Skip to main content
PMC home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1995 Feb;71(2):357–362. doi: 10.1038/bjc.1995.72

Proliferating cell nuclear antigen (PCNA) immunostaining--a prognostic factor in ovarian cancer?

H Thomas 1, M M Nasim 1, C E Sarraf 1, M R Alison 1, S Love 1, H E Lambert 1, P Price 1
PMCID: PMC2033602  PMID: 7841053

Abstract

The measurement of tumour cell proliferation is becoming increasingly recognised in defining prognostic groups. Proliferating cell nuclear antigen (PCNA) immunolocalisation can be used as an index of cell proliferation and may define the extent of departure from normal growth control. The monoclonal antibody PC10 stains PCNA in archival paraffin-embedded tissue. This study investigates its potential as a prognostic marker in early and advanced ovarian cancer. A three-stage immunoperoxidase technique was developed to detect the monoclonal antibody PC10. Archival paraffin-embedded tissue from 19 stage I ovarian tumours (13 malignant and six borderline) and 79 advanced (stage IIb-IV) ovarian tumours (patients entered into the Third North-West Thames Ovarian Cancer Trial) was immunostained with PC10. PC10 immunostaining was performed successfully in 91.8% of cases. The PC10 labelling index (PC10 LI) ranged from 1.5% to 88% with a mean value of 47.4%. Stage I borderline tumours had significantly lower PCNA labelling indexes than stage I malignant tumours (P < 0.048). In advanced disease there was an inverse correlation between PC10 and overall survival, and in those patients who underwent good debulking surgery (37 patients with disease < 2 cm diameter) a low PC10 value (< 36.5%) correlated with improved survival (log-rank trend test for survival, chi 2 = 5.75, P = 0.017). PCNA immunostaining defines a good prognostic subgroup in adequately debulked patients with ovarian cancer.

Full text

PDF
357

Images in this article

358Figure 1
on p.358

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allegranza A., Girlando S., Arrigoni G. L., Veronese S., Mauri F. A., Gambacorta M., Pollo B., Dalla Palma P., Barbareschi M. Proliferating cell nuclear antigen expression in central nervous system neoplasms. Virchows Arch A Pathol Anat Histopathol. 1991;419(5):417–423. doi: 10.1007/BF01605076. [DOI] [PubMed] [Google Scholar]
  2. Avanzi G. C., Porcu P., Brizzi M. F., Ghigo D., Bosia A., Pegoraro L. Interleukin 3-dependent proliferation of the human Mo-7e cell line is supported by discrete activation of late G1 genes. Cancer Res. 1991 Mar 15;51(6):1741–1743. [PubMed] [Google Scholar]
  3. Barnabei V. M., Miller D. S., Bauer K. D., Murad T. M., Rademaker A. W., Lurain J. R. Flow cytometric evaluation of epithelial ovarian cancer. Am J Obstet Gynecol. 1990 Jun;162(6):1584–1592. doi: 10.1016/0002-9378(90)90924-v. [DOI] [PubMed] [Google Scholar]
  4. Bravo R., Celis J. E. A search for differential polypeptide synthesis throughout the cell cycle of HeLa cells. J Cell Biol. 1980 Mar;84(3):795–802. doi: 10.1083/jcb.84.3.795. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bravo R., Frank R., Blundell P. A., Macdonald-Bravo H. Cyclin/PCNA is the auxiliary protein of DNA polymerase-delta. Nature. 1987 Apr 2;326(6112):515–517. doi: 10.1038/326515a0. [DOI] [PubMed] [Google Scholar]
  6. Burstin S. J., Meiss H. K., Basilico C. A temperature-sensitive cell cycle mutant of the BHK cell line. J Cell Physiol. 1974 Dec;84(3):397–408. doi: 10.1002/jcp.1040840308. [DOI] [PubMed] [Google Scholar]
  7. Dawson A. E., Norton J. A., Weinberg D. S. Comparative assessment of proliferation and DNA content in breast carcinoma by image analysis and flow cytometry. Am J Pathol. 1990 May;136(5):1115–1124. [PMC free article] [PubMed] [Google Scholar]
  8. DeCaprio J. A., Ludlow J. W., Lynch D., Furukawa Y., Griffin J., Piwnica-Worms H., Huang C. M., Livingston D. M. The product of the retinoblastoma susceptibility gene has properties of a cell cycle regulatory element. Cell. 1989 Sep 22;58(6):1085–1095. doi: 10.1016/0092-8674(89)90507-2. [DOI] [PubMed] [Google Scholar]
  9. Decker D. G., Mussey E., Williams T. J., Taylor W. F. Proceedings: Grading of gynecologic malignancy: epithelial ovarian cancer. Proc Natl Cancer Conf. 1972;7:223–231. [PubMed] [Google Scholar]
  10. Frankfurt O. S. Mitotic cycle and cell differentiation in squamous cell carcinomas. Int J Cancer. 1967 Jul 15;2(4):304–310. doi: 10.1002/ijc.2910020405. [DOI] [PubMed] [Google Scholar]
  11. Garcia R. L., Coltrera M. D., Gown A. M. Analysis of proliferative grade using anti-PCNA/cyclin monoclonal antibodies in fixed, embedded tissues. Comparison with flow cytometric analysis. Am J Pathol. 1989 Apr;134(4):733–739. [PMC free article] [PubMed] [Google Scholar]
  12. Hall P. A., Levison D. A., Woods A. L., Yu C. C., Kellock D. B., Watkins J. A., Barnes D. M., Gillett C. E., Camplejohn R., Dover R. Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: an index of cell proliferation with evidence of deregulated expression in some neoplasms. J Pathol. 1990 Dec;162(4):285–294. doi: 10.1002/path.1711620403. [DOI] [PubMed] [Google Scholar]
  13. Hollstein M., Sidransky D., Vogelstein B., Harris C. C. p53 mutations in human cancers. Science. 1991 Jul 5;253(5015):49–53. doi: 10.1126/science.1905840. [DOI] [PubMed] [Google Scholar]
  14. Jain S., Filipe M. I., Hall P. A., Waseem N., Lane D. P., Levison D. A. Prognostic value of proliferating cell nuclear antigen in gastric carcinoma. J Clin Pathol. 1991 Aug;44(8):655–659. doi: 10.1136/jcp.44.8.655. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Jaskulski D., deRiel J. K., Mercer W. E., Calabretta B., Baserga R. Inhibition of cellular proliferation by antisense oligodeoxynucleotides to PCNA cyclin. Science. 1988 Jun 10;240(4858):1544–1546. doi: 10.1126/science.2897717. [DOI] [PubMed] [Google Scholar]
  16. Kallioniemi O. P., Punnonen R., Mattila J., Lehtinen M., Koivula T. Prognostic significance of DNA index, multiploidy, and S-phase fraction in ovarian cancer. Cancer. 1988 Jan 15;61(2):334–339. doi: 10.1002/1097-0142(19880115)61:2<334::aid-cncr2820610224>3.0.co;2-m. [DOI] [PubMed] [Google Scholar]
  17. Kamel O. W., LeBrun D. P., Davis R. E., Berry G. J., Warnke R. A. Growth fraction estimation of malignant lymphomas in formalin-fixed paraffin-embedded tissue using anti-PCNA/Cyclin 19A2. Correlation with Ki-67 labeling. Am J Pathol. 1991 Jun;138(6):1471–1477. [PMC free article] [PubMed] [Google Scholar]
  18. Lambert H. E., Rustin G. J., Gregory W. M., Nelstrop A. E. A randomized trial comparing single-agent carboplatin with carboplatin followed by radiotherapy for advanced ovarian cancer: a North Thames Ovary Group study. J Clin Oncol. 1993 Mar;11(3):440–448. doi: 10.1200/JCO.1993.11.3.440. [DOI] [PubMed] [Google Scholar]
  19. Levine A. J., Momand J., Finlay C. A. The p53 tumour suppressor gene. Nature. 1991 Jun 6;351(6326):453–456. doi: 10.1038/351453a0. [DOI] [PubMed] [Google Scholar]
  20. Lipponen P. K., Eskelinen M. J. Cell proliferation of transitional cell bladder tumours determined by PCNA/cyclin immunostaining and its prognostic value. Br J Cancer. 1992 Jul;66(1):171–176. doi: 10.1038/bjc.1992.237. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Liu Y. C., Marraccino R. L., Keng P. C., Bambara R. A., Lord E. M., Chou W. G., Zain S. B. Requirement for proliferating cell nuclear antigen expression during stages of the Chinese hamster ovary cell cycle. Biochemistry. 1989 Apr 4;28(7):2967–2974. doi: 10.1021/bi00433a034. [DOI] [PubMed] [Google Scholar]
  22. Louis D. N., Edgerton S., Thor A. D., Hedley-Whyte E. T. Proliferating cell nuclear antigen and Ki-67 immunohistochemistry in brain tumors: a comparative study. Acta Neuropathol. 1991;81(6):675–679. doi: 10.1007/BF00296379. [DOI] [PubMed] [Google Scholar]
  23. Mercer W. E., Shields M. T., Amin M., Sauve G. J., Appella E., Romano J. W., Ullrich S. J. Negative growth regulation in a glioblastoma tumor cell line that conditionally expresses human wild-type p53. Proc Natl Acad Sci U S A. 1990 Aug;87(16):6166–6170. doi: 10.1073/pnas.87.16.6166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Mercer W. E., Shields M. T., Lin D., Appella E., Ullrich S. J. Growth suppression induced by wild-type p53 protein is accompanied by selective down-regulation of proliferating-cell nuclear antigen expression. Proc Natl Acad Sci U S A. 1991 Mar 1;88(5):1958–1962. doi: 10.1073/pnas.88.5.1958. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Miyachi K., Fritzler M. J., Tan E. M. Autoantibody to a nuclear antigen in proliferating cells. J Immunol. 1978 Dec;121(6):2228–2234. [PubMed] [Google Scholar]
  26. Nurse P. Ciba Medal Lecture. Eukaryotic cell-cycle control. Biochem Soc Trans. 1992 May;20(2):239–242. doi: 10.1042/bst0200239. [DOI] [PubMed] [Google Scholar]
  27. Oka K., Hoshi T., Arai T. Prognostic significance of the PC10 index as a prospective assay for cervical cancer treated with radiation therapy alone. Cancer. 1992 Sep 15;70(6):1545–1550. doi: 10.1002/1097-0142(19920915)70:6<1545::aid-cncr2820700617>3.0.co;2-s. [DOI] [PubMed] [Google Scholar]
  28. Pignatelli M., Stamp G. W., Kafiri G., Lane D., Bodmer W. F. Over-expression of p53 nuclear oncoprotein in colorectal adenomas. Int J Cancer. 1992 Mar 12;50(5):683–688. doi: 10.1002/ijc.2910500503. [DOI] [PubMed] [Google Scholar]
  29. Prelich G., Kostura M., Marshak D. R., Mathews M. B., Stillman B. The cell-cycle regulated proliferating cell nuclear antigen is required for SV40 DNA replication in vitro. Nature. 1987 Apr 2;326(6112):471–475. doi: 10.1038/326471a0. [DOI] [PubMed] [Google Scholar]
  30. Rosa J. C., Mendes R., Filipe M. I., Morris R. W. Measurement of cell proliferation in gastric carcinoma: comparative analysis of Ki-67 and proliferative cell nuclear antigen (PCNA). Histochem J. 1992 Feb;24(2):93–101. doi: 10.1007/BF01082445. [DOI] [PubMed] [Google Scholar]
  31. Rutgers D. H., Wils I. S., Schaap A. H., van Lindert A. C. DNA flow cytometry, histological grade, stage, and age as prognostic factors in human epithelial ovarian carcinomas. Pathol Res Pract. 1987 Apr;182(2):207–213. doi: 10.1016/s0344-0338(87)80106-1. [DOI] [PubMed] [Google Scholar]
  32. Sarraf C. E., McCormick C. S., Brown G. R., Price Y. E., Hall P. A., Lane D. P., Alison M. R. Proliferating cell nuclear antigen immunolocalization in gastro-intestinal epithelia. Digestion. 1991;50(2):85–91. doi: 10.1159/000200744. [DOI] [PubMed] [Google Scholar]
  33. Talavera A., Basilico C. Temperature sensitive mutants of BHK cells affected in cell cycle progression. J Cell Physiol. 1977 Sep;92(3):425–436. doi: 10.1002/jcp.1040920310. [DOI] [PubMed] [Google Scholar]
  34. Tubiana M., Courdi A. Cell proliferation kinetics in human solid tumors: relation to probability of metastatic dissemination and long-term survival. Radiother Oncol. 1989 May;15(1):1–18. doi: 10.1016/0167-8140(89)90113-8. [DOI] [PubMed] [Google Scholar]
  35. Visakorpi T., Kallioniemi O. P., Heikkinen A., Koivula T., Isola J. Small subgroup of aggressive, highly proliferative prostatic carcinomas defined by p53 accumulation. J Natl Cancer Inst. 1992 Jun 3;84(11):883–887. doi: 10.1093/jnci/84.11.883. [DOI] [PubMed] [Google Scholar]
  36. Volm M., Brüggemann A., Günther M., Kleine W., Pfleiderer A., Vogt-Schaden M. Prognostic relevance of ploidy, proliferation, and resistance-predictive tests in ovarian carcinoma. Cancer Res. 1985 Oct;45(10):5180–5185. [PubMed] [Google Scholar]
  37. Waseem N. H., Lane D. P. Monoclonal antibody analysis of the proliferating cell nuclear antigen (PCNA). Structural conservation and the detection of a nucleolar form. J Cell Sci. 1990 May;96(Pt 1):121–129. doi: 10.1242/jcs.96.1.121. [DOI] [PubMed] [Google Scholar]
  38. Woods A. L., Hall P. A., Shepherd N. A., Hanby A. M., Waseem N. H., Lane D. P., Levison D. A. The assessment of proliferating cell nuclear antigen (PCNA) immunostaining in primary gastrointestinal lymphomas and its relationship to histological grade, S+G2+M phase fraction (flow cytometric analysis) and prognosis. Histopathology. 1991 Jul;19(1):21–27. doi: 10.1111/j.1365-2559.1991.tb00890.x. [DOI] [PubMed] [Google Scholar]
  39. van Dierendonck J. H., Wijsman J. H., Keijzer R., van de Velde C. J., Cornelisse C. J. Cell-cycle-related staining patterns of anti-proliferating cell nuclear antigen monoclonal antibodies. Comparison with BrdUrd labeling and Ki-67 staining. Am J Pathol. 1991 May;138(5):1165–1172. [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES