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Head and Neck Pathology

, Volume 13, Issue 4, pp 535–542 | Cite as

Immunolocalization of Cancer Stem Cells Marker ALDH1 and its Association with Tumor Budding in Oral Squamous Cell Carcinoma

  • Helvécio Marangon Junior
  • Victória Vasconcellos Moreira Melo
  • Ângela Braga Caixeta
  • Giovanna Ribeiro Souto
  • Paulo Eduardo Alencar Souza
  • Maria Cássia Ferreira de Aguiar
  • Martinho Campolina Rebello HortaEmail author
Original Paper

Abstract

Tumor budding is a prognostic marker for oral squamous cell carcinoma (OSCC) characterized by the presence of isolated or small clusters of neoplastic cells at the tumor invasive front. Aldehyde dehydrogenase-1 (ALDH1) is associated with tumorigenesis, linked to treatment resistance and shown to identify cancer stem cells (CSC)-like cells. This study aimed to evaluate the expression of ALDH1 and its association with tumor budding in OSCC. Immunohistochemistry was employed in 163 OSCC samples to identify pancytokeratin (AE1/AE3) and ALDH1. While pancytokeratin (AE1/AE3) identified squamous tumor buds, the CSC-like cells were identified using ALDH1. A Chi square test was used to evaluate association between ALDH1 expression and tumor budding, while McNemar’s test was used to identify differences in ALDH1 expression between the budding area and the area outside the budding. A positive expression of ALDH1 was observed in 47.24% of the samples and in 70% of anatomic locations affected. No association was observed between ALDH1 expression and tumor budding (p > 0.05). In tumors with high-intensity tumor budding, ALDH1 expression was higher in the budding area than in the area outside the budding (p < 0.05). The finding that tumor bud cells in OSCC show phenotypic characteristics of CSC-like cells reinforces the relevance of tumor budding in determining the biological behavior of this malignant neoplasm. Moreover, the presence of CSC-like cells in nearly half of evaluated samples of OSCC and in most of the affected anatomic locations is in accordance with the CSC model of oral carcinogenesis.

Keywords

Oral cancer Squamous cell carcinoma Cancer stem cells Aldehyde dehydrogenase-1 Tumor budding 

Notes

Acknowledgements

This study was supported by Grants from Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG CDS-APQ-01806/14 and FAPEMIG CDS-PPM-00653-16). The authors are grateful to Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). MCRH is a research fellow of FAPEMIG (CDS-PPM-00653-16); MCFA is a research fellow of CNPq; HMJ had a CAPES fellowship for this study; and VVMM and ABC had PROBIC-FAPEMIG fellowships (PROBIC 10499/2016). The authors also wish to thank the invaluable technical assistance provided by Mrs. Maria Reni Gonçalves Moitinha and Ms. Andreia Alves Cardoso.

References

  1. 1.
    El-Naggar AK, Chan JKC, Grandis JR, Takata T, Slootweg PJ. WHO Classification of Head and Neck Tumours. 4th ed. Lyon: IARC Press; 2017.Google Scholar
  2. 2.
    Kademani D, Bell RB, Bagheri S, Holmgren E, Dierks E, Potter B, Homer L. Prognostic factors in intraoral squamous cell carcinoma: the influence of histologic grade. J Oral Maxillofac Surg. 2005;63:1599–605.CrossRefGoogle Scholar
  3. 3.
    Layland MK, Sessions DG, Lenox J. The influence of lymph node metastasis in the treatment of squamous cell carcinoma of the oral cavity, oropharynx, larynx, and hypopharynx: N0 versus N+. Laryngoscope. 2005;115:629–39.CrossRefGoogle Scholar
  4. 4.
    Tsai MS, Chen WC, Lai CH, Chen YY, Chen MF. Epigenetic therapy regulates the expression of ALDH1 and immunologic response: relevance to the prognosis of oral cancer. Oral Oncol. 2017;73:88–96.  https://doi.org/10.1016/j.oraloncology.2017.08.007.CrossRefPubMedGoogle Scholar
  5. 5.
    Mannelli G, Gallo O. Cancer stem cells hypothesis and stem cells in head and neck cancers. Cancer Treat Rev. 2012;38:515–39.  https://doi.org/10.1016/j.ctrv.2011.11.007.CrossRefPubMedGoogle Scholar
  6. 6.
    Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005;5:744–9.CrossRefGoogle Scholar
  7. 7.
    Clay MR, Tabor M, Owen JH, Carey TE, Bradford CR, Wolf GT, Wicha MS, Prince ME. Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck. 2010;32:1195–201.  https://doi.org/10.1002/hed.21315.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Duester G. Retinoic acid synthesis and signaling during early organogenesis. Cell. 2008;134:921–31.  https://doi.org/10.1016/j.cell.2008.09.002.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Wang LM, Kevans D, Mulcahy H, O’Sullivan J, Fennelly D, Hyland J, O’Donoghue D, Sheahan K. Tumor Budding is a Strong and Reproducible Prognostic Marker in T3N0 Colorectal Cancer. Am J Surg Pathol. 2009;33:134–41.  https://doi.org/10.1097/PAS.0b013e318184cd55.CrossRefPubMedGoogle Scholar
  10. 10.
    Wang C, Huang H, Huang Z, Wang A, Chen X, Huang L, Zhou X, Liu X. Tumor budding correlates with poor prognosis and epithelial-mesenchymal transition in tongue squamous cell carcinoma. J Oral Pathol Med. 2011;40:545–51.  https://doi.org/10.1111/j.1600-0714.2011.01041.x.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Almangush A, Pirinen M, Heikkinen I, Mäkitie AA, Salo T, Leivo I. Tumour budding in oral squamous cell carcinoma: a meta-analysis. Br J Cancer. 2018;118:577–86.  https://doi.org/10.1038/bjc.2017.425.CrossRefPubMedGoogle Scholar
  12. 12.
    Sim J, Wright CC. The kappa statistic in reliability studies: use, interpretation, and sample size requirements. Phys Ther. 2005;85:257–68.PubMedGoogle Scholar
  13. 13.
    Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics. 1977;33:159–74.CrossRefGoogle Scholar
  14. 14.
    Hildebrand LC, Carvalho AL, Lauxen IS, Nör JE, Cerski CT, Sant’Ana Filho M. Spatial distribution of cancer stem cells in head and neck squamous cell carcinomas. J Oral Pathol Med. 2014;43:499–506.  https://doi.org/10.1111/jop.12169.CrossRefPubMedGoogle Scholar
  15. 15.
    Yu Z, Pestell TG, Lisanti MP, Pestell RG. Cancer stem cells. Int J Biochem Cell Biol. 2012;44:2144–51.  https://doi.org/10.1016/j.biocel.2012.08.022.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Frank NY, Schatton T, Frank MH. The therapeutic promise of the cancer stem cell concept. J Clin Invest. 2010;120:41–50.  https://doi.org/10.1172/JCI41004.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Baillie R, Tan ST, Itinteang T. Cancer Stem cells in oral cavity squamous cell carcinoma: a review. Front Oncol. 2017;7:112.  https://doi.org/10.3389/fonc.2017.00112.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Qian X, Wagner S, Ma C, Coordes A, Gekeler J, Klussmann JP, Hummel M, Kaufmann AM, Albers AE. Prognostic significance of ALDH1A1-positive cancer stem cells in patients with locally advanced, metastasized head and neck squamous cell carcinoma. J Cancer Res Clin Oncol. 2014;140:1151–8.  https://doi.org/10.1007/s00432-014-1685-4.CrossRefPubMedGoogle Scholar
  19. 19.
    Xu J, Müller S, Nannapaneni S, Pan L, Wang Y, Peng X, Wang D, Tighiouart M, Chen Z, Saba NF, Beitler JJ, Shin DM, Chen ZG. Comparison of quantum dot technology with conventional immunohistochemistry in examining aldehyde dehydrogenase 1A1 as a potential biomarker for lymph node metastasis of head and neck cancer. Eur J Cancer. 2012;48:1682–91.  https://doi.org/10.1016/j.ejca.2011.12.029.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Luo WR, Gao F, Li SY, Yao KT. Tumour budding and the expression of cancer stem cell marker aldehyde dehydrogenase 1 in nasopharyngeal carcinoma. Histopathology. 2012;61:1072–81.  https://doi.org/10.1111/j.1365-2559.2012.04350.x.CrossRefPubMedGoogle Scholar
  21. 21.
    Attramadal CG, Kumar S, Boysen ME, Dhakal HP, Nesland JM, Bryne M. Tumor budding, EMT and cancer stem cells in T1-2/N0 oral squamous cell carcinomas. Anticancer Res. 2015;35:6111–20.PubMedGoogle Scholar
  22. 22.
    Michifuri Y, Hirohashi Y, Torigoe T, Miyazaki A, Kobayashi J, Sasaki T, Fujino J, Asanuma H, Tamura Y, Nakamori K, Hasegawa T, Hiratsuka H, Sato N. High expression of ALDH1 and SOX2 diffuse staining pattern of oral squamous cell carcinomas correlates to lymph node metastasis. Pathol Int. 2012;62:684–9.  https://doi.org/10.1111/j.1440-1827.2012.02851.x.CrossRefPubMedGoogle Scholar
  23. 23.
    Chen YC, Chen YW, Hsu HS, Tseng LM, Huang PI, Lu KH, Chen DT, Tai LK, Yung MC, Chang SC, Ku HH, Chiou SH, Lo WL. Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem Biophys Res Commun. 2009;385:307–13.  https://doi.org/10.1016/j.bbrc.2009.05.048.CrossRefPubMedGoogle Scholar
  24. 24.
    Marangon Junior H, Leão PLR, Melo VVM, Caixeta ÂB, Souza PEA, de Aguiar MCF, Horta MCR. Cell proliferation is associated with intensity of tumor budding in oral squamous cell carcinoma. J Oral Pathol Med. 2018;47:128–35.  https://doi.org/10.1111/jop.12653.CrossRefPubMedGoogle Scholar
  25. 25.
    Almangush A, Bello IO, Keski-Säntti H, Mäkinen LK, Kauppila JH, Pukkila M, Hagström J, Laranne J, Tommola S, Nieminen O, Soini Y, Kosma VM, Koivunen P, Grénman R, Leivo I, Salo T. Depth of invasion, tumor budding, and worst pattern of invasion: prognostic indicators in early-stage oral tongue cancer. Head Neck. 2014;36:811–8.  https://doi.org/10.1002/hed.23380.CrossRefPubMedGoogle Scholar
  26. 26.
    Seki M, Sano T, Yokoo S, Oyama T. Histologic assessment of tumor budding in preoperative biopsies to predict nodal metastasis in squamous cell carcinoma of the tongue and floor of the mouth. Head Neck. 2016;38:E1582–90.  https://doi.org/10.1002/hed.24282.CrossRefPubMedGoogle Scholar
  27. 27.
    de Araújo RF Jr, Barboza CA, Clebis NK, de Moura SA, Lopes Costa Ade L. Prognostic significance of the anatomical location and TNM clinical classification in oral squamous cell carcinoma. Med Oral Patol Oral Cir Bucal. 2008;13:E344–7.PubMedGoogle Scholar
  28. 28.
    Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H, Fields JZ, Wicha MS, Boman BM. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cell (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 2009;69:3382–9.  https://doi.org/10.1158/0008-5472.CAN-08-4418.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Liang D, Shi Y. Aldehyde dehydrogenase-1 is a specific marker for stem cells in human lung adenocarcinoma. Med Oncol. 2012;29:633–9.  https://doi.org/10.1007/s12032-011-9933-9.CrossRefPubMedGoogle Scholar
  30. 30.
    Shackleton M, Quintana E, Fearon ER, Morrison SJ. Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell. 2009;138:822–9.  https://doi.org/10.1016/j.cell.2009.08.017.CrossRefPubMedGoogle Scholar
  31. 31.
    Routray S, Mohanty N. Cancer stem cells accountability in progression of head and neck squamous cell carcinoma: the most recent trends! Mol Biol Int. 2014;2014:375325.  https://doi.org/10.1155/2014/375325.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    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.  https://doi.org/10.1016/j.oraloncology.2013.04.002.CrossRefPubMedGoogle Scholar
  33. 33.
    Rodini CO, Lopes NM, Lara VS, Mackenzie IC. Oral cancer stem cells - properties and consequences. J Appl Oral Sci. 2017;25:708–15.  https://doi.org/10.1590/1678-7757-2016-0665.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Marcato P, Dean CA, Giacomantonio CA, Lee PW. Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle. 2011;10:1378–84.CrossRefGoogle Scholar
  35. 35.
    Deng S, Yang X, Lassus H, Liang S, Kaur S, Ye Q, Li C, Wang LP, Roby KF, Orsulic S, Connolly DC, Zhang Y, Montone K, Bützow R, Coukos G, Zhang L. Distinct expression levels and patterns of stem cell marker, aldehyde dehydrogenase isoform 1 (ALDH1), in human epithelial cancers. PLoS One. 2010;5:e10277.  https://doi.org/10.1371/journal.pone.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Almangush A, Leivo I, Siponen M, Sundquist E, Mroueh R, Mäkitie AA, Soini Y, Haglund C, Nieminen P, Salo T. Evaluation of the budding and depth of invasion (BD) model in oral tongue cancer biopsies. Virchows Arch. 2018;472:231–6.  https://doi.org/10.1007/s00428-017-2212-1.CrossRefPubMedGoogle Scholar
  37. 37.
    Marangon Junior H, Rocha VN, Leite CF, de Aguiar MC, Souza PE, Horta MC. Laminin-5 gamma 2 chain expression is associated with intensity of tumor budding and density of stromal myofibroblasts in oral squamous cell carcinoma. J Oral Pathol Med. 2013;43:199–204.  https://doi.org/10.1111/jop.12121.CrossRefPubMedGoogle Scholar
  38. 38.
    Leão PLR, Marangon Junior H, Melo VVM, Caixeta ÂB, Souza PEA, de Aguiar MCF, Horta MCR. Reproducibility, repeatability, and level of difficulty of two methods for tumor budding evaluation in oral squamous cell carcinoma. J Oral Pathol Med. 2017;46:949–55.  https://doi.org/10.1111/jop.12578.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Helvécio Marangon Junior
    • 1
    • 2
  • Victória Vasconcellos Moreira Melo
    • 1
  • Ângela Braga Caixeta
    • 1
  • Giovanna Ribeiro Souto
    • 1
  • Paulo Eduardo Alencar Souza
    • 1
  • Maria Cássia Ferreira de Aguiar
    • 3
  • Martinho Campolina Rebello Horta
    • 1
    • 4
    Email author
  1. 1.Oral Pathology Section, School of DentistryPontifical Catholic University of Minas Gerais (PUC Minas)Belo HorizonteBrazil
  2. 2.Centro Universitário de Patos de Minas (UNIPAM)Patos de MinasBrazil
  3. 3.Department of Oral Diagnosis and Pathology, School of DentistryFederal University of Minas Gerais (UFMG)Belo HorizonteBrazil
  4. 4.Departamento de OdontologiaPontifícia Universidade Católica de Minas GeraisBelo HorizonteBrazil

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