Skip to main content
SpringerLink
Log in

Combined analysis of biomarkers of proliferation and apoptosis in colon cancer: an immunohistochemistry-based study using tissue microarray

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Background

Disturbance of the balance between proliferation and apoptosis is an important hallmark of tumor development. The goal of this study was to develop a descriptive parameter that represents this imbalance and relate this parameter to clinical outcome in all four stages of colon cancer.

Material and methods

The study population consisted of 285 stage I–IV colon cancer patients of which a tumor tissue microarray (TMA) was available. TMA sections were immunohistochemically stained and quantified for the presence of Ki67 and cleaved caspase-3 tumor expression. These results were used to develop the combined apoptosis proliferation (CAP) parameter and correlated to patient outcome.

Results

The CAP parameter was significantly related to clinical outcome; patients with CAP ++ (high level of both apoptosis and proliferation) showed the best outcome perspectives (overall survival (OS), p = 0.004 and disease-free survival (DFS), p = 0.009). The effect of the CAP parameter was related to tumor microsatellite status and indirectly to tumor location, where left-sided tumors with CAP + − (high level of proliferation, low level of apoptosis) showed a worse prognosis (DFS p value 0.02) and right-sided tumors with CAP + − had a better prognosis (DFS p value 0.032). With stratified analyses, the CAP parameter remained significant in stage II tumors only.

Conclusions

The CAP parameter, representing outcome of the balance between the level of apoptosis and proliferation, can be used as a prognostic marker in colon cancer patients for both DFS and OS, particularly in left-sided, microsatellite stable tumors when tumor–node–metastasis (TNM) stage is taken into account.

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
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Bedi A, Pasricha PJ, Akhtar AJ et al (1995) Inhibition of apoptosis during development of colorectal cancer. Cancer Res 55(9):1811–1816

    CAS  PubMed  Google Scholar 

  2. Ramachandran A, Madesh M, Balasubramanian KA (2000) Apoptosis in the intestinal epithelium: its relevance in normal and pathophysiological conditions. J Gastroenterol Hepatol 15(2):109–120

    Article  CAS  PubMed  Google Scholar 

  3. Takano Y, Saegusa M, Ikenaga M, Mitomi H, Okayasu I (1996) Apoptosis of colon cancer: comparison with Ki-67 proliferative activity and expression of p53. J Cancer Res Clin Oncol 122(3):166–170

    CAS  PubMed  Google Scholar 

  4. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674

    Article  CAS  PubMed  Google Scholar 

  5. Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70

    Article  CAS  PubMed  Google Scholar 

  6. Evan GI, Vousden KH (2001) Proliferation, cell cycle and apoptosis in cancer. Nature 411(6835):342–348

    Article  CAS  PubMed  Google Scholar 

  7. Flohil CC, Janssen PA, Bosman FT (1996) Expression of Bcl-2 protein in hyperplastic polyps, adenomas, and carcinomas of the colon. J Pathol 178(4):393–397

    Article  CAS  PubMed  Google Scholar 

  8. Garrity MM, Burgart LJ, Mahoney MR et al (2004) Prognostic value of proliferation, apoptosis, defective DNA mismatch repair, and p53 overexpression in patients with resected Dukes’ B2 or C colon cancer: a North Central Cancer Treatment Group Study. J Clin Oncol 22(9):1572–1582

    Article  CAS  PubMed  Google Scholar 

  9. Moss SF, Liu TC, Petrotos A et al (1996) Inward growth of colonic adenomatous polyps. Gastroenterology 111(6):1425–1432

    Article  CAS  PubMed  Google Scholar 

  10. Sinicrope FA, Roddey G, McDonnell TJ et al (1996) Increased apoptosis accompanies neoplastic development in the human colorectum. Clin Cancer Res 2(12):1999–2006

    CAS  PubMed  Google Scholar 

  11. Sinicrope FA, Hart J, Hsu HA et al (1999) Apoptotic and mitotic indices predict survival rates in lymph node-negative colon carcinomas. Clin Cancer Res 5(7):1793–1804

    CAS  PubMed  Google Scholar 

  12. Sugao Y, Koji T, Yao T, Ueki T, Tsuneyoshi M (2000) The incidence of apoptosis during colorectal tumorigenesis. Int J Surg Pathol 8(2):123–132

    Article  PubMed  Google Scholar 

  13. Brown JM, Attardi LD (2005) The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 5(3):231–237

    CAS  PubMed  Google Scholar 

  14. Scopa CD, Tsamandas AC, Zolota V et al (2003) Potential role of bcl-2 and ki-67 expression and apoptosis in colorectal carcinoma: a clinicopathologic study. Dig Dis Sci 48(10):1990–1997

    PubMed  Google Scholar 

  15. de Bruin EC, van de Velde CJ, van de Pas S et al (2006) Prognostic value of apoptosis in rectal cancer patients of the Dutch total mesorectal excision trial: radiotherapy is redundant in intrinsically high-apoptotic tumors. Clin Cancer Res 12(21):6432–6436

    Article  PubMed  Google Scholar 

  16. de Heer P, de Bruin EC, Klein-Kranenbarg E et al (2007) Caspase-3 activity predicts local recurrence in rectal cancer. Clin Cancer Res 13(19):5810–5815

    Article  PubMed  Google Scholar 

  17. Fluge O, Gravdal K, Carlsen E et al (2009) Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis. Br J Cancer 101(8):1282–1289

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Guastadisegni C, Colafranceschi M, Ottini L, Dogliotti E (2010) Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur J Cancer 46(15):2788–2798

    Article  CAS  PubMed  Google Scholar 

  19. Jonges LE, Nagelkerke JF, Ensink NG et al (2001) Caspase-3 activity as a prognostic factor in colorectal carcinoma. Lab Invest 81(5):681–688

    Article  CAS  PubMed  Google Scholar 

  20. Kimura T, Tanaka S, Haruma K et al (2000) Clinical significance of MUC1 and E-cadherin expression, cellular proliferation, and angiogenesis at the deepest invasive portion of colorectal cancer. Int J Oncol 16(1):55–64

    CAS  PubMed  Google Scholar 

  21. Pollack A, DeSilvio M, Khor LY et al (2004) Ki-67 staining is a strong predictor of distant metastasis and mortality for men with prostate cancer treated with radiotherapy plus androgen deprivation: Radiation Therapy Oncology Group Trial 92-02. J Clin Oncol 22(11):2133–2140

    Article  CAS  PubMed  Google Scholar 

  22. Salminen E, Palmu S, Vahlberg T, Roberts PJ, Soderstrom KO (2005) Increased proliferation activity measured by immunoreactive Ki67 is associated with survival improvement in rectal/recto sigmoid cancer. World J Gastroenterol 11(21):3245–3249

    PubMed  Google Scholar 

  23. Zeestraten EC, Maak M, Shibayama M et al (2012) Specific activity of cyclin-dependent kinase I is a new potential predictor of tumour recurrence in stage II colon cancer. Br J Cancer 106(1):133–140

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Menezes HL, Juca MJ, Gomes EG et al (2010) Analysis of the immunohistochemical expressions of p53, bcl-2 and Ki-67 in colorectal adenocarcinoma and their correlations with the prognostic factors. Arq Gastroenterol 47(2):141–147

    Article  PubMed  Google Scholar 

  25. Michael-Robinson JM, Reid LE, Purdie DM et al (2001) Proliferation, apoptosis, and survival in high-level microsatellite instability sporadic colorectal cancer. Clin Cancer Res 7(8):2347–2356

    CAS  PubMed  Google Scholar 

  26. Baretton GB, Diebold J, Christoforis G et al (1996) Apoptosis and immunohistochemical bcl-2 expression in colorectal adenomas and carcinomas. Aspects of carcinogenesis and prognostic significance. Cancer 77(2):255–264

    Article  CAS  PubMed  Google Scholar 

  27. Kawasaki H, Altieri DC, Lu CD et al (1998) Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. Cancer Res 58(22):5071–5074

    CAS  PubMed  Google Scholar 

  28. Soini Y, Paakko P, Lehto VP (1998) Histopathological evaluation of apoptosis in cancer. Am J Pathol 153(4):1041–1053

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487(7407):330-7

  30. Kim GP, Colangelo LH, Wieand HS et al (2007) Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol 25(7):767–772

    Article  CAS  PubMed  Google Scholar 

  31. Okon K, Demczuk S, Klimkowska A et al (2006) Correlation of microsatellite status, proliferation, apoptotic and selected immunohistochemical markers in colorectal carcinoma studied with tissue microarray. Pol J Pathol 57(2):105–111

    CAS  PubMed  Google Scholar 

  32. Dolcetti R, Viel A, Doglioni C et al (1999) High prevalence of activated intraepithelial cytotoxic T lymphocytes and increased neoplastic cell apoptosis in colorectal carcinomas with microsatellite instability. Am J Pathol 154(6):1805–1813

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Surgical Oncology, Leiden University Medical Center, P.O Box 9600, 2300 RC, Leiden, The Netherlands

    M. S. Reimers, E. C. M. Zeestraten, T. C. van Alphen, J. W. T. Dekker, S. Saadatmand, G. J. Liefers, C. J. H. van de Velde & P. J. K. Kuppen

  2. Department of Statistics, Leiden University Medical Center, Leiden, The Netherlands

    H. Putter

Authors
  1. M. S. Reimers
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. C. M. Zeestraten
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. T. C. van Alphen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. W. T. Dekker
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. H. Putter
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S. Saadatmand
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G. J. Liefers
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. C. J. H. van de Velde
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. P. J. K. Kuppen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P. J. K. Kuppen.

Additional information

M. S. Reimers and E. C. M. Zeestraten contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Reimers, M.S., Zeestraten, E.C.M., van Alphen, T.C. et al. Combined analysis of biomarkers of proliferation and apoptosis in colon cancer: an immunohistochemistry-based study using tissue microarray. Int J Colorectal Dis 29, 1043–1052 (2014). https://doi.org/10.1007/s00384-014-1930-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-014-1930-y

Keywords

Search

Navigation