Pathology & Oncology Research

, Volume 20, Issue 2, pp 277–284 | Cite as

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

  • Stamatios TheocharisEmail author
  • Jerzy Klijanienko
  • Constantinos Giaginis
  • Paraskevi Alexandrou
  • Efstratios Patsouris
  • Xavier Sastre-Garau


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.


Mobile tongue squamous cell carcinoma Ephrin receptors Clinicopathological parameters Prognosis Immunohistochemistry 



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.


  1. 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 208:453–461PubMedCrossRefGoogle Scholar
  2. 2.
    Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133:38–52PubMedCrossRefGoogle Scholar
  3. 3.
    Nakamoto M, Bergemann AD (2002) Diverse role for the Eph family of receptor tyrosine kinases in carcinogenesis. Microsc Res Tech 59:58–67PubMedCrossRefGoogle Scholar
  4. 4.
    Surawska H, Ma PC, Salgia R (2004) The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev 15:419–433PubMedCrossRefGoogle Scholar
  5. 5.
    Cheng N, Brantley DM, Chen J (2002) The ephrins and Eph receptors in angiogenesis. Cytokine Growth Factor Rev 13:75–85PubMedCrossRefGoogle Scholar
  6. 6.
    Brandley-Sieders DM, Chen J (2007) Eph receptor tyrosine kinase in angiogenesis: from development to disease. Angiogenesis 7:17–28CrossRefGoogle Scholar
  7. 7.
    Castaño J, Davalos V, Schwartz S Jr, Arango D (2008) EPH receptors in cancer. Histol Histopathol 23:1011–1023PubMedGoogle Scholar
  8. 8.
    Ireton RC, Chen J (2005) EphA2 receptor tyrosine kinase as a promising target for cancer therapeutics. Curr Cancer Drug Targets 5:149–157PubMedCrossRefGoogle Scholar
  9. 9.
    Brantley-Sieders D, Schmidt S, Parker M, Chen J (2004) Eph receptor tyrosine kinases in tumor and tumor microenvironment. Curr Pharm Des 10:3431–3442PubMedCrossRefGoogle Scholar
  10. 10.
    Heroult M, Schaffner F, Augustin HG (2004) Eph receptor and ephrin ligand-mediated interactions during angiogenesis and tumor progression. Exp Cell Res 312:642–650CrossRefGoogle Scholar
  11. 11.
    Canto MT, Devesa SS (2002) Oral cavity and pharynx cancer incidence in the United States, 1975–1988. Oral Oncol 38:610–617PubMedCrossRefGoogle Scholar
  12. 12.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ (2007) Cancer statistics. CA Cancer J Clin 57:43–66PubMedCrossRefGoogle Scholar
  13. 13.
    Brenner H (2002) Long-term survival rates of cancer patients achieved by the end of the 20th century: a period analysis. Lancet 360:1131–1135PubMedCrossRefGoogle Scholar
  14. 14.
    Shiboski CH, Schmidt BL, Jordan RC (2005) Tongue and tonsil carcinoma: increasing trends in the U.S. population ages 20–44 years. Cancer 103:1843–1849PubMedCrossRefGoogle Scholar
  15. 15.
    Sano D, Myers JN (2007) Metastasis of squamous cell carcinoma of the oral tongue. Cancer Metastasis Rev 26:645–662PubMedCrossRefGoogle Scholar
  16. 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 83:614–619PubMedCentralPubMedCrossRefGoogle Scholar
  17. 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 99:1121–1128PubMedCentralPubMedCrossRefGoogle Scholar
  18. 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 16:267–276PubMedCrossRefGoogle Scholar
  19. 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–BR265PubMedCentralPubMedCrossRefGoogle Scholar
  20. 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 29:167–178PubMedCrossRefGoogle Scholar
  21. 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 54:463–467PubMedCrossRefGoogle Scholar
  22. 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, LyonGoogle Scholar
  23. 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 24:513–520CrossRefGoogle Scholar
  24. 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 75:1649–1656PubMedCrossRefGoogle Scholar
  25. 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 40:706–714CrossRefGoogle Scholar
  26. 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 59:514–525PubMedCrossRefGoogle Scholar
  27. 27.
    Dong Y, Wang J, Sheng Z et al (2009) Downregulation of EphA1 in colorectal carcinomas correlates with invasion and metastasis. Mod Pathol 22:151–160PubMedCrossRefGoogle Scholar
  28. 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 11:605–611PubMedGoogle Scholar
  29. 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 12:353–360PubMedCrossRefGoogle Scholar
  30. 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 60:1086–1091PubMedCentralPubMedCrossRefGoogle Scholar
  31. 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 19:1369–1377PubMedCrossRefGoogle Scholar
  32. 32.
    Lin YG, Han LY, Kamat AA et al (2007) EphA2 overexpression is associated with angiogenesis in ovarian cancer. Cancer 109:332–340PubMedCrossRefGoogle Scholar
  33. 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 15:473–478PubMedCrossRefGoogle Scholar
  34. 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 163:2271–2276PubMedCentralPubMedCrossRefGoogle Scholar
  35. 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 9:613–618PubMedGoogle Scholar
  36. 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 44:1110–1117PubMedCrossRefGoogle Scholar
  37. 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 115:2684–2692PubMedCentralPubMedCrossRefGoogle Scholar
  38. 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 103:657–663PubMedCrossRefGoogle Scholar
  39. 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 19:151–156PubMedGoogle Scholar
  40. 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 11:226–231PubMedGoogle Scholar
  41. 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 14:5650–5656PubMedCentralPubMedCrossRefGoogle Scholar
  42. 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 8:79PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Pasquale EB (2010) Eph receptors and ephrins in cancer: bidirectional signalling and beyond. Nat Rev Cancer 10:165–180PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Tandon M, Vemula SV, Mittal SK (2011) Emerging strategies for EphA2 receptor targeting for cancer therapeutics. Expert Opin Ther Targets 15:31–51PubMedCentralPubMedCrossRefGoogle Scholar
  45. 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 65:6910–6918PubMedCrossRefGoogle Scholar
  46. 46.
    Shahzad MM, Lu C, Lee JW et al (2009) Dual targeting of EphA2 and FAK in ovarian carcinoma. Cancer Biol Ther 8:1027–1034PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Zhuang G, Brantley-Sieders DM, Vaught D et al (2010) Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res 70:299–308PubMedCrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2013

Authors and Affiliations

  • Stamatios Theocharis
    • 1
    • 2
    Email author
  • Jerzy Klijanienko
    • 1
  • Constantinos Giaginis
    • 2
    • 3
  • Paraskevi Alexandrou
    • 2
  • Efstratios Patsouris
    • 2
  • Xavier Sastre-Garau
    • 1
  1. 1.Department of PathologyInstitut CurieParisFrance
  2. 2.First Department of Pathology, Medical SchoolNational and Kapodistrian University of AthensAthensGreece
  3. 3.Department of Food Science and NutritionUniversity of the AegeanMyrinaGreece

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