Skip to main content
SpringerLink
Log in

Apoptosis and expression of the proto-oncogenesbcl-2 and p53 and the proliferation factor Ki-67 in human medullary thyroid carcinoma

  • Clinical Research
  • Published:
Endocrine Pathology Aims and scope Submit manuscript

Abstract

Apoptosis and immunoreactivity forbcl-2, p53, and Ki-67 were studied in 21 patients with medullary thyroid carcinoma (MTC). The DNA nick end labeling method was used to assess apoptosis. The relationships between the different factors were analyzed, as were their relations to clinicopathological data, including survival. More than 80% of the tumors harbored apoptotic cells. Tumors in individuals who had died of the MTC disease had a higher percentage of apoptosis. All cases demonstrated immunoreactivity tobcl-2; disease-free individuals had a higher rate than those with recurrent disease. No obvious pattern could be discerned in the relation of p53 or Ki-67 to the outcome of the MTC disease. An inverse correlation betweenbcl-2 and apoptosis (r=−0.81;p<0.01) was demonstrated.bcl-2 was significantly (p=0.014) associated with apoptosis even after taking both p53 and Ki-67 into consideration, but these two factors were unrelated to apoptosis. None of the factors studied were correlated to crude survival, either in univariate or in multivariate analyses. This study established thatbcl-2 immunoreactivity is closely associated with apoptosis in MTC, suggesting that a downregulation of thebcl-2 protein is related to a more aggressive growth rate and might be a useful marker for the evaluation of MTC.

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

Similar content being viewed by others

References

  1. Chandler D, El-naggar AK, Brisbay S, Redline RW, McDonnell TJ. Apoptosis and expression of the bcl-2 proto-oncogene in the fetal and adult human kidney: evidence for the contribution of bcl-2 expression to renal carcinogenesis. Hum Pathol 25:789–796, 1994.

    Article  PubMed  CAS  Google Scholar 

  2. Aihara M, Truong LD, Dunn JK, Wheeler TM, Scardino PT, Thompson TC. Frequency of apoptotic bodies positively correlates with gleason grade in prostate cancer. Hum Pathol 25:797–801, 1994.

    Article  PubMed  CAS  Google Scholar 

  3. Bourhis J, Bosq J, Wilson GD, Bressac B, Talbot M, Leridant AM, Dendale R, Janin N, Armand JP, Luboinski B, Malaise EP, Wibault P, Eschwege F. Correlation between p53 gene expression and tumor-cell proliferation in oropharyngeal cancer. Int J Cancer 57:458–462, 1994.

    Article  PubMed  CAS  Google Scholar 

  4. Cotter TG, Lennon SV, Glynn JG, Martin SJ. Cell death via apoptosis and its relationship to growth, development and differentiation of both tumour and normal cells. Anticancer Res 10:1153–1160, 1990.

    PubMed  CAS  Google Scholar 

  5. Dobashi Y, Sakamoto A, Sugimura H, Mernyei M, Machinami R. Overexpression of p53 as possible prognostic factor in human thyroid carcinoma. Am J Surg Pathol 17:375–381, 1993.

    Article  PubMed  CAS  Google Scholar 

  6. Gerdes J, Li L, Schlueter C, Duchrow M, Wohlenberg C, Gerlach C, Stahmer I, Kloth S, Brandt E, Flad HD. Immunobiochemical and molecular biologic characterization of the cell proliferation-associated nuclear antigen that is defined by monoclonal antibody Ki67. Am J Pathol 138:867–873, 1991.

    PubMed  CAS  Google Scholar 

  7. Hague A, Moorghen M, Hicks D, Chapman M, Paraskeva C. bcl-2 expression in human colorectal adenomas and carcinomas. Oncogene 9:3367–3370, 1994.

    PubMed  CAS  Google Scholar 

  8. Ito K, Watanabe K, Nasim S, Sasano H, Sato S, Yajima A, Silverberg SG, Garrett CT. Prognostic significance of p53 overexpression in endometrial cancer. Cancer Res 54:4667–4670, 1994.

    PubMed  CAS  Google Scholar 

  9. Joensuu H, Pylkkänen L, Toikkanen S. bcl-2 protein expression and long-term survival in breast cancer. Am J Pathol 145:1191–1198, 1994.

    PubMed  CAS  Google Scholar 

  10. Kushima R, Moritani S, Hattori T. Overexpression of p53 protein in gastric carcinomas: relationship with development, progression and mucin-histochemical differentiation. Cancer J 7:192–197, 1994.

    Google Scholar 

  11. Porter PL, Gown AM, Kramp SG, Coltrera MD. Widespread p53 overexpression in human malignant tumors: an immunohistochemical study using methacarn-fixed, embedded tissue. Am J Pathol 140:145–153, 1992.

    PubMed  CAS  Google Scholar 

  12. Porter MJ, Field JK, Lee JCK, Leung SF, Lo D, Hasselt CAV. Detection of the tumour suppressor gene p53 in nasopharyngeal carcinoma in Hong Kong Chinese. Anticancer Res 14:1357–1360, 1994.

    PubMed  CAS  Google Scholar 

  13. Skalova A, Lehtonen H, Boguslawsky KV, Leivo I. Prognostic significance of cell proliferation in mucoepidermoid carcinomas of the salivary gland: clinicopathological study using MIB 1 antibody in paraffin sections. Hum Pathol 25:929–935 1994.

    Article  PubMed  CAS  Google Scholar 

  14. Teh M, Wee A, Path MRC, Raju GC. An immunohistochemical study of p53 protein in gallbladder and extrahepatic bile duct/ampullary carcinomas. Cancer 74:1542–1545, 1994.

    Article  PubMed  CAS  Google Scholar 

  15. LeBrun DP, Wamke RA, Cleary ML. Expression of bcl-2 fetal tissues suggests a role in morphogenesis. Am J Pathol 142:743–753, 1993.

    PubMed  CAS  Google Scholar 

  16. Novack DV, Korsmeyer SJ. bcl-2 protein expression during murine development. Am J Pathol 145:61–73, 1994.

    PubMed  CAS  Google Scholar 

  17. Baer R. bcl-2 breathes life into embryogenesis. Am J Pathol 145:7–10, 1994.

    PubMed  CAS  Google Scholar 

  18. Gusterson B, Anbazhagan R, Waren W, Midgely C, Lane P, O’Hare M, Stamps A, Carter R, Jayatilake H. Expression of p53 in pre-malignant and malignant squamous epithelium. Oncogene 6:1785–1789, 1992.

    Google Scholar 

  19. Key G, Becker MHG, Baron B, Duchrow M, Schluter C, Flad HD, Gerdes J. New Ki-67-equivalent murine monoclonal antibodies (MIB 1–3) generated against bacterially expressed parts of the Ki-67 cDNA containing three 62 base pair repetitive elements encoding for the Ki-67 epitope. Lab Invest 68:629–636, 1993.

    PubMed  CAS  Google Scholar 

  20. Reinariz JJ, George E, Lindgren BR, Niehans GA. Expression of p53, transforming growth factor alpha, epidermal growth factor receptor, and c-erbB-2 in endometrial carcinoma and correlation with survival and known predictors of survival. Hum Pathol 25:1075–1083, 1994.

    Article  Google Scholar 

  21. Sasano H, Garrett CT. Oncogenes in gynecological tumors. Curr Top Pathol 85:357–372, 1992.

    PubMed  CAS  Google Scholar 

  22. Roncalli M, Viale G, Grimelius L, Johansson H, Wilander E, Alfano RM, Springall D, Battezzati PM, Polak JM, Coggi G. Prognostic value of N-myc immunoreactivity in medullary thyroid carcinoma. Cancer 74:134–141, 1994.

    Article  PubMed  CAS  Google Scholar 

  23. Gavrieli Y, Sherman Y, Ben-Sasson SA. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501, 1992.

    Article  PubMed  CAS  Google Scholar 

  24. Rosai J, Carcangiu ML, Delellis RA. Tumors of the thyroid gland. Atlas of tumor pathology. 3rd ser. Washington, DC: Fascicle 5, Armed Forces Institute of Pathology, 1992; 207–240.

  25. Bergholm U. Medullary thyroid carcinoma in Sweden. Compr Summ Uppsala Diss Faculty Med 189:1–32, 1989.

    Google Scholar 

  26. Quinn CM, Wright NA. The clinical assessment of proliferation and growth in human tumours: evaluation of methods and applications as prognostic variables. J Pathol 160:93–102, 1990.

    Article  PubMed  CAS  Google Scholar 

  27. Duncan AMV, Heddle JA, Blakey DH. Mechanism of induction of nuclear anomalies by γ-radiation in the colonic epithelium of the mouse. Cancer Res 45:250–252, 1985.

    PubMed  CAS  Google Scholar 

  28. Lee FD. Importance of apoptosis in the histopathology of drug related lesions in the large intestine. J Clin Pathol 46:118–122, 1993.

    Article  PubMed  CAS  Google Scholar 

  29. Willingham MC, Bhalla K. Transient mitotic phase localization of bcl-2 oncoprotein in human carcinoma cells and its possible role in prevention of apoptosis. J Histochem Cytochem 42:441–450, 1994.

    PubMed  CAS  Google Scholar 

  30. Hockenbery DM, Oltvai ZN, Yin XM, Milliman CL, Korsmeyer J. bcl-2 functions in an anti-oxidant pathway to prevent apoptosis. Cell 75:241–251, 1993.

    Article  PubMed  CAS  Google Scholar 

  31. Pezzella F, Turley H, Kuzu I, Tungekar MF, Dunnill MS, Pierce CB, Harris A, Gatter KC, Mason DY. bcl-2 protein in non-small-cell lung carcinoma. N Engl J Med 329:690–694, 1993.

    Article  PubMed  CAS  Google Scholar 

  32. Korsmeyer SJ. bcl-2 initiates a new category of oncogenes: regulators of cell death. Blood 80:879–886, 1992.

    PubMed  CAS  Google Scholar 

  33. Nakagawa K, Yarnamura K, Maeda S, Ichihashi M. bcl-2 expression in epidermal keratinocytic diseases. Cancer 74:1720–1724, 1994.

    Article  PubMed  CAS  Google Scholar 

  34. McDonnell TJ, Troncoso P, Brisbay SM, Logothetis C, Chung LWK, Hsieh JT, Tu SM, Campbell ML. Expression of the protooncogene bcl-2 in the prostate and its association with emergence of androgen-independent prostate cancer. Cancer Res 52:6940–6944, 1992.

    PubMed  CAS  Google Scholar 

  35. Viale G, Roncalli M, Grimelius, Graziani D, Johansson H, Bergholm U. Prognostic value of bcl-2 immunoreactivity in medullary thyroid carcinoma. Hum Pathol 26:945–950, 1995.

    Article  PubMed  CAS  Google Scholar 

  36. Kanavaros P, Loannidou D, Tzardi M, Datseris G, Katsantonis J, Delidis G, Tosca A. Mycosis fungoides: expression of C-myc p62, p53, bcl-2 and PCNA proteins and absence of association with Epstein-Barr virus. Pathol Res Pract 190:767–774, 1994.

    PubMed  CAS  Google Scholar 

  37. Pezzella F, Morrison H, Jones M, Lane D, Harris AJ, Mason DY. Immunohistochemical detection of p53 and bcl-2 proteins in non-Hodgkin’s lymphoma. Histopathology 22:39–44, 1993.

    Article  PubMed  CAS  Google Scholar 

  38. Marin MC, Hsu B, Meyn RE, Donehower LA, El-naggar AK, McDonnell TJ. Evidence that p53 and bcl-2 are regulators of a common cell death pathway important for in vivo lymphomagenesis. Oncogene 9:3107–3112, 1994.

    PubMed  CAS  Google Scholar 

  39. Shaw P, Bovey R, Tardy S, Sahli R, Sordat B, Costa J. Induction of apoptosis by wild-type p53 in a human colon tumor-derived cell line. Proc Natl Acad Sci USA 89:4495–4499, 1992.

    Article  PubMed  CAS  Google Scholar 

  40. Dobashi Y, Sugimura H, Sakamoto A, Mernyei M, Mori M, Oyama T, Machinami R. Stepwise participation of p53 gene mutation during differentiation of human thyroid carcinomas. Diagn Mol Pathol 3:9–14, 1994.

    Article  PubMed  CAS  Google Scholar 

  41. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman B, Reed J. Tumor suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 9:1799–1805, 1994.

    PubMed  CAS  Google Scholar 

  42. Pelosi G, Bresaola E, Rodella S, Manfrin E, Piubello Q, Schiavon I, Iannucci A. Expression of proliferation cell nuclear antigen, Ki-67 antigen, estrogen receptor protein, and tumor suppressor p53 gene in cytologic samples of breast cancer: an immunochemical study with clinical, pathological, and histologic correlations. Diagn Cytopathol 11:131–140, 1994.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pathology, University Hospital, S-751 85, Uppsala, Sweden

    Wenliang Wang MD, Erik Wilander MD & Lars Grimelius MD

  2. Department of Surgery, University Hospital, S-751 85, Uppsala, Sweden

    Henry Johansson MD & Ulla Bergholm MD

  3. Department of Pathology, 4th Military Medical University, Xian, People’s Republic of China

    Wenliang Wang MD

Authors
  1. Wenliang Wang MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Henry Johansson MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ulla Bergholm MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Erik Wilander MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lars Grimelius MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, W., Johansson, H., Bergholm, U. et al. Apoptosis and expression of the proto-oncogenesbcl-2 and p53 and the proliferation factor Ki-67 in human medullary thyroid carcinoma. Endocr Pathol 7, 37–45 (1996). https://doi.org/10.1007/BF02739913

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02739913

Key Words

Search

Navigation