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Clinical Significance of EphB4 and EphB6 Expression in Human Malignant and Benign Thyroid Lesions

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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, angiogenesis and metastasis. The present study aimed to evaluate the clinical significance of EphB4 and EphB6 protein expression in human malignant and benign thyroid lesions. EphB4 and EphB6 protein expression was assessed immunohistochemically on paraffin-embedded thyroid tissues obtained from 127 patients with benign (n = 71) and malignant (n = 56) thyroid lesions. Enhanced EphB4 and EphB6 expression was more frequently observed in malignant compared to benign thyroid lesions (p = 0.0508 and p = 0.0006, respectively). EphB4 and EphB6 expression also provided a distinct discrimination between papillary carcinoma and hyperplastic nodules (p = 0.0302 and p = 0.0013, respectively). In malignant thyroid lesions, enhanced EphB4 expression was significantly associated with larger tumor size (p = 0.0366). Enhanced EphB6 expression was significantly associated with larger tumor size (p = 0.0366), the presence of lymph node metastases (p = 0.0023), the presence of capsular (p = 0.0038), lymphatic (p = 0.0053) and vascular invasion (p = 0.0018) and increased risk of recurrence rate (p = 0.0038). The present study supported evidence that EphB4 and mainly EphB6 may participate in the malignant thyroid transformation, reinforcing their utility as useful biomarkers and possible therapeutic targets in this type of neoplasia.

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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  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  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  CAS  PubMed  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  CAS  PubMed  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. Leenhardt L, Grosclaude P, Cherie-Challine L (2004) Increased incidence of thyroid carcinoma in France: a true epidemic or thyroid nodule management effects? Report from the French Thyroid Cancer Committee. Thyroid 14:1056–1060

    Article  PubMed  Google Scholar 

  9. Jemal A, Siegel R, Ward E et al (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249

    Article  PubMed  Google Scholar 

  10. Hundahl SA, Fleming ID, Fremgen AM et al (1998) A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995. Cancer 83:2638–2648

    Article  CAS  PubMed  Google Scholar 

  11. Gharib H, Papini E (2007) Thyroid nodules: clinical importance, assessment, and treatment. Endocrinol Metab Clin North Am 36:707–735

    Article  CAS  PubMed  Google Scholar 

  12. Schlumberger M, Lacroix L, Russo D, Filetti S, Bidart JM (2007) Defects in iodide metabolism in thyroid cancer and implications for the follow-up and treatment of patients. Nat Clin Pract Endocrinol Metab 3:260–269

    Article  CAS  PubMed  Google Scholar 

  13. Stang MT, Carty SE (2009) Recent developments in predicting thyroid malignancy. Curr Opin Oncol 21:11–17

    Article  PubMed  Google Scholar 

  14. Fischer S, Asa L (2008) Application of immunohistochemistry to thyroid neoplasms. Arch Pathol Lab Med 132:359–372

    PubMed  Google Scholar 

  15. Vriens MR, Schreinemakers JM, Suh I et al (2009) Diagnostic markers and prognostic factors in thyroid cancer. Future Oncol 5:1283–1293

    Article  CAS  PubMed  Google Scholar 

  16. Aisner DL, Sams SB (2012) The role of cytology specimens in molecular testing of solid tumors: techniques, limitations, and opportunities. Diagn Cytopathol 40:511–524

    Article  PubMed  Google Scholar 

  17. 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  CAS  PubMed  Google Scholar 

  18. Giaginis C, Tsoukalas N, Bournakis E et al (2014) Ephrin (Eph) receptor A1, A4, A5 and A7 expression in human non-small cell lung carcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients’ survival. BMC Clin Pathol 14:8

    Article  PubMed  PubMed Central  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  PubMed Central  Google Scholar 

  20. Theocharis S, Klijanienko J, Giaginis C, Alexandrou P, Patsouris E, Sastre-Garau X (2013) 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. doi:10.1007/s12253-013-9692-3

    PubMed  Google Scholar 

  21. Yin H, Lu C, Tang Y, Wang H, Wang H, Wang J (2013) Enhanced expression of EphrinB1 is associated with lymph node metastasis and poor prognosis in breast cancer. Cancer Biomark 13:261–267

    CAS  PubMed  Google Scholar 

  22. Ji XD, Li G, Feng YX et al (2011) EphB3 is overexpressed in non-small-cell lung cancer and promotes tumor metastasis by enhancing cell survival and migration. Cancer Res 71:1156–1166

    Article  CAS  PubMed  Google Scholar 

  23. Li M, Zhao ZW, Zhang Y, Xin Y (2011) Over-expression of Ephb4 is associated with carcinogenesis of gastric cancer. Dig Dis Sci 56:698–706

    Article  CAS  PubMed  Google Scholar 

  24. Lu Z, Zhang Y, Li Z et al (2012) Overexpression of the B-type Eph and ephrin genes correlates with progression and pain in human pancreatic cancer. Oncol Lett 3:1207–1212

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Oshima T, Akaike M, Yoshihara K et al (2008) Overexpression of EphA4 gene and reduced expression of EphB2 gene correlates with liver metastasis in colorectal cancer. Int J Oncol 33:573–577

    CAS  PubMed  Google Scholar 

  26. Wang H, Wen J, Wang H et al (2013) Loss of expression of EphB1 protein in serous carcinoma of ovary associated with metastasis and poor survival. Int J Clin Exp Pathol 7:313–321

    PubMed  PubMed Central  Google Scholar 

  27. Xuqing W, Lei C, Zhengfa M et al (2012) EphB4 is overexpressed in papillary thyroid carcinoma and promotes the migration of papillary thyroid cancer cells. Tumour Biol 33:1419–1427

    Article  PubMed  Google Scholar 

  28. Tang XX, Zhao H, Robinson ME et al (2000) Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma. Proc Natl Acad Sci U S A 97:10936–10941

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Hafner C, Bataille F, Meyer S et al (2003) Loss of EphB6 expression in metastatic melanoma. Int J Oncol 23:1553–1559

    CAS  PubMed  Google Scholar 

  30. Rosai J, Appendix C (2004) Staging of cancer. In: Houston M (ed) Rosai and Ackerman’s surgical pathology, 9th edn. Mosby, London, pp 2809–2810

    Google Scholar 

  31. Tuttle RM, Tala H, Shah J et al (2010) Estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation: using response to therapy variables to modify the initial risk estimates predicted by the new American Thyroid Association staging system. Thyroid 20:1341

    Article  CAS  PubMed  Google Scholar 

  32. Tu Y, He S, Fu J et al (2012) Expression of EphrinB2 and EphB4 in glioma tissues correlated to the progression of glioma and the prognosis of glioblastoma patients. Clin Transl Oncol 14:214–220

    Article  CAS  PubMed  Google Scholar 

  33. Alam SM, Fujimoto J, Jahan I, Sato E, Tamaya T (2009) Coexpression of EphB4 and ephrinB2 in tumor advancement of uterine cervical cancers. Gynecol Oncol 114:84–98

    Article  CAS  PubMed  Google Scholar 

  34. Zheng MF, Ji Y, Wu XB, Ye SG, Chen JY (2012) EphB4 gene polymorphism and protein expression in non-small-cell lung cancer. Mol Med Rep 6:405–408

    CAS  PubMed  Google Scholar 

  35. Sinha UK, Mazhar K, Chinn SB et al (2006) The association between elevated EphB4 expression, smoking status, and advanced-stage disease in patients with head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 132:1053–1059

    Article  PubMed  Google Scholar 

  36. Davalos V, Dopeso H, Castaño J et al (2006) EPHB4 and survival of colorectal cancer patients. Cancer Res 66:8943–8948

    Article  CAS  PubMed  Google Scholar 

  37. Takai N, Miyazaki T, Fujisawa K, Nasu K, Miyakawa I (2001) Expression of receptor tyrosine kinase EphB4 and its ligand ephrin-B2 is associated with malignant potential in endometrial cancer. Oncol Rep 8:567–573

    CAS  PubMed  Google Scholar 

  38. Alam SM, Fujimoto J, Jahan I, Sato E, Tamaya T (2008) Coexpression of EphB4 and ephrinB2 in tumour advancement of ovarian cancers. Br J Cancer 98:845–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Tang XX, Evans AE, Zhao H et al (1999) High-level expression of EPHB6, EFNB2, and EFNB3 is associated with low tumor stage and high TrkA expression in human neuroblastomas. Clin Cancer Res 5:1491–1496

    CAS  PubMed  Google Scholar 

  40. Xi HQ, Wu XS, Wei B, Chen L (2012) Eph receptors and ephrins as targets for cancer therapy. J Cell Mol Med 16:2894–2909

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ferguson BD, Liu R, Rolle CE et al (2013) The EphB4 receptor tyrosine kinase promotes lung cancer growth: a potential novel therapeutic target. PLoS One 8:e67668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hasina R, Mollberg N, Kawada I et al (2013) Critical role for the receptor tyrosine kinase EPHB4 in esophageal cancers. Cancer Res 73:184–194

    Article  CAS  PubMed  Google Scholar 

  43. Spannuth WA, Mangala LS, Stone RL et al (2010) Converging evidence for efficacy from parallel EphB4-targeted approaches in ovarian carcinoma. Mol Cancer Ther 9:2377–2388

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Conflicts of interest

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. First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 75 M. Asias str., Goudi, Athens, 11527, Greece

    Constantinos Giaginis, Paraskevi Alexandrou, Elpida Poulaki, Ioanna Delladetsima, Efstratios Patsouris & Stamatios Theocharis

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

    Constantinos Giaginis

  3. Department of Biochemistry, Medical School, University of Athens, Athens, Greece

    Constantinos Troungos

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  1. Constantinos Giaginis
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  2. Paraskevi Alexandrou
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  4. Ioanna Delladetsima
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  6. Efstratios Patsouris
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  7. Stamatios Theocharis
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Correspondence to Stamatios Theocharis.

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Giaginis, C., Alexandrou, P., Poulaki, E. et al. Clinical Significance of EphB4 and EphB6 Expression in Human Malignant and Benign Thyroid Lesions. Pathol. Oncol. Res. 22, 269–275 (2016). https://doi.org/10.1007/s12253-014-9879-2

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  • DOI: https://doi.org/10.1007/s12253-014-9879-2

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