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Ephrin Receptor (Eph) -A1, -A2, -A4 and -A7 Expression in Mobile Tongue Squamous Cell Carcinoma: Associations with Clinicopathological Parameters and Patients Survival

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Pathology & Oncology Research

Abstract

Ephrin receptors (Ephs) are frequently overexpressed in a wide variety of human malignant tumors, being associated with tumor growth, invasion, metastasis and angiogenesis. The present study aimed to evaluate the clinical significance of Eph-A1, -A2, -A4 and -A7 protein expression in mobile tongue squamous cell carcinoma (SCC). Eph-A1, -A2, -A4 and -A7 protein expression was assessed immunohistochemically on 37 mobile tongue SCC tissue samples and was analyzed in relation with clinicopathological characteristics, overall and disease-free patients’ survival. All the examined mobile tongue SCC cases were found positive for Eph-A1, -A2, -A4 and -A7. Significant associations were noted between high Eph-A1, -A4 and -A7 expression and absence of lymph node metastases (p = 0.0263, p = 0.0461 and p = 0.0461, respectively). High Eph-A1, -A2 and -A7 expression was significantly more frequently observed in patients presenting absence of vascular invasion (p = 0.0444), dense stromal inflammatory reaction (p = 0.0063) and female gender (p = 0.0327), respectively. Mobile tongue SCC patients with high Eph-A7 expression presented longer overall and disease-free survival compared to those with low Eph-A7 expression (log-rank test, p = 0.0093 and p = 0.0164, respectively). In multivariate analysis, Eph-A7 expression was identified as independent prognostic factor of overall survival (Cox-regression analysis, p = 0.0426). The present study supported evidence that Ephs may participate in the malignant transformation of mobile tongue SCC, reinforcing their utility as clinical markers for patients’ management and prognosis, as also as targets for potential therapeutic intervention in tongue chemoprevention.

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References

  1. Zhang J, Hughes SE (2006) Role of the ephrin and Ephrin receptor tyrosine kinase families in angiogenesis and development of the cardiovascular system. J Pathol 208:453–461

    Article  PubMed  CAS  Google Scholar 

  2. Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133:38–52

    Article  PubMed  CAS  Google Scholar 

  3. Nakamoto M, Bergemann AD (2002) Diverse role for the Eph family of receptor tyrosine kinases in carcinogenesis. Microsc Res Tech 59:58–67

    Article  PubMed  CAS  Google Scholar 

  4. Surawska H, Ma PC, Salgia R (2004) The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev 15:419–433

    Article  PubMed  CAS  Google Scholar 

  5. Cheng N, Brantley DM, Chen J (2002) The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev 13:75–85

    Article  PubMed  CAS  Google Scholar 

  6. Brandley-Sieders DM, Chen J (2007) Eph receptor tyrosine kinase in angiogenesis: from development to disease. Angiogenesis 7:17–28

    Article  Google Scholar 

  7. Castaño J, Davalos V, Schwartz S Jr, Arango D (2008) EPH receptors in cancer. Histol Histopathol 23:1011–1023

    PubMed  Google Scholar 

  8. Ireton RC, Chen J (2005) EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Curr Cancer Drug Targets 5:149–157

    Article  PubMed  CAS  Google Scholar 

  9. Brantley-Sieders D, Schmidt S, Parker M, Chen J (2004) Eph receptor tyrosine kinases in tumor and tumor microenvironment. Curr Pharm Des 10:3431–3442

    Article  PubMed  CAS  Google Scholar 

  10. Heroult M, Schaffner F, Augustin HG (2004) Eph receptor and ephrin ligand-mediated interactions during angiogenesis and tumor progression. Exp Cell Res 312:642–650

    Article  CAS  Google Scholar 

  11. Canto MT, Devesa SS (2002) Oral cavity and pharynx cancer incidence in the United States, 1975–1988. Oral Oncol 38:610–617

    Article  PubMed  Google Scholar 

  12. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics. CA Cancer J Clin 57:43–66

    Article  PubMed  Google Scholar 

  13. Brenner H (2002) Long-term survival rates of cancer patients achieved by the end of the 20th century: a period analysis. Lancet 360:1131–1135

    Article  PubMed  Google Scholar 

  14. Shiboski CH, Schmidt BL, Jordan RC (2005) Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20–44 years. Cancer 103:1843–1849

    Article  PubMed  Google Scholar 

  15. Sano D, Myers JN (2007) Metastasis of squamous cell carcinoma of the oral tongue. Cancer Metastasis Rev 26:645–662

    Article  PubMed  CAS  Google Scholar 

  16. Kantola S, Parikka M, Jokinen K et al (2000) Prognostic factors in tongue cancer-relative importance of demographic, clinical and histopathological factors. Br J Cancer 83:614–619

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  17. Wangsa D, Ryott M, Avall-Lundquist E et al (2008) Ki-67 expression predicts locoregional recurrence in stage I oral tongue carcinoma. Br J Cancer 99:1121–1128

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  18. Giaginis C, Tsourouflis G, Zizi-Serbetzoglou A, Kouraklis G, Chatzopoulou E, Theocharis S (2010) Clinical significance of Ephrin (Eph)-A1, -A2, -A4, -A5 and -A7 receptors in pancreatic ductal adenocarcinoma. Pathol Oncol Res 16:267–276

    Article  PubMed  CAS  Google Scholar 

  19. Karidis NP, Giaginis C, Tsourouflis G, Alexandrou P, Delladetsima I, Theocharis S (2011) Eph-A2 and Eph-A4 expression in human benign and malignant thyroid lesions: an immunohistochemical study. Med Sci Monit 17:BR257–BR265

    Article  PubMed Central  PubMed  Google Scholar 

  20. Brandwein-Gensler M, Teixeira MS, Lewis CM et al (2005) Oral squamous cell carcinoma: histological risk assessment, but not margin status, is strongly predictive of local disease-free and overall survival. Am J Surg Pathol 29:167–178

    Article  PubMed  Google Scholar 

  21. Shintani S, Matsura H, Hasegawa Y, Nakayama B, Fujimoto Y (1997) The relationship of shape of tumor invasion to depth of invasion and cervical lymph node metastasis in squamous cell carcinoma of the tongue. Oncology 54:463–467

    Article  PubMed  CAS  Google Scholar 

  22. Barnes L, Eveson JW, Reichert P, Sidransky D (2005) World Health Organization classifications tumours. Pathology and genetics of head and neck tumours. IARC Press, Lyon

    Google Scholar 

  23. Po Wing Yen A, Lam KY, Lam LK et al (2002) Prognostic factors clinically stage I and II oral tongue carcinoma: a comparative study of stage, thickness, shape, growth pattern, invasive front malignancy grading, Martinez-Gimeno score and pathologic features. Head Neck 24:513–520

    Article  Google Scholar 

  24. Klijanienko J, el-Naggar AK, de Braud F (1995) Tumor vascularization, mitotic index, histopathologic grade, and DNA ploidy in the assessment of 114 head and neck squamous cell carcinomas. Cancer 75:1649–1656

    Article  PubMed  CAS  Google Scholar 

  25. Theocharis S, Klijanienko J, Giaginis C et al (2011) Histone deacetylase (HDAC)-1 and −2 expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival. J Oral Med Pathol 40:706–714

    Article  Google Scholar 

  26. Theocharis S, Klijanienko J, Giaginis C et al (2011) Metallothionein expression in mobile tongue squamous cell carcinoma: associations with clinicopathological parameters and patients survival. Histopathology 59:514–525

    Article  PubMed  Google Scholar 

  27. Dong Y, Wang J, Sheng Z et al (2009) Downregulation of EphA1 in colorectal carcinomas correlates with invasion and metastasis. Mod Pathol 22:151–160

    Article  PubMed  CAS  Google Scholar 

  28. Saito T, Masuda N, Miyazaki T et al (2004) Expression of EphA2 and E-cadherin in colorectal cancer: correlation with cancer metastasis. Oncol Rep 11:605–611

    PubMed  CAS  Google Scholar 

  29. Abraham S, Knapp DW, Cheng L et al (2006) Expression of EphA2 and Ephrin A-1 in carcinoma of the urinary bladder. Clin Cancer Res 12:353–360

    Article  PubMed  CAS  Google Scholar 

  30. Holm R, Knopp S, Suo Z, Tropè C, Nesland JM (2007) Expression of EphA2 and EphrinA-1 in vulvar carcinomas and its relation to prognosis. J Clin Pathol 60:1086–1091

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  31. Hafner C, Becker B, Landthaler M, Vogt T (2006) Expression profile of Eph receptors and ephrin ligands in human skin and downregulation of EphA1 in nonmelanoma skin cancer. Mod Pathol 19:1369–1377

    Article  PubMed  CAS  Google Scholar 

  32. Lin YG, Han LY, Kamat AA et al (2007) EphA2 overexpression is associated with angiogenesis in ovarian cancer. Cancer 109:332–340

    Article  PubMed  CAS  Google Scholar 

  33. Yuan W, Chen Z, Wu S et al (2009) Expression of EphA2 and E-cadherin in Gastric Cancer: correlated with Tumor Progression and Lymphogenous Metastasis. Pathol Oncol Res 15:473–478

    Article  PubMed  CAS  Google Scholar 

  34. Zeng G, Hu Z, Kinch MS et al (2003) High-level expression of EphA2 receptor tyrosine kinase in prostatic intraepithelial neoplasia. Am J Pathol 163:2271–2276

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  35. Kinch MS, Moore MB, Harpole DH (2003) Predictive value of the EphA2 receptor tyrosine kinase in lung cancer recurrence and survival. Clin Cancer Res 9:613–618

    PubMed  CAS  Google Scholar 

  36. Shao Z, Zhang WF, Chen XM, Shang ZJ (2008) Expression of EphA2 and VEGF in squamous cell carcinoma of the tongue: correlation with the angiogenesis and clinical outcome. Oral Oncol 44:1110–1117

    Article  PubMed  CAS  Google Scholar 

  37. Kamat AA, Coffey D, Merritt WM et al (2009) EphA2 overexpression is associated with lack of hormone receptor expression and poor outcome in endometrial cancer. Cancer 115:2684–2692

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  38. Miyazaki T, Kato H, Fukuchi M, Nakajima M, Kuwano H (2003) EphA2 overexpression correlates with poor prognosis in esophageal squamous cell carcinoma. Int J Cancer 103:657–663

    Article  PubMed  CAS  Google Scholar 

  39. Wang LF, Fokas E, Bieker M et al (2008) Increased expression of EphA2 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients. Oncol Rep 19:151–156

    PubMed  Google Scholar 

  40. Herrem CJ, Tatsumi T, Olson KS et al (2005) Expression of EphA2 is prognostic of disease-free interval and overall survival in surgically treated patients with renal cell carcinoma. Clin Cancer Res 11:226–231

    PubMed  CAS  Google Scholar 

  41. Oki M, Yamamoto H, Taniguchi H, Adachi Y, Imai K, Shinomura Y (2008) Overexpression of the receptor tyrosine kinase EphA4 in human gastric cancers. World J Gastroenterol 14:5650–5656

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  42. Wang LF, Fokas E, Juricko J et al (2008) Increased expression of EphA7 correlates with adverse outcome in primary and recurrent glioblastoma multiforme patients. BMC Cancer 8:79

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  43. Pasquale EB (2010) Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 10:165–180

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  44. Tandon M, Vemula SV, Mittal SK (2011) Emerging strategies for EphA2 receptor targeting for cancer therapeutics. Expert Opin Ther Targets 15:31–51

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  45. Landen CN Jr, Chavez-Reyes A, Bucana C et al (2005) Therapeutic EphA2 gene targeting in vivo using neutral liposomal small interfering RNA delivery. Cancer Res 65:6910–6918

    Article  PubMed  CAS  Google Scholar 

  46. Shahzad MM, Lu C, Lee JW et al (2009) Dual targeting of EphA2 and FAK in ovarian carcinoma. Cancer Biol Ther 8:1027–1034

    Article  PubMed Central  PubMed  CAS  Google Scholar 

  47. Zhuang G, Brantley-Sieders DM, Vaught D et al (2010) Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res 70:299–308

    Article  PubMed  CAS  Google Scholar 

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Acknowledgment

We thank Mrs Sofia Mastoraki and Mr Stylianos Georgiou for their excellent technical assistance.

Conflict of Interest Statement

All authors verify that they have not accepted any funding or support from an organization that may in any way gain or lose financially from the results of the present study. All authors verify that they have not been employed by an organization that may in any way gain or lose financially from the results of the present study. None authors have any other conflicting interest.

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Authors and Affiliations

  1. Department of Pathology, Institut Curie, Paris, France

    Stamatios Theocharis, Jerzy Klijanienko & Xavier Sastre-Garau

  2. First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias str., Goudi, Athens, GR11527, Greece

    Stamatios Theocharis, Constantinos Giaginis, Paraskevi Alexandrou & Efstratios Patsouris

  3. Department of Food Science and Nutrition, University of the Aegean, Myrina, Lemnos, Greece

    Constantinos Giaginis

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  1. Stamatios Theocharis
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  2. Jerzy Klijanienko
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  6. Xavier Sastre-Garau
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Correspondence to Stamatios Theocharis.

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Theocharis, S., Klijanienko, J., Giaginis, C. et al. Ephrin Receptor (Eph) -A1, -A2, -A4 and -A7 Expression in Mobile Tongue Squamous Cell Carcinoma: Associations with Clinicopathological Parameters and Patients Survival. Pathol. Oncol. Res. 20, 277–284 (2014). https://doi.org/10.1007/s12253-013-9692-3

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  • DOI: https://doi.org/10.1007/s12253-013-9692-3

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