ISSN: 2161-0681
Journal of Clinical & Experimental Pathology
Make the best use of Scientific Research and information from our 700+ peer reviewed, Open Access Journals that operates with the help of 50,000+ Editorial Board Members and esteemed reviewers and 1000+ Scientific associations in Medical, Clinical, Pharmaceutical, Engineering, Technology and Management Fields.
  • Review Article   
  • J Clin Exp Pathol 2014, Vol 4(3): 175
  • DOI: 10.4172/2161-0681.1000175

The Prognostic Influence of CD44 in Oral Squamous Cell Carcinoma

Lucinei Roberto Oliveira1*, Andrielle Castilho-Fernandes2 and Alfredo Ribeiro-Silva3
1Department of Pathology, Vale do Rio Verde University (UninCor), Tres Coraçoes-MG, Brazil
2Departamento de Química, Centro de Nanotecnologia e Engenharia de Tecidos, Universidade de São Paulo, Brazil
3Department of Pathology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto-SP, Brazil
*Corresponding Author: Lucinei Roberto Oliveira, Vale do Rio Verde University (UninCor), Avenida Castelo Branco 82, Tres Coraçoes, Minas Gerais, Brazil, Tel: 55 35 3239 1280, Fax: 55 35 3239 1280, Email: lucinei@yahoo.com

Received: 23-Apr-2014 / Accepted Date: 24-May-2014 / Published Date: 27-May-2014 DOI: 10.4172/2161-0681.1000175

Abstract

Oral Squamous Cell Carcinoma (OSCC) is the most frequent malignant tumor of the oral cavity, exhibiting a heterogeneous behavior. Because the mortality rate for this tumor has essentially remained unchanged over the last few decades, the need exists for more reliable prognostic factors in OSCC. The objective of this review was to examine the relevance of CD44 expression on the prognosis of OSCC patients through a critical analysis of the most significant current scientific literature on this subject. We found that most investigations of CD44 expression in OSCC over the years have demonstrated some prognostic influence, although there were significant differences among the studies. Certain studies have also demonstrated that CD44 may be an important biomarker of Cancer Stem Cells (CSCs) in OSCC. However, as with the discrepancies regarding the true prognostic value of CD44 in OSCC, some studies have indicated that CD44 might be limited in the identification of oral CSCs. Thus, according to our findings, additional and more standardized research should be conducted to validate the CD44 molecule as a reliable biomarker of prognosis and of CSCs in OSCC.

Keywords: Oral cancer; CD44; Cancer stem cells; Prognosis

314201

Introduction

Oral Squamous Cell Carcinoma (OSCC) is the most frequent malignant tumor of the oral cavity with a mortality rate that has essentially remained unchanged over the last few decades. For this reason, the discovery of more reliable prognostic biomarkers to guide therapeutic planning in OSCC has garnered considerable interest [1,2].

The transmembrane glycoproteins of the CD44 family are the major human cell surface receptors for hyaluronate, which also bind extracellular matrix proteins and certain growth factors, and act in a diverse range of physiological and pathological processes such as cellular adhesion, migration, angiogenesis, certain lymphocyte functions, and in the dissemination of malignant cells [3-7].

The CD44 gene is unique for all the various isoforms of the protein, and includes at least 19 exons. Exons 1-5 and 16-19 are spliced together to form a transcript known as CD44s isoform, whereas exons 6-15 are variable, generating several isoforms of the CD44 molecule [8]. Thus, the CD44 family consists of a standard form of CD44 (CD44s) and an alternative splice variant (CD44v). The association of the CD44 family with metastasis formation and prognosis in several tumors has been controversial, particularly in oral cancer, and remains inconclusive [3,7].

Recent studies have demonstrated that malignant neoplasms are organized as hierarchical tissues containing differentiated cells with a small subpopulation of proliferating and undifferentiated cells, the so-called cancer stem cells (CSCs) [9]. The CSC theory postulates that only a specific subset of cancer cells within a tumor exhibits stem cell characteristics (e.g., the ability to self-renew and to proliferate extensively), which can sustain growth and promote the recurrence and metastasis of malignant neoplasms [10,11]. In head and neck squamous cell carcinomas (HNSCCs), the CSCs have been previously observed to occur in low percentages, and it has been demonstrated that they can be characterized according to CD44 expression levels [10,12].

Due to conflicting results that have been recently published regarding the influence of CD44 expression on OSCC prognosis, the purpose of the present manuscript was to review the relevance of CD44 expression on prognosis in OSCC patients through a critical analysis of the most significant current scientific literature on this topic.

314202

CD44 Does Not Significantly Influence OSCC Prognosis

The CD44 proteins are commonly found in epithelial tissues and were previously established to be important regulatory factors in normal squamous epithelium for processes such as cellular adhesion and cell–cell interaction [13]. Although this protein has been previously associated with infiltration and metastatic dissemination when expressed in neoplastic squamous epithelium [14-16]. Controversial results have been reported with numerous investigations that demonstrate conflicting findings for OSCC [17-21]. According to Bloor et al. [17] and Mascolo et al. [20], is appears unlikely that CD44 expression has value as a prognostic marker in OSCC.

These findings underscore the fact that certain studies have indicated that CD44 does not influence OSCC prognosis and that these discrepant results in this field require additional clarification and research with improved standardization of the methods used among the studies.

314203

CD44 Significantly Influences OSCC Prognosis

Over the years, most studies of CD44 expression in OSCC have demonstrated some prognostic influence [2,22-24]. Interestingly, earlier investigations found that the reduced expression of CD44 was a significant predictor of poor prognosis in most OSCC studies [22,23,25,26]. On the other hand, current studies on this subject have indicated a poor prognosis in OSCC associated with strong CD44 expression [2,19,27,28].

This variability of results may be a consequence of the lack of standardization in research on this topic, particularly in relation to the anatomical region [2,3]. According to Kokko et al. [19], significant differences exist regarding the results of CD44 expression and its prognostic influence according to the anatomical location in the head and neck region. Yet, several investigators have grouped certain HNSCCs together with the oral tumors, as well as those of the oropharynx and larynx, which have a different prognosis [6,29,30].

Because the CD44 family consists of a standard form of CD44 (CD44s) and its alternative splice variants (CD44v) [3], it is currently becoming evident that discrepancies in the OSCC ability for recurrence, loco regional or distant metastasis, as well as in the radioresistance of its malignant cells, may be mainly due to the overexpression of a specific CD44 isoform [31].

The low expression of CD44s on tumor cells was significantly correlated with poor prognosis in tongue carcinomas [32], whereas the absence of CD44v expression was associated with a shorter survival time in lip OSSC [26]. On the other hand, Bankfalvi et al. [33] found that the increased immunoexpression of the CD44v9 alternative splice isoform along with a loss of CD44s, v4, and v7 was significantly associated with a poorer clinical outcome in OSCC. In some other cases, the overexpression of CD44v (v3 and v6) appears to reflect the cellular invasiveness and leads to the increased aggressiveness of some HNSCCs, as well as that of OSCCs [34], given that these different isoforms are also associated with lymph node metastasis and chemoresistance [35]. Moreover, an increased expression of CD44 standard and variant isoforms was also confirmed in most oral dysplasias, which also exhibited a selective accumulation of CD44s, v3, v4 and v9 in OSCC at the invasive tumor front [33,36].

314204

CD44 as a Cancer Stem Cell Marker in Head and Neck Cancer

Notably, some studies have demonstrated that CD44 may be an important biomarker of a cellular subpopulation of CSCs in head and neck cancer [10,12,31]. The first evidence that the malignant cells of head and neck carcinomas have a hierarchy of development and contain a subpopulation of cells with self-renewal and differentiation capacities was reported by Prince et al. [10], who also associated the CD44 expression with the CSC immunophenotype. Accordingly, significant resistance to apoptosis has been demonstrated for the CD44-positive cells in HNSCC [37,38] and additional studies have observed an association of CD44 overexpression with certain other putative CSC biomarkers such as CD24 and CD133, which also demonstrate significant prognostic influences in OSCC [2,6].

As with the discrepancies regarding the true prognostic value of CD44 in OSCC, a recent study has indicated that CD44 may be a limited biomarker of oral CSCs in the determination of the CSC immunophenotype [39], whereas other studies have demonstrated that the CD44-negative cells in HNSCC also have stem cell-like traits [40]. Accordingly, Clay et al. [18] also recently suggested that it was unlikely that CD44-positive cells were a pure population of CSCs, highlighting the need to combine such studies with other CSC markers.

As previously discussed, it is well established that CD44, the product of a single gene, exists as several isoforms generated by alternative exon splicing and posttranslational modifications, and that one or more of the CD44 splice-variant isoforms can be differentially expressed in some tumors and may also affect the CSCs identification [41].

314205

Final Considerations

The precise understanding of CD44 regulation mechanisms in OSCC is essential to furthering research on cancer progression and invasiveness, as well as to the acquisition of additional knowledge on tumor prognosis. However, no consensus has still emerged on this subject and the conflicting results reported regarding CD44 immunoexpression in OSCC prognosis and CSC identification can be attributed to factors such as different selection criteria of OSCC patients and variation of different alternative isoforms of CD44 with limited commercially available antibodies directed against them, as well as to the contrasting technical methods used for evaluation, as in the different antibodies and cutoff values selected [2,3,16,28]. To overcome these shortcomings, a novel anti-CD44 monoclonal antibody must be needed, or setting the primer for CD44 to detect wide range of splice variants. Thus, most current investigations regarding the CD44 association with the CSC immunophenotype have demonstrated that additional and better-standardized studies are required to elucidate these hypotheses.

314208

Conclusion

The literature still contains widespread discrepant findings regarding the prognostic influence of CD44 expression in relation to OSCC. Additionally, investigators continue to seek reliable biological evidence of the CD44 molecule as a CSC biomarker in OSCC. Thus, standardized additional studies are needed to validate the CD44 molecule as a reliable biomarker of prognosis and of CSCs in OSCC.

314211

References

  1. Carinci F, Lo Muzio L, Piattelli A, Rubini C, Chiesa F, et al. (2005) Potential markers of tongue tumor progression selected by cDNA microarray. Int J Immunopathol Pharmacol 18: 513-524.
  2. Oliveira LR, Oliveira-Costa JP, Araujo IM, Soave DF, Zanetti JS, et al. (2011) Cancer stem cell immunophenotypes in oral squamous cell carcinoma. J Oral Pathol Med 40: 135-142.
  3. Oliveira LR, Ribeiro-Silva A (2011) Prognostic significance of immunohistochemical biomarkers in oral squamous cell carcinoma. Int J Oral Maxillofac Surg 40: 298-307.
  4. Naor D1, Wallach-Dayan SB, Zahalka MA, Sionov RV (2008) Involvement of CD44, a molecule with a thousand faces, in cancer dissemination. Semin Cancer Biol 18: 260-267.
  5. Richard V, Pillai MR (2010) The stem cell code in oral epithelial tumorigenesis: 'the cancer stem cell shift hypothesis'. Biochim Biophys Acta 1806: 146-162.
  6. Oliveira LR, Castilho-Fernandes A, Oliveira-Costa JP, Soares FA, Zucoloto S, et al. (2013) CD44+/CD133+ immunophenotype and matrix metalloproteinase-9: Influence on prognosis in early-stage oral squamous cell carcinoma. Head Neck .
  7. Biddle A, Gammon L, Fazil B, Mackenzie IC (2013) CD44 staining of cancer stem-like cells is influenced by down-regulation of CD44 variant isoforms and up-regulation of the standard CD44 isoform in the population of cells that have undergone epithelial-to-mesenchymal transition. PLoS One 8: e57314.
  8. van Weering DH, Baas PD, Bos JL (1993) A PCR-based method for the analysis of human CD44 splice products. PCR Methods Appl 3: 100-106.
  9. Lobo NA, Shimono Y, Qian D, Clarke MF (2007) The biology of cancer stem cells. Annu Rev Cell Dev Biol 23: 675-699.
  10. Prince ME, Sivanandan R, Kaczorowski A, Wolf GT, Kaplan MJ, 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 U S A 104: 973-978.
  11. Graziano A, d'Aquino R, Tirino V, Desiderio V, Rossi A, et al. (2008) The stem cell hypothesis in head and neck cancer. J Cell Biochem 103: 408-412.
  12. Harper LJ, Piper K, Common J, Fortune F, Mackenzie IC (2007) Stem cell patterns in cell lines derived from head and neck squamous cell carcinoma. J Oral Pathol Med 36: 594-603.
  13. Bajorath J (2000) Molecular organization, structural features, and ligand binding characteristics of CD44, a highly variable cell surface glycoprotein with multiple functions. Proteins 39: 103-11.
  14. Seiter S, Arch R, Reber S, Komitowski D, Hofmann M, et al. (1993) Prevention of tumor metastasis formation by anti-variant CD44. J Exp Med 177: 443-455.
  15. Rudzki Z, Jothy S (1997) CD44 and the adhesion of neoplastic cells. Mol Pathol 50: 57-71.
  16. Wang SJ, Wreesmann VB, Bourguignon LY (2007) Association of CD44 V3-containing isoforms with tumor cell growth, migration, matrix metalloproteinase expression, and lymph node metastasis in head and neck cancer. Head Neck 29: 550-558.
  17. Bloor BK, Rajarajan A, Jaafary-Haghighat K, Odell EW (2002) Transcription and expression of CD44 variant exons by oro-pharyngeal squamous cell carcinomas. Int J Oncol 21: 907-913.
  18. Clay MR, Tabor M, Owen JH, Carey TE, Bradford CR, et al. (2010) Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck 32: 1195-1201.
  19. Kokko LL, Hurme S, Maula SM, Alanen K, Grénman R, et al. (2011) Significance of site-specific prognosis of cancer stem cell marker CD44 in head and neck squamous-cell carcinoma. Oral Oncol 47: 510-516.
  20. Mascolo M, Ilardi G, Romano MF, Celetti A, Siano M, et al. (2012) Overexpression of chromatin assembly factor-1 p60, poly(ADP-ribose) polymerase 1 and nestin predicts metastasizing behaviour of oral cancer. Histopathology 61: 1089-1105.
  21. Rajarajan A, Stokes A, Bloor BK, Ceder R, Desai H, et al. (2012) CD44 expression in oro-pharyngeal carcinoma tissues and cell lines. PLoS One 7: e28776.
  22. Sato S, Miyauchi M, Takekoshi T, Zhao M, Kudo Y, et al. (2000) Reduced expression of CD44 variant 9 is related to lymph node metastasis and poor survival in squamous cell carcinoma of tongue. Oral Oncol 36: 545-549.
  23. Carinci F, Stabellini G, Calvitti M, Pelucchi S, Targa L, et al. (2002) CD44 as prognostic factor in oral and oropharyngeal squamous cell carcinoma. J Craniofac Surg 13: 85-89.
  24. Kosunen A, Pirinen R, Ropponen K, Pukkila M, Kellokoski J, et al. (2007) CD44 expression and its relationship with MMP-9, clinicopathological factors and survival in oral squamous cell carcinoma. Oral Oncol 43: 51-59.
  25. Masuda M, Kuratomi Y, Shiratsuchi H, Nakashima T, Naonobu K, et al. (2000) Decreased CD44H expression in early-stage tongue carcinoma associates with late nodal metastases following interstitial brachytherapy. Head Neck 22: 662-665.
  26. García-Montesinos-Perea B, Val-Bernal JF, Saiz-Bustillo R (2005) Epidermoid carcinoma of the lip: an immunohistochemical study. Med Oral Patol Oral Cir Bucal 10: 454-461.
  27. Joshua B, Kaplan MJ, Doweck I, Pai R, Weissman IL, et al. (2012) Frequency of cells expressing CD44, a head and neck cancer stem cell marker: correlation with tumor aggressiveness. Head Neck 34: 42-49.
  28. Lindquist D, Ahrlund-Richter A, Tarján M, Tot T, Dalianis T (2012) Intense CD44 expression is a negative prognostic factor in tonsillar and base of tongue cancer. Anticancer Res 32: 153-161.
  29. Oliver AJ, Helfrick JF, Gard D (1996) Discussion. Primary oral squamous cell carcinoma: a review of 92 cases. J Oral Maxillofac Surg 54: 949-954.
  30. Chai L, Liu H, Zhang Z, Wang F, Wang Q, et al. (2014) CD44 expression is predictive of poor prognosis in pharyngolaryngeal cancer: systematic review and meta-analysis. Tohoku J Exp Med 232: 9-19.
  31. Trapasso S, Allegra E (2012) Role of CD44 as a marker of cancer stem cells in head and neck cancer. Biologics 6: 379-383.
  32. González-Moles MA, Gil-Montoya JA, Ruiz-Avila I, Esteban F, Delgado-Rodriguez M, et al. (2007) Prognostic significance of p21WAF1/CIP1, p16INK4a and CD44s in tongue cancer. Oncol Rep 18: 389-396.
  33. Bánkfalvi A, Krassort M, Buchwalow IB, Végh A, Felszeghy E, et al. (2002) Gains and losses of adhesion molecules (CD44, E-cadherin, and beta-catenin) during oral carcinogenesis and tumour progression. J Pathol 198: 343-351.
  34. Kunishi M, Kayada Y, Yoshiga K (1997) Down-regulated expression of CD44 variant 6 in oral squamous cell carcinomas and its relationship to regional lymph node metastasis. Int J Oral Maxillofac Surg 26: 280-283.
  35. Bourguignon LY, Earle C, Wong G, Spevak CC, Krueger K (2012) Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene 31: 149-160.
  36. Sterz CM, Kulle C, Dakic B, Makarova G, Böttcher MC, et al. (2010) A basal-cell-like compartment in head and neck squamous cell carcinomas represents the invasive front of the tumor and is expressing MMP-9. Oral Oncol 46: 116-122.
  37. Okamoto A, Chikamatsu K, Sakakura K, Hatsushika K, Takahashi G, et al. (2009) Expansion and characterization of cancer stem-like cells in squamous cell carcinoma of the head and neck. Oral Oncol 45: 633-639.
  38. Chikamatsu K, Ishii H, Takahashi G, Okamoto A, Moriyama M, et al. (2012) Resistance to apoptosis-inducing stimuli in CD44+ head and neck squamous cell carcinoma cells. Head Neck 34: 336-343.
  39. Simionescu C, Margaritescu C, Surpateanu M, Mogoanta L, Zavoi R, et al. (2008) The study of E-cadherine and CD44 immunoexpression in oral squamous cell carcinoma. Rom J Morphol Embryol 49: 189-193.
  40. Oh SY, Kang HJ, Kim YS, Kim H, Lim YC (2013) CD44-negative cells in head and neck squamous carcinoma also have stem-cell like traits. Eur J Cancer 49: 272-280.
  41. Groma V, Kazanceva A, Nora-Krukle Z, Murovska M (2012) Oropharyngeal malignant epithelial cell, lymphocyte and macrophage CD44 surface receptors for hyaluronate are expressed in sustained EBV infection: immunohistochemical data and EBV DNA tissue indices. Pathol Res Pract 208: 518-526.

Citation: Oliveira LR, Castilho-Fernandes A, Ribeiro-Silva A (2014) The Prognostic Influence of CD44 in Oral Squamous Cell Carcinoma. J Clin Exp Pathol 4:175. DOI: 10.4172/2161-0681.1000175

Copyright: © 2014 Oliveira LR, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Top