Advances in Clinical and Experimental Medicine

Adv Clin Exp Med
Impact Factor (IF) – 1.227
Index Copernicus (ICV 2018) – 157.72
MNiSW – 40
Average rejection rate – 84.38%
ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download PDF

Advances in Clinical and Experimental Medicine

2007, vol. 16, nr 2, March-April, p. 197–204

Publication type: original article

Language: English

Creative Commons BY-NC-ND 3.0 Open Access

Immunohistochemical Evaluation of Neoepitope Cytokeratin 18 Expression in Relation to p53 Protein in Ovarian Carcinoma

Immunohistochemiczna ocena występowania neoepitopu cytokeratyny 18 z uwzględnieniem ekspresji białka p53 w rakach jajnika

Julia K. Bar1,, Ewa Wyrodek1,, Marian Gryboś2,, Marian Gabryś3,

1 Chair and Department of Clinical Immunology, Silesian Piasts University of Medicine in Wrocław, Poland

2 First Department of Gynecology, Silesian Piasts University of Medicine in Wrocław, Poland

3 Second Department of Gynecology, Silesian Piasts University of Medicine in Wrocław, Poland

Abstract

Background. One of the major reasons for lack of response to therapy (both chemotherapy and radiotherapy) and the development of progression may be defects in the apoptotic cell death mechanism.
Objectives. Assessing the expression of caspase−cleaved cytokeratin 18 (CK18) (M30) in ovarian carcinoma and the relationship between cytokeratin 18 expression, clinicopathological parameters, and overexpression of p53 protein in tumors.
Material and Methods. The expressions of neoepitope cytokeratin 18 (clone M30) and p53 protein were evaluated by immunohistochemistry in frozen tissue sections from one hundred nine patients with primary ovarian carcinoma.
Results. Positive cytoplasmic staining for cytokeratin 18 (M30) was detected in 52 (47.7%) of the 109 ovarian carcinomas. The distribution of CK 18 positivity in ovarian carcinoma showed interand intra−tumoral heterogeneity. No association was observed between CK18 expression and clinicopathological parameters. Moreover, tumors showing CK18 staining were observed more frequently in FIGO stages III/IV. Nuclear accumulation of p53 protein was found in 58 (53.2%) of the ovarian carcinomas. The range of p53 positivity varied between 10–90% cells of ovarian carcinomas. Marginally significant differences between FIGO stage and p53 overexpression were found (p = 0.07). The association between different degrees of cytokeratin 18 or p53 expression and clinicopathological parameters was not statistically significant. Moreover, the expression of CK18 in over 30% of carcinoma cells was observed in well−differentiated ovarian carcinomas, whereas p53 expression above or below 30% of cells was independent of FIGO and comparable in moderately and poorly differentiated carcinomas. No relationship between cytokeratin 18 (M30) and p53 overexpression in the subgroups was observed.
Conclusion. These results suggest that the expression of caspase−cleaved cytokeratin 18 on the surface of ovarian carcinoma cells is independent of p53 protein expression. The neoepitope of cytokeratin 18 may be used as an additional marker for detecting apoptosis in ovarian carcinoma.

Streszczenie

Wprowadzenie. Jedną z przyczyn rozwoju procesu nowotworowego jest brak odpowiedzi na chemioterapię i radioterapię będącą następstwem uszkodzeń w mechanizmach warunkujących apoptozę komórek nowotworowych.
Cel pracy. Ocena występowania neoepitopu cytokeratyny 18 (CK18) (M30) w rakach jajnika z uwzględnieniem wskaźników klinicznych i patologicznych raka jajnika oraz obecności białka p53.
Materiał i metody. Występowanie cytokeratyny 18 (M30) oraz białka p53 oceniano metodą immunoperoksydazową na materiale tkankowym pochodzącym z 109 pierwotnych raków jajnika.
Wyniki. Cytoplazmatyczną obecność cytokeratyny 18 (M30) stwierdzono w 52/109 (47,7%) raków jajnika. Obserwowano heterogenne występowanie cytokeratyny 18 zarówno w całej badanej grupie raków, jak i w indywidualnych przypadkach. Nie stwierdzono zależności między występowaniem cytokeratyny 18 a typem histologicznym, stopniem zróżnicowania raka jajnika oraz stopniem zaawansowania choroby. W przypadkach III/IVo wg FIGO obecność cytokeratyny 18 stwierdzono jednak częściej. Jądrową akumulację białka p53 wykazano w 58/109 (53,2%) raków jajnika, przy czym dodatnia reakcja immunohistochemiczna dotyczyła 10–90% powierzchni tkanki nowotworowej. Obecność białka p53 częściej stwierdzano w III/IVo aniżeli w I/IIo wg FIGO, wykazane różnice były na granicy statystycznej istotności (p = 0,07). Nie stwierdzono wzajemnych zależności między zakresem immunoreaktywności cytokeratyny 18 (> 30% lub < 30% dodatniej tkanki) a białkiem p53 oraz wskaźnikami klinicznym i patologicznymi raków jajnika.
Wnioski. Wyniki badań wykazały, że ekspresja neopepitopu cytokeratyny 18 w komórkach raka jajnika jest niezależna od obecności białka p53. Stwierdzono, że neoepitop cytokeratyny 18 może być dodatkowym wartościowym markerem oceny procesu apoptozy w rakach jajnika.

Key words

immunohistochemistry, ovarian carcinoma, p53, neoepitope cytokeratin 18, M30 CytoDEATH

Słowa kluczowe

immunohistochemia, rak jajnika, białko p53, neoepitop cytokeratyny 18, M30 – CytoDEATH

References (23)

  1. Nnene IO, Nieto JJ, Crow JC, Sundaresan M, MacLean AB, Perrett CW, Hardiman P: Cell cycle and apoptotic proteins in relation to ovarian epithelial morphology. Gynecol Oncol 2004, 92, 247–251.
  2. Holdenrieder S, Stieber P: Apoptotic markers in cancer. Clin Biochemistry 2004, 37, 605–617.
  3. Schaer P: Spontaneous DNA damage, genome instability, and cancer – when DNA replication escape control. Cell 2001, 104, 329–332.
  4. Fridman JS, Lowe SW: Control of apoptosis by p53. Oncogene 2003, 22, 9030–9040.
  5. Hofseth LJ, Hussain SP, Harris CC: p53: 25 years after its discovery. Trends Farmacol Sci 2004, 4, 177–181.
  6. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis – the p53 network. J Cell Sci 2003, 116, 4077–4085.
  7. Mihara M Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM: P53 has direct apoptogenic role at the mitochondria. Mol Cell 2003, 11, 577–590.
  8. Sun Sh−Y, Hail NJr, Lotan R: Apoptosis as a novel target for cancer chemoprevention. J Natl Cancer Inst 2004, 96, 662–672.
  9. Leers M P G, Kölgen W, Björklund V, Bergman T, Tribbick G, Persson B, Björklund P, Ramaekers FCS, Björklund B, Nap M, Jornvall H, Schutte B: Immunocytochemical detection and mapping of cytokeratin 18 neoepitope exposed during early apoptosis. J Pathol 1999, 187, 5, 567–572.
  10. Kusama K, Jiang Y, Ohno J, Shikata H, Ishikawa F, Taguchi K, Kikuchi K, Mori K, Sakashita H, Sakagami H, Kaneko T, Yamamoto Y: Immunohistochemical detection of cytokeratin 18 and its neo−epitope in human salivary glands and pleomorphic adenomas. Anticancer Res 2000, 20, 2485–2487.
  11. Ferrandina G, Ranelletti FO, Larocca LM, Maggiano N, Fruscella E, Legge F, Santeusanio G, Bombonati A, Mancuso S, Scambia G: Tamoxifen modulates the expression of Ki67, apoptosis and microvessel density in cervical cancer. Clin Cancer Res 2001, 7, 2656–2661.
  12. Kramer G, Erdal H, Mertens HJMM, Nap M, Mauermann J, Steiner G, Marberger M, Bivén K, Shoshan MC, Linder S: Differentiation between cell death modes using measurements of different soluble forms of extracellular cytokeratin 18. Cancer Res 2004, 64, 1751–1756.
  13. Liu A, Chen L, Ngan HY, Khoo US, Zhao Y, Cheung AN: Apoptotic and proliferative activity in ovarian benign, borderline and malignant tumors. Chin Med Sci J 2002, 17, 106–111.
  14. Tewari KS, Kyshtoobayeva AS, Mehta RS, Yu I−R, Burger RA, DiSaia PhJ, Fruehauf JP. Biomarker conservation in primary and metastatic epithelial ovarian cancer. Gynecol Oncol 2000, 78, 130–136.
  15. Yu J, Zhang L: Apoptosis in human cancer cells. Curr Opin Oncol 2004, 16, 19–24.
  16. Ueno T, Toi M, Biven K, Bando H, Ogawa T, Linder S: Measurement of an apoptotic product in the sera of breast cancer patients. Eur J Cancer 2003, 39, 769–774.
  17. Morsi HM, Leers MP, Jager W, Björklund V, Radespiel−Troger M, Kabarity H, Nap M, Lang N: The patterns of expression of an apoptosis−related CK18 neoepitope, the bcl−2 proto−oncogene, and Ki67 proliferation marker in normal, hyperplastic, and malignant endometrium. Int J Gynecol Pathol 2000, 19, 118–126.
  18. Kupryjańczyk J, Szymańska T, Mądry R, Timorek A, Stelmachów J, Karpińska G, Rembiszewska A, Ziólkowska I, Kraszewska E, Dębniak J, Emerich J, Ułańska M, Płużańska A, Jędryka M, Goluda M, Chudecka−Głaz A, Rzepka−Górska I, Klimek M, Urbański K, Bręborowicz J, Zieliński J, Markowska J: Evaluation of clinical significance of TP53, BCl−2, BAX and MEKI expression in 229 ovarian carcinomas treated with platinum−based regimen. Br J Cancer 2003, 88, 848–854.
  19. Sengupta PS, McGown AT, Bajaj V, Blackhall F, Swindell R, Bromley M, Shanks JH, Ward T, Buckley CH, Reynolds K, Slade RJ, Jayson GC: P53 and related proteins in epithelial ovarian cancer. Eur J Cancer 2000, 36, 2317–2328.
  20. Skirnisdóttir J, Sorbe B, Seidal T: P53, bcl−2 and bax: their relationship and effect on prognosis in early stage epithelial ovarian carcinoma. Int J Gynecol Cancer 2001, 11, 147–158.
  21. Geisler JP, Geisler HE, Miller GA, Wiemann MC, Zhou Z, Crabtree W.: p53 and bcl−2 in epithelial ovarian carcinoma: their value as prognostic indicators at a median follow−up of 60 months. Gynecol Oncol 2000, 77, 278–282.
  22. Schuyer M, van der Burg, Henzen−Logmans SC, Fieret JM, Klijn JGM, Look MP, Feokens JA, Stoter G, Bem EMJ: Reduced expression of Bax is associated with poor prognosis in patients with epithelial ovarian cancer: a multifactorial analysis of TP53, p21, Bax and Bcl−2. Br J Cancer 2001, 85, 1359–1367.
  23. Bar JK, Grelewski P, Popiela A, Noga L, Rabczyński J: Type IV collagen and CD44v6 expression in benign, malignant primary and metastatic ovarian tumors: correlation with Ki−67 and p53 immunoreactivity. Gynecol Oncol 2004, 95, 23–31.