Skip to main content

Advertisement

SpringerLink
Log in

Immunohistochemical assessment of Eph/ephrin expression in oral squamous cell carcinoma and precursor lesions

  • Original Article
  • Published:
Odontology Aims and scope Submit manuscript

Abstract

To evaluate erythropoietin-producing hepatocellular carcinoma (Eph)/Eph receptor-interaction protein (ephrin) expression in oral squamous cell carcinoma (OSCC) and oral epithelial precursor lesions (OEPLs), EphA2, EphB4, and ephrinB2 were examined and compared with microvessel density (MVD) and lymphatic vessel density (LVD). Samples from 73 OSCC and 43 OEPLs patients were immunohistochemically analyzed with antibodies against EphA2, EphB4, ephrinB2, CD34, and D2-40. Results were compared with clinicopathological findings. Immunohistochemical reactivity for EphA2, EphB4, and ephrinB2 was detected in epithelial cells and some stromal vascular cells in OEPLs and OSCC, proportionately with the level of malignancy. The number of blood vessel endothelial cells stained with CD34 and lymphatic vessel endothelial cells stained with D2-40 was increased in OEPLs and OSCC. In OSCC, ephrinB2 and EphB4 exhibited significant correlation with recurrence and invasion depth, respectively. MVD was significantly lower in slight lymphocytic reaction than in prominent stromal reaction. Association was found between LVD and T classification, postoperative metastasis, survival, mode of invasion, and invasion depth. Expression of EphA2, EphB4, ephrinB2, MVD, and LVD might be associated with malignant potential of the oral epithelium. Angiogenesis and lymphangiogenesis appear to be related to progression of potentially malignant oral lesions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Gale N, Hille J, Jordan RC, Nadal A, Williams MD. Tumors of the oral cavity and mobile tongue. WHO classification of head and neck tumours. Lyon: IARC Press; 2017. p. 91–3.

    Google Scholar 

  2. Warnakulasuriya S. Global epidemiology of oral and oropharyngeal cancer. Oral Oncol. 2009;45(4–5):309–16.

    Article  Google Scholar 

  3. Kouketsu A, Sato I, Abe S, Oikawa M, Shimizu Y, Takahashi T, et al. Detection of human papillomavirus infection in oral squamous cell carcinoma: a cohort study of Japanese patients. J Oral Pathol Med. 2016;45(8):565–72.

    Article  Google Scholar 

  4. Kujan O, Oliver RJ, Khattab A, Roberts SA, Thakker N, Sloan P, et al. Evaluation of a new binary system of grading oral epithelial dysplasia for prediction of malignant transformation. Oral Oncol. 2006;42(10):987–93.

    Article  Google Scholar 

  5. O’Reilly MS, Boehm T, Shing Y, Fukai N, Vasios G, Lane WS, et al. Endostatin: an endogenous inhibitor of angiogenesis and tumor growth. Cell. 1997;88(2):277–85.

    Article  Google Scholar 

  6. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;6:401–10.

    Article  Google Scholar 

  7. Cao R, Björndahl MA, Religa P, Clasper S, Garvin S, Galter D, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell. 2004;4:333–45.

    Article  Google Scholar 

  8. Morisada T, Oike Y, Yamada Y, Urano T, Akao M, Kubota Y, et al. Angiopoietin-1 promotes LYVE-1-positive lymphatic vessel formation. Blood. 2005;105(12):4649–56.

    Article  Google Scholar 

  9. Kubo H, Cao R, Bräkenhielm E, Mäkinen T, Cao Y, Alitalo K. Blockade of vascular endothelial growth factor receptor-3 signaling inhibits fibroblast growth factor-2-induced lymphangiogenesis in mouse cornea. Proc Natl Acad Sci USA. 2002;99(13):8868–73.

    Article  Google Scholar 

  10. Saito Y, Nakagami H, Morishita R, Takami Y, Kikuchi Y, Hayashi H, et al. Transfection of human hepatocyte growth factor gene ameliorates secondary lymphedema via promotion of lymphangiogenesis. Circulation. 2006;114(11):1177–84.

    Article  Google Scholar 

  11. Kreppel M, Scheer M, Drebber U, Ritter L, Zöller JE. Impact of podoplanin expression in oral squamous cell carcinoma: clinical and histopathologic correlations. Virchows Arch. 2010;456(5):473–82.

    Article  Google Scholar 

  12. Bunget A, Fronie A, Afrem E, Corlan Puşcu D, Manolea H, Dan AR, et al. Microscopic aspects of angiogenesis and lymphangiogenesis in oral squamous cell carcinoma. Rom J Morphol Embryol. 2013;54(3):623–7.

    PubMed  Google Scholar 

  13. Shao Z, Zhang WF, Chen XM, Shang ZJ. Expression of EphA2 and VEGF in squamous cell carcinoma of the tongue: correlation with the angiogenesis and clinical outcome. Oral Oncol. 2008;44(12):1110–7.

    Article  Google Scholar 

  14. Naruse T, Yamamoto S, Yamada S, Takahashi H, Matsushita Y, Imayama N, et al. Immunohistochemical study of vascular endothelial growth factor-C/vascular endothelial growth factor receptor-3 expression in oral tongue squamous cell carcinoma: correlation with the induction of lymphangiogenesis. Oncol Lett. 2015;4:2027–34.

    Article  Google Scholar 

  15. Holder N, Klein R. Eph receptors and ephrins: effectors of morphogenesis. Development. 1999;126(10):2033–44.

    PubMed  Google Scholar 

  16. Pasquale EB. Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol. 2005;6:462–75.

    Article  Google Scholar 

  17. Ogawa K, Pasqualini R, Lindberg RA, Kain R, Freeman AL, Pasquale EB. The ephrin-A1 ligand and its receptor, EphA2, are expressed during tumor neovascularization. Oncogene. 2000;19(52):6043–52.

    Article  Google Scholar 

  18. Kataoka H, Igarashi H, Kanamori M, Ihara M, Wang JD, Wang YJ, et al. Correlation of EPHA2 overexpression with high microvessel count in human primary colorectal cancer. Cancer Sci. 2004;95(2):136–41.

    Article  Google Scholar 

  19. Wang HU, Chen ZF, Anderson DJ. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by EphrinB2 and its receptor EphB4. Cell. 1998;93(5):741–53.

    Article  Google Scholar 

  20. Sharma GK, Dhillon VK, Masood R, Maceri DR. Overexpression of EphB4, EphrinB2, and epidermal growth factor receptor in papillary thyroid carcinoma: a pilot study. Head Neck. 2015;37(7):964–9.

    Article  Google Scholar 

  21. Alam SM, Fujimoto J, Jahan I, Sato E, Tamaya T. Coexpression of EphB4 and ephrinB2 in tumor advancement of uterine cervical cancers. Gynecol Oncol. 2009;114(1):84–8.

    Article  Google Scholar 

  22. Ozgür E, Heidenreich A, Dagtekin O, Engelmann U, Bloch W. Distribution of EphB4 and EphrinB2 in normal and malignant urogenital tissue. Urol Oncol. 2011;29(1):78–84.

    Article  Google Scholar 

  23. Sobin LH, Gospodarowicz MK, Wittekind CH, editors. UICC TNM classification of malignant tumours. Hoboken: Wiley-Blackwell; 2009. p. 22–9.

    Google Scholar 

  24. Yamamoto E, Miyakawa A, Kohama G. Mode of invasion and lymph node metastasis in squamous cell carcinoma of the oral cavity. Head Neck Surg. 1984;5:938–47.

    Article  Google Scholar 

  25. Weidner N, Semple JP, Welch WR, Folkman J. Tumor angiogenesis and metastasis—correlation in invasive breast carcinoma. N Engl J Med. 1991;324(1):1–8.

    Article  Google Scholar 

  26. Khan Z, Tiwari RP, Mulherkar R, Sah NK, Prasad GB, Shrivastava BR, et al. Detection of survivin and p53 in human oral cancer: correlation with clinicopathologic findings. Head Neck. 2009;8:1039–48.

    Article  Google Scholar 

  27. Miyahara M, Tanuma J, Sugihara K, Semba I. Tumor lymphangiogenesis correlates with lymph node metastasis and clinicopathologic parameters in oral squamous cell carcinoma. Cancer. 2007;110(6):1287–94.

    Article  Google Scholar 

  28. Watanabe S, Kato M, Kotani I, Ryoke K, Hayashi K. Lymphatic vessel density and vascular endothelial growth factor expression in squamous cell carcinomas of lip and oral cavity: a clinicopathological analysis with immunohistochemistry using antibodies to D2-40 VEGF-C and VEGF-D. Yonago Acta Med. 2013;56:29–37.

    PubMed  PubMed Central  Google Scholar 

  29. Agarwal D, Pardhe N, Bajpai M, Gupta S, Mathur N, Vanaki SS, et al. Characterization, localization and patterning of lymphatics and blood vessels in oral squamous cell carcinoma: a comparative study using D2-40 and CD-34 IHC marker. J Clin Diagn Res. 2014;10:86–9.

    Google Scholar 

  30. Nakaya H, Kawashiri S, Tanaka A, Noguchi N, Kato K, Hase T, et al. Influences of angiogenesis and lymphangiogenesis on cancerous invasion in experimentally induced tongue carcinoma. J Oral Pathol Med. 2005;34(2):87–92.

    Article  Google Scholar 

  31. Goes RS, Carvalho JP, Almeida BG, Bacchi CE, Goes JC, Calil MA, et al. Intratumoral lymphatic vessel density in vulvar squamous cell carcinomas: a possible association with favorable prognosis. Int J Gynecol Pathol. 2012;1:8–14.

    Article  Google Scholar 

Download references

Acknowledgements

This study was approved by the appropriate ethical review boards, and participants provided written informed consent prior to participating in the study.

Author information

Authors and Affiliations

  1. Division of Oral and Maxillofacial Surgery, Department of Oral Medicine and Surgery, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Hiroki Saito, Atsumu Kouketsu & Tetsu Takahashi

  2. Division of Oral Pathology, Department of Oral Medicine and Surgery, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan

    Hiroki Saito, Mariko Oikawa, Atsumu Kouketsu & Hiroyuki Kumamoto

Authors
  1. Hiroki Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mariko Oikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Atsumu Kouketsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tetsu Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Hiroyuki Kumamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroki Saito.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saito, H., Oikawa, M., Kouketsu, A. et al. Immunohistochemical assessment of Eph/ephrin expression in oral squamous cell carcinoma and precursor lesions. Odontology 108, 166–173 (2020). https://doi.org/10.1007/s10266-019-00466-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10266-019-00466-y

Keywords

Search

Navigation