigenetic signatures of stem-cell identity. Nat Rev Cancer, 8, 263-71.
  67. Thomasson H, Edenberg H, Crabb D, et al (1991). Alcohol and aldehyde dehydrogenase genotypes and alcoholism in Chinese men. Am J Hum Genet, 148, 677-81.
  68. Sun S, Wang Z (2011). Head neck squamous cell carcinoma c-Met+ cells display cancer stem cell properties and are responsible for cisplatin-resistance and metastasis. Int J Cancer, 129, 2337-48.
  69. Thiery J (2002). Epithelial-mesenchymal transitions in tumour progression. Nat Rev Cancer, 2, 442-54.
  70. Thiery J, Acloque H, YJ Huang R, et al (2009). Epithelial-mesenchymal transitions in development and disease. Cell, 139, 871-90.
  71. Till J, McCulloch E (1961). A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res, 14, 213-22.
  72. Valk-lingbeek M, Bruggeman S, Van Lohuizen M (2004). Stem cells and cancer; the polycomb connection. Cell, 118, 409-18.
  73. Vlashi E, McBride W, Pajonk, F (2009). Radiation responses of cancer stem cells. J Cell Biochem, 108, 339-42.
  74. Visus C, Ito D, Amoscato A, et al (2007). Identification of human aldehyde dehydrogenase 1 family member A1 as a novel CD8+ T-cell-defined tumor antigen in squamous cell carcinoma of the head and neck. Cancer Res, 67, 10538-45.
  75. Visvader J, Lindeman G (2008). Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer, 8, 755-68.
  76. Wang S, Wong G, de Heer A, et al (2009). CD44 variant isoforms in head and neck squamous cell carcinoma progression. Laryngoscope, 119, 1518-30.
  77. Xia H, Cheung WK, Sze J, et al (2010). MiR-200a regulates epithelial-mesenchymal to stem-like transition via ZEB2 and ${\beta}$-catenin signaling. J Biol Chem, 285, 36995-7004.
  78. Whiteman E, Liu C, Fearon E, et al (2008). The transcription factor snail represses Crumbs3 expression and disrupts apico-basal polarity complexes. Oncogene, 27, 3875-9.
  79. Widschwendter M, Fiegl H, Egle D, et al (2007). Epigenetic stem cell signature in cancer. Nat Genet, 39, 157-8.
  80. Wollenberg B (2011). Implication of stem cells in the biology and therapy of head and neck cancer. GMS Curr Top Otolaryngol Head Neck Surg, 10.
  81. Yang A, Fan F, Camp E (2006). Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res, 12, 4147-53.
  82. Yang J, Mani S, Donaher J, et al (2004). Twist a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell, 117, 927-39.
  83. Yang M, Wu M, Chiou S, et al (2008). Direct regulation of TWIST by HIF-1a promotes metastasis. Nat Cell Biol, 10, 295-305.
  84. Yang M, Hsu D, Wang H, et al (2010). Bmi-1 is essential in twist1-induced epithelial-mesenchymal transition. Nat Cell Biol, 12, 982-92.
  85. Zhang P, Zhang Y, Mao L, et al (2009). Side population in oral squamous cell carcinoma possesses tumor stem cell phenotypes. Cancer Lett, 277, 227-34.
  86. 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 Lett, 289, 151-60.
  87. Zhang Z, Neiva K, Lingen M, et al (2010). VEGF-dependent tumor angiogenesis requires inverse and reciprocal regulation of VEGFR1 and VEGFR2. Cell Death Differ, 17, 499-512.
  88. Zhang Z, Filho M, Nor J (2012). The biology of head and neck cancer stem cells. Oral Oncol, 48, 1-9.
  89. Zhou L, Wei X, Cheng L, et al (2007). CD133,one of the markers of cancer stem cells in Hep-2cell line. Laryngoscope, 117, 455-60.

Cited by

  1. ALDH1 in Combination with CD44 as Putative Cancer Stem Cell Markers are Correlated with Poor Prognosis in Urothelial Carcinoma of the Urinary Bladder vol.15, pp.5, 2014,
  2. MicroRNAs in Cervical Cancer: Evidences for a miRNA Profile Deregulated by HPV and Its Impact on Radio-Resistance vol.19, pp.5, 2014,
  3. Clinicopathological Significance of CD133 and ALDH1 Cancer Stem Cell Marker Expression in Invasive Ductal Breast Carcinoma vol.16, pp.17, 2015,
  4. The role of CD29-ILK-Akt signaling-mediated epithelial–mesenchymal transition of liver epithelial cells and chemoresistance and radioresistance in hepatocellular carcinoma cells vol.32, pp.5, 2015,
  5. Honokiol inhibits sphere formation and xenograft growth of oral cancer side population cells accompanied with JAK/STAT signaling pathway suppression and apoptosis induction vol.16, pp.1, 2016,
  6. The upregulated α-catulin expression was involved in head-neck squamous cell carcinogenesis by promoting proliferation, migration, invasion, and epithelial to mesenchymal transition vol.37, pp.2, 2016,
  7. Prognostic Value of Cancer Stem Cell Markers in Head and Neck Squamous Cell Carcinoma: a Meta-analysis vol.7, pp.2045-2322, 2017,
  8. Increased expression of CD44 is associated with more aggressive behavior in clear cell renal cell carcinoma vol.12, pp.1, 2018,
  9. Influence of CD133+ expression on patients' survival and resistance of CD133+ cells to anti-tumor reagents in gastric cancer vol.5, pp.12, 2015,
  10. The Epithelial-to-Mesenchymal Transition-Like Process in Glioblastoma: An Updated Systematic Review and In Silico Investigation vol.37, pp.2, 2016,
  11. The promise of stem cell markers in the diagnosis and therapy of epithelial dysplasia and oral squamous cell carcinoma vol.233, pp.11, 2018,