Skip to main content

Advertisement

SpringerLink
Log in

Oral Cancer and Cancer Stem Cells: Relevance to Oral Cancer Risk Factors, Premalignant Lesions, and Treatment

  • Oral Neoplasia (F Alawi and A Le, Section Editors)
  • Published:
Current Oral Health Reports Aims and scope Submit manuscript

Abstract

Cancer stem cells are recognized as the most critical cancer cells. They are responsible for cancer progression, the development of metastasis, and treatment failures. There are a number of well-studied surface proteins and enzymatic processes that can be used to isolate cancer stem cells from the bulk of the other cancer cells. The role of cancer stems cells in premalignant lesions of the oral cancer is poorly understood but slowly evolving. Novel therapies are being developed to more effectively eradicate cancer stem cells and improve patient outcomes. Efforts to improve our understanding of this important subpopulation of cancer cells is vital in directing further studies to advance our ability to prevent patients from developing oral cancer and to providing more effective treatment for those that do.

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.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Papagerakis S, Pannone G, Zheng L, About I, Taqid N, Nguyen NPT, et al. Oral epithelial stem cells—implications in normal development and cancer metastasis. Exp Cell Res. 2014;325(2):111–29. Comprehensive review of oral cavity cancer stem cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. González-Moles MA, Scully C, Ruiz-Ávila I, Plaza-Campillo JJ. The cancer stem cell hypothesis applied to oral carcinoma. Oral Oncol. 2013;49:738–46. Provides a basis for understanding the current state of cancer stem cell research with a focus on oral cavity cancer.

    Article  PubMed  Google Scholar 

  3. Al-Hajj M, Becker MW, Wicha M, et al. Therapeutic implications of cancer stem cells. Curr Opin Genet Dev. 2004;14(1):43–7.

    Article  CAS  PubMed  Google Scholar 

  4. Azizi E, Wicha MS. Point: cancer stem cells—the evidence accumulates. Clin Chem. 2013;59(1):205–7.

    Article  CAS  PubMed  Google Scholar 

  5. Athanassiou-Papaefthymiou M, Shkeir O, Kim D, Divi V, Matossian M, Owen JH, et al. Evaluation of CD44 variant expression in oral, head and neck squamous cell carcinomas using a triple approach and its clinical significance. Int J Immunopathol Pharmacol. 2014;27(3):337–49.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367(6464):645–8.

    Article  CAS  PubMed  Google Scholar 

  7. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A. 2003;100(7):3983–8. Erratum in: Proc Natl Acad Sci U S A. 2003 May 27; 100(11):6890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Prince ME, Sivanandan R, Kaczorowski A, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci. 2007;104(3):973–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Clay MR, Tabor M, Owen J, et al. Aldehyde dehydrogenase activity alone can identify cancer stem cells in head and neck squamous cell cancer. Head Neck. 2010;32(9):1195–201.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res. 2003;63:5821–8.

    CAS  PubMed  Google Scholar 

  11. Alamgeer M, Peacock CD, Matsui W, et al. Cancer stem cells in lung cancer: evidence and controversies. Respirology. 2013;18:757–64.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Li C, Heidt DG, Dalerba P, et al. Identification of pancreatic cancer stem cells. Cancer Res. 2007;67:1030–7.

    Article  CAS  PubMed  Google Scholar 

  13. Yamashita T, Wang XW. Cancer stem cells in the development of liver cancer. J Clin Investig. 2013;1911–1918.

  14. Takaishi S, Okumura T, Tu S, et al. Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells. 2009;27:1006–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Vaiopoulos AG, Kostakis ID, Koutsilieris M, et al. Colorectal cancer stem cells. Stem Cells. 2012;30:363–71.

    Article  CAS  PubMed  Google Scholar 

  16. Park IK, Morrison SJ, Clarke MF. Bmi1, stem cells, and senescence regulation. J Clin Invest. 2004;113(2):175–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chinn SB, Darr OA, Owen JH, et al. Cancer stem cells: mediators of tumorigenesis and metastasis in head and neck squamous cell carcinoma. Head Neck. 2015;37(3):317–26.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wang SJ, Wong G, de Heer AM, et al. CD44 variant isoforms in head and neck squamous cell carcinoma progression. Laryngoscope. 2009;119(8):1518–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Biddle A, Liang X, Gammon L, et al. Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res. 2011;71:5317–26.

    Article  CAS  PubMed  Google Scholar 

  20. Gemenetzidis E, Gammon L, Biddle A, et al. Invasive oral cancer stem cells display resistance to ionising radiation. Oncotarget. 2015. doi:10.18632/oncotarget.6268.

    PubMed  PubMed Central  Google Scholar 

  21. Desiderio V, Papagerakis P, Tirino V, Zheng L, Matossian M, Prince ME, et al. Increased fucosylation has a pivotal role in invasive and metastatic properties of head and neck cancer stem cells. Oncotarget. 2015;6(1):71–84.

    PubMed  PubMed Central  Google Scholar 

  22. Chen YC, Chen YW, Hsu HS, et al. Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem Biophys Res Commun. 2009;385(3):307–13.

    Article  CAS  PubMed  Google Scholar 

  23. Ginestier C, Hur MH, Charafe-Jauffret E, 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 

  24. Sophos NA, Vasiliou V. Aldehyde dehydrogenase gene superfamily: the 2002 update. Chem Biol Interact. 2003;143–144:5–22.

    Article  PubMed  Google Scholar 

  25. Kurth I, Hein L, Mäbert K, et al. Cancer stem cell related markers of radioresistance in head and neck squamous cell carcinoma. Oncotarget. 2015;6(33):34494–509.

    PubMed  PubMed Central  Google Scholar 

  26. Lu C, Xu F, Gu J, et al. Clinical and biological significance of stem-like CD133+ CXCR4+ cells in esophageal squamous cell carcinoma. J Thorac Cardiovasc Surg. 2015;15(2):386–95.

    Article  Google Scholar 

  27. Zhou L, Wei X, Cheng L, Tian J, Jiang JJ. CD133, one of the markers of cancer stem cells in Hep-2 cell line. Laryngoscope. 2007;117(3):455–60.

    Article  CAS  PubMed  Google Scholar 

  28. Zhang Z, Filho MS, Nör JE. The biology of head and neck cancer stem cells. Oral Oncol. 2012;48(1):1–9.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Mărgăritescu C, Pirici D, Simionescu C, et al. The utility of CD44, CD117 and CD133 in identification of cancer stem cells (CSC) in oral squamous cell carcinomas (OSCC). Rom J Morphol Embryol. 2011;52(3 Suppl):985–93.

    PubMed  Google Scholar 

  30. Van Leenders GJ, Sookhlall R, Teubel WJ, et al. Activation of c-MET induces a stem-like phenotype in human prostate cancer. PLoS One. 2011;6(11):e26753. doi:10.1371/journal.pone.0026753.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Vermeulen L, De Sousa E, Melo F, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12:468–76.

    Article  CAS  PubMed  Google Scholar 

  32. Ohnish T, Daikuhara Y. Hepatocyte growth factor/scatter factor in development, inflammation and carcinogenesis: its expression and role in oral tissues. Arch Oral Biol. 2003;48:797–804.

    Article  Google Scholar 

  33. Lim YC, Han JH, Kang HJ, et al. Overexpression of c-Met promotes invasion and metastasis of small oral tongue carcinoma. Oral Oncol. 2012;48:1114–9.

    Article  CAS  PubMed  Google Scholar 

  34. Lim YC, Kang HJ, Moon JH. c-Met pathway promotes self-renewal and tumorigenecity of head and neck squamous cell carcinoma stem-like cell. Oral Oncol. 2014;50(7):633–9.

    Article  CAS  PubMed  Google Scholar 

  35. Tabor MH, Clay MR, Owen JH, et al. Head and neck cancer stem cells: the side population. Laryngoscope. 2011;121(3):527–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wang YH, Li F, Luo B, et al. A side population of cells from a human pancreatic carcinoma cell line harbors cancer stem cell characteristics. Neoplasm. 2009;56(5):371–8.

    Article  CAS  Google Scholar 

  37. Ho MM, Ng AV, Lam S, et al. Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. Cancer Res. 2007;67(10):4827–33.

    Article  CAS  PubMed  Google Scholar 

  38. Yu D, Jin C, Liu Y, et al. Clinical implications of cancer stem cell-like side population cells in human laryngeal cancer. Tumour Biol. 2013;34(6):3603–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zhang P, Zhang Y, Mao L, et al. Side population in oral squamous cell carcinoma possesses tumor stem cell phenotypes. Cancer Lett. 2009;277(2):227–34.

    Article  CAS  PubMed  Google Scholar 

  40. Alcantara Llaguno SR, Chen J, Parada LF. Signaling in malignant astrocytomas: role of neural stem cells and its therapeutic implications. Clin Cancer Res. 2009;15:7124–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pezzuto F, Buonaguro L, Caponigro F, Ionna F, Starita N, Annunziata C, et al. Update on head and neck cancer: current knowledge on epidemiology, risk factors, molecular features and novel therapies. Oncology. 2015;89(3):125–36. Comprehensive review of the risk factors and molecular biology of head and neck squamous cell cancer.

    Article  PubMed  Google Scholar 

  42. White AC, Tran K, Khuu J, Dang C, et al. Defining the origins of Ras/p53-mediated squamous cell carcinoma. Proc Natl Acad Sci. 2011;108:7425–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Lapouge G, Youssef KK, Vokaer B, et al. Identifying the cellular origin of squamous skin tumors. Proc Natl Acad Sci. 2011;108:7431–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tang X, Scognamiglio T, Gudas LJ. Basal stem cells contribute to squamous cell carcinomas in the oral cavity. Carcinogenesis. 2013;34(5):1158–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Hashibe M, Brennan P, Chuang SC, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the International Head and Neck Cancer Epidemiology Consortium. Cancer Epidemiol Biomarkers Prev. 2009;18:541–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. National Cancer Institute and Centers for Disease Control and Prevention. Smokeless tobacco and public health: a global perspective. NIH Publication No. 14–7983. Bethesda, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Institutes of Health, National Cancer Institute. 2014.

  47. Hecht SS. Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst. 1999;91:1194–210.

    Article  CAS  PubMed  Google Scholar 

  48. Yu C-C, Chang Y-C. Enhancement of cancer stem-like and epithelial–mesenchymal transdifferentiation property in oral epithelial cells with long-term nicotine exposure: reversal by targeting SNAIL. Toxicol Appl Pharmacol. 2013;226:459–69.

    Article  Google Scholar 

  49. Druesne-Pecollo N, Tehard B, Mallet Y, et al. Alcohol and genetic polymorphisms: effect on risk of alcohol-related cancer. Lancet Oncol. 2009;10:173–80.

    Article  CAS  PubMed  Google Scholar 

  50. Seitz HK, Stickel F. Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism. Genes Nutr. 2010;5:121–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Osei-Sarfo K, Tang XH, Urvalek AM, et al. The molecular features of tongue epithelium treated with the carcinogen 4-nitroquinoline-1-oxide and alcohol as a model for HNSCC. Carcinogenesis. 2013;34(11):2673–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363(1):24–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Fakhry C, Zhang Q, Nguyen-Tan PF, et al. Human papillomavirus and overall survival after progression of oropharyngeal squamous cell carcinoma. Clin Oncol. 2014;32(30):3365–73.

    Article  Google Scholar 

  54. Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C. Epidemiology of human papillomavirus positive head and neck squamous cell carcinoma. J Clin Oncol. 2015;33(29):3235–42. Comprehensive review of the epidemiology of HPV infection.

    Article  PubMed  Google Scholar 

  55. Egawa N, Egawa K, Griffin H, et al. Human papillomaviruses, epithelial tropisms, and the development of neoplasia. Viruses. 2015;2007(7):3863–90.

    Article  Google Scholar 

  56. Hsu YC, Fuchs E. Emerging interactions between skin stem cells and their niches. Nat Med. 2014;20(8):847–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Pullos AN, Castilho RM, Squarize CH. HPV infection of the head and neck region and its stem cells. J Dent Res. 2015;94(11):1532–43. Provides a review of HPV infection and its relevance to head and neck cancer and treatment.

    Article  CAS  PubMed  Google Scholar 

  58. Modur V, Thomas-Robbins K, Rao K. HPV and CSC in HNSCC cisplatin resistance. Front Biosci (Elite Ed). 2015;7:58–66.

    Article  Google Scholar 

  59. Tang AL, Owen JH, Hauff SJ, et al. Head and neck cancer stem cells: the effect of HPV—an in vitro and mouse study. Otolaryngol Head Neck Surg. 2013;149(2):252–60.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Zhang M, Kumar B, Piao L, et al. Elevated intrinsic cancer stem cell population in human papillomavirus-associated head and neck squamous cell carcinoma. Cancer. 2014;120(7):992–1001.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Rietbergen MM, Martens-de Kemp SR, Bloemena E, et al. Cancer stem cell enrichment marker CD98: a prognostic factor for survival in patients with human papillomavirus-positive oropharyngeal cancer. Eur J Cancer. 2014;50(4):765–73.

    Article  CAS  PubMed  Google Scholar 

  62. Zimmermann M, Zouhair A, Azria D, et al. The epidermal growth factor receptor (EGFR) in head and neck cancer: its role and treatment implications. Radiat Oncol. 2006;1:11. Published Online.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Fitzpatrick SG, Katz J. The association between periodontal disease and cancer: a review of the literature. J Dent. 2010;38(2):83–95.

    Article  PubMed  Google Scholar 

  64. Ahn J, Chen CY, Hayes RB. Oral microbiome and oral and gastrointestinal cancer risk. Cancer Causes Control. 2012;23:399–404.

    Article  PubMed  PubMed Central  Google Scholar 

  65. Ha NH, Woo BH, Kim DJ, et al. Prolonged and repetitive exposure to Porphyromonas gingivalis increases aggressiveness of oral cancer cells by promoting acquisition of cancer stem cell properties. Tumor Biol. 2015. doi:10.1007/s13277-015-3764-9. Published on-line first.

    Google Scholar 

  66. Liu W, Wang YF, Zhou HW, et al. Malignant transformation of oral leukoplakia: a retrospective cohort study of 218 Chinese patients. BMC Cancer. 2010;10:685.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Liu W, Wu L, Shen X, et al. Expression patterns of cancer stem cell markers ALDH1 and CD133 correlate with a high risk of malignant transformation of oral leukoplakia. Cancer. 2013;132:868–74.

    CAS  Google Scholar 

  68. Feng JQ, Xu ZY, Shi LJ, et al. Expression of cancer stem cell markers ALDH1 and Bmi1 in oral erythroplakia and the risk of oral cancer. J Oral Pathol Med. 2013;42:148–53.

    Article  CAS  PubMed  Google Scholar 

  69. van der Waal I. Potentially malignant disorders of the oral and oropharyngeal mucosa; present concepts of management. Oral Oncol. 2010;46:423–5.

    Article  PubMed  Google Scholar 

  70. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer. 1953;6:963–8.

    Article  CAS  PubMed  Google Scholar 

  71. Simple M, Suresh A, Das D, et al. Cancer stem cells and field cancerization of oral squamous cell carcinoma. Oral Oncol. 2015;51:643–51.

    Article  CAS  PubMed  Google Scholar 

  72. Bourguignon LY, Wong G, Earle C, et al. 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. J Biol Chem. 2012;287(39):32800–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Damek-Poprawa M, Volgina A, Korostoff J, et al. Targeted inhibition of CD133+ cells in oral cancer cell lines. J Dent Res. 2011;90(5):638–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Waldron NN, Kaufman DS, Oh S, et al. Targeting tumor-initiating cancer cells with dCD133KDEL shows impressive tumor reductions in a xenotransplant model of human head and neck cancer. Mol Cancer Ther. 2011;10(10):1829–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Murillo-Sauca O, Chung MK, Shin JH, et al. CD271 is a functional and targetable marker of tumor-initiating cells in head and neck squamous cell carcinoma. Oncotarget. 2014;5(16):6854–66.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Li Q, Lu L, Tao H, et al. Generation of a novel dendritic-cell vaccine using melanoma and squamous cancer stem cells. J Vis Exp. 2014;83:e50561.

    PubMed  Google Scholar 

  77. Ning N, Pan Q, Zheng F, et al. Cancer stem cell vaccination confers significant antitumor immunity. Cancer Res. 2012;72(7):1853–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Kuo SZ, Blair KJ, Rahimy E, et al. Salinomycin induces cell death and differentiation in head and neck squamous cell carcinoma stem cells despite activation of epithelial-mesenchymal transition and Akt. BMC Cancer. 2012;12:556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chiu CC, Lee LY, Li YC, et al. Grp78 as a therapeutic target for refractory head-neck cancer with CD24(−)CD44(+) stemness phenotype. Cancer Gene Ther. 2013;20(11):606–15.

    Article  CAS  PubMed  Google Scholar 

  80. Bertrand G, Maalouf M, Boivin 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 

  81. Gan GN, Eagles J, Keysar SB. Hedgehog signaling drives radioresistance and stroma-driven tumor repopulation in head and neck squamous cancers. Cancer Res. 2014;74(23):7024–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Ma L, Zhang G, Miao XB, et al. Cancer stem-like cell properties are regulated by EGFR/AKT/B-catenin signaling and preferentially inhibited by gefitinib in nasopharyngeal carcinoma. FEBS J. 2013;280(9):2027–41. 79.

    Article  CAS  PubMed  Google Scholar 

  83. Dragu DL, Necula LG, Bleotu C, et al. Therapies targeting cancer stem cells: current trends and future challenges. World J Stem Cells. 2015;7(9):1185–201. Thoughtful and well written summary of novel treatments targeting cancer stem cells.

    PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Otolaryngology-HNS, University of Michigan, 1500 East Medical Center Drive, 1904 Taubman Center, Ann Arbor, MI, 48108, USA

    Victoria M. Prince, Silvana Papagerakis & Mark E. Prince

Authors
  1. Victoria M. Prince
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvana Papagerakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mark E. Prince
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mark E. Prince.

Ethics declarations

Conflict of Interest

Victoria M Prince, Silvana Papagerakis, and Mark E Prince declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Oral Neoplasia

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Prince, V.M., Papagerakis, S. & Prince, M.E. Oral Cancer and Cancer Stem Cells: Relevance to Oral Cancer Risk Factors, Premalignant Lesions, and Treatment. Curr Oral Health Rep 3, 65–73 (2016). https://doi.org/10.1007/s40496-016-0081-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40496-016-0081-3

Keywords

Search

Navigation