IMMUNOHISTOCHEMICAL EXPRESSION OF CD44 IN PATIENTS WITH HEPATOCELLULAR CARCINOMA

  • Dafina Nikolova University Clinic of Gastroenterohepatology,Faculty of Medicine University“St.Cyril&Methodius”, Skopje, R.of North Macedonia
  • Viktorija Chaloska Ivanova University Clinic of Gastroenterohepatology,Faculty of Medicine University“St.Cyril&Methodius”, Skopje, R.of North Macedonia
  • Rubens Jovanovic Institute of Pathology, Faculty of Medicine, University of ’’St. Cyril and Methodius”, Skopje, R.of North Macedonia
  • Vesna Janevska Institute of Pathology, Faculty of Medicine, University of ’’St. Cyril and Methodius”, Skopje, R.of North Macedonia
  • Emilija Nikolovska Trpcevska University Clinic of Gastroenterohepatology,Faculty of Medicine University“St.Cyril&Methodius”, Skopje, R.of North Macedonia
  • Ance Volkanovska Nikolovska University Clinic of Gastroenterohepatology,Faculty of Medicine University“St.Cyril&Methodius”, Skopje, R.of North Macedonia

Abstract

 Introduction: CD44, a transmembrane glycoprotein with a role in cell-cell and cell-matrix interactions and one of the stem cell markers, is considered to participate in progression and prognosis of hepatocellular carcinoma (HCC), which makes it a potential prognostic marker and therapeutic target. We aimed to evaluate immunoexpression of CD44 in tumor and surrounding non-tumor liver tissue and to correlate it to multiple clinicopathological data in order to determine its prognostic value in patients from the Republic of North Macedonia. Material and Methods: Presence of the immunosignal and the percentage of CD44+ tumor cells at the whole tumor tissue sample and adjacent cirrhotic liver tissue were semi-quantitatively determined.The immunohistochemistry results were correlated to B and C hepatitis, tumor dimensions, enlarged lymph nodes, T status, differentiation (G), microvascular invasion, and survival. Results: We found a significant difference in CD44 expression between tumor and non-tumor liver tissue (p < 0.000) and significantly higher CD44 expression was also found in T4 tumors in comparison with T1 tumors (p < 0.01). Conclusion:  Expression of CD44 was significantly higher in tumor in comparison to non-tumor tissue and was significantly associated to T4 local tumor growth, making it a potential prognostic marker and therapeutic target.


Keywords: CD44, HCC, immunohistochemistry, T status, survival

References

1. Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell Biol
2003; 4:33–45.
2. Qin LX, Tang ZY. The prognostic molecular markers in hepatocellular carcinoma. World J Gastroenterol. 2002
Jun;8(3):385-92.
3. Senbanjo LT, Chellaiah MA. CD44: A Multifunctional Cell Surface Adhesion Receptor Is a Regulator of
Progression and Metastasis of Cancer Cells. Front. Cell Dev. Biol. 2017;5:18.
4. Qiu L, Li H, Fu S, Chen X, Lu L. Surface markers of liver cancer stem cells and innovative targeted-therapy
strategies for HCC. Oncol Lett. 2018 Feb;15(2):2039-48.
5. Luo Y, Tan Y. Prognostic value of CD44 expression in patients with hepatocellular carcinoma: meta-analysis.
Cancer Cell Int. 2016; 16: 47.
6. Orian-Rousseau V. CD44, a therapeutic target for metastasising tumors. Eur J Cancer. 2010;46(7):1271–7.
7. Maisel D, Birzele F, Voss E, Nopora A, Bader S, Friess T, Goller B et al. Targeting Tumor Cells with Anti-CD44
Antibody Triggers Macrophage-Mediated Immune Modulatory Effects in a Cancer Xenograft Model. PLoS ONE.
2016; 11(7): e0159716.
8. Nikolova D, Chalovska V, Ivanova MG, Nikolovska E, Volkanovska A, Orovchanec N, Kostadinova Kunovska S et
al. Immunohistochemical Expression of Epidermal Growth Factor Receptor in Hepatocellular Carcinoma.
Contributions 2018 ;39(2-3):21-8.
9. Nikolova D, Ivanova V, Dimitrova M, Jovanovik R, Kunovska S, Orovcanec N, Kostadinova Kunovska S et al.
Hepatocellular carcinoma - clinicopathological characteristics, survival, and expression of various histologic
molecular markers. Pol J Pathol. 2019;70(4):269-76.
10. Amin MB, Edge SB, Green F, Greene F, Byrd DR, Brookland RK, Washington MK et al. (eds). AJCC cancer
staging manual, 8th edition. Switzerland: Springer, 2017: 237-44
11. Puoti C. New insights on hepatocellular carcinoma: epidemiologyand clinical aspects. Hepatoma Res
2018;4:57.
12. Villanueva A. Hepatocellular Carcinoma. N Engl J Med 2019; 380:1450-62.
13. Bruix J, Sherman M, American Association for the Study of Liver Diseases: Management of hepatocellular
carcinoma: An update. Hepatology 2011;53: 1020 2.
14. Woerns MA, Galle PR. Future perspectives in hepatocellular carcinoma. Digest Liver Dis 2010;42 (Suppl 3):
S302 9.
15. Thillai K, Ross P, Sarker D. Molecularly targeted therapy for advanced hepatocellular carcinoma - a drug
development crisis? World J Gastrointest Oncol. 2016;8(2): 173–85.
16. Setshedi M, Andersson M, Kgatle MM, Roberts L. Molecular and cellular oncogenic mechanisms in
hepatocellular carcinoma. S Afr Med J. 2018;108(8b):41-6.
17. Rozeik MS, Hammam OA, Ali AI, Magdy M, Khalil H, Anas A, El Hassan AAA et al. Evaluation of CD44 and CD133
as markers of liver cancer stem cells in Egyptian patients with HCV-induced chronic liver diseases versus
hepatocellular carcinoma. Electron Physician. 2017;9(7):4708-17.
18. Langan CR, Mullinax EJ, Raiji TM, Upham T, Summers T, Stojadinovic A, Avital I et al. Colorectal Cancer
Biomarkers and the Potential Role of Cancer Stem Cells. J Cancer. 2013; 4(3): 241–250.
19. Kuşoğlu A, Biray Avcı Ç. Cancer stem cells: A brief review of the current status. Gene. 2019;681:80-85.
20. Crupi MJF, Bell JC, Singaravelu R. Concise Review: Targeting Cancer Stem Cells and Their Supporting Niche
Using Oncolytic Viruses. Stem Cells. 2019;37(6):716-23.
21. Lee JS, Heo J, Libbrecht L, Chu IS, Kaposi-Novak P, Calvisi DF, Mikaelyan A et al. A novel prognostic subtype of
human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med. 2006;12(4):410-6.
22. Asai R, Tsuchiya H, Amisaki M, Makimoto K, Takenaga A, Sakabe T, Hoi S et al. CD44 standard isoform is
involved in maintenance of cancer stem cells of a hepatocellular carcinoma cell line. Cancer Med.
2019;8(2):773-82.
23. Endo K, Terada T. Protein expression of CD44 (standard and variant isoforms) in hepatocellular carcinoma:
relationships with tumor grade, clinicopathologic parameters, p53 expression, and patient survival. J Hepatol.
2000;32(1):78-84.
24. Mima K, Okabe H, Ishimoto T, Hayashi H, Nakagawa S, Kuroki H, Miyake K, et al. The expression levels of
CD44v6 are correlated with the invasiveness of hepatocellular carcinoma in vitro, but do not appear to be
clinically significant. Oncol Lett. 2012; 3(5): 1047–51.
25. Zhu Z, Hao X, Yan M, Yao M, Ge C, Gu J, Li J. Cancer stem/progenitor cells are highly enriched in CD133+CD44+
population in hepatocellular carcinoma. Int J Cancer. 2010;126(9):2067-78.
26. Iacob R, Herlea V, Popa C, Nastase A, Ghetea L, Iacob S, Botea F et al. Prognostic Significance of CD44
Expression in Hepatocellular Carcinoma Following a Potentially Curative Treatment. J. Transl. Med. Res
2016;21(4):267-73.
27. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, Cosme de Oliveira A et al., for the SHARP
Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008;359:378-90
28. Gunia S, Hussein S, Radu DL, Putz KM, Brayer R, Hecker H, Samil GF et al. CD44s-targeted treatment with
monoclonal antibody blocks intracerebral invasion and growth of 9L gliosarcoma. Clin Exp Metastasis
1999;17:221-30.
29. Breyer R, Hussein S, Radu DL, Putz KM, Gunia S, Hecker H, Samii M et al. Disruption of intracerebral
progression of C6 rat glioblastoma by in vivo treatment with anti-CD44 monoclonal antibody. J Neurosurg
2000;92:140-9.
30. Maisel D, Birzele F, Voss E, Nopora A, Bader S, Friess T, Goller B et al. Targeting Tumor Cells with Anti-CD44
Antibody Triggers Macrophage-Mediated Immune Modulatory Effects in a Cancer Xenograft Model. PLoS
One. 2016 27;11(7):e0159716.
31. Zhang S, Wu CC, Fecteau JF, Cui B, Chen L, Zhang L, Wu R et al. Targeting chronic lymphocytic leukemia cells
with a humanized monoclonal antibody specific for CD44. Proc Natl Acad Sci USA. 2013;110:6127–32.
32. Cho JH, Lee SC, Ha NR, Lee SJ, Yoon MY. A novel peptide-based recognition probe for the sensitive detection
of CD44 on breast cancer stem cells. Mol Cell Probes. 2015;29:492-9.
33. Philip PA, Mooney M, Jaffe D, Eckhardt G, Moore M, Meropol N, Emens L et al. Consensus report of the
national cancer institute clinical trials planning meeting on pancreas cancer treatment. J Clin Oncol.
2009;27:5660–9.
Published
2020-07-06
How to Cite
NIKOLOVA, Dafina et al. IMMUNOHISTOCHEMICAL EXPRESSION OF CD44 IN PATIENTS WITH HEPATOCELLULAR CARCINOMA. Journal of Morphological Sciences, [S.l.], v. 3, n. 2, p. 22-28, july 2020. ISSN 2545-4706. Available at: <http://jms.mk/jms/article/view/109>. Date accessed: 22 oct. 2020.
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