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

Int J Colorectal Dis. 2014 Sep;29(9):1043-52. doi: 10.1007/s00384-014-1930-y. Epub 2014 Jun 21.


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.

MeSH terms

  • Aged
  • Analysis of Variance
  • Apoptosis*
  • Biomarkers, Tumor / analysis*
  • Caspase 3 / analysis
  • Cell Proliferation*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / mortality
  • Colonic Neoplasms / pathology*
  • Disease-Free Survival
  • Female
  • Humans
  • Immunohistochemistry
  • Ki-67 Antigen / analysis
  • Male
  • Microsatellite Instability
  • Neoplasm Staging
  • Retrospective Studies
  • Tissue Array Analysis


  • Biomarkers, Tumor
  • Ki-67 Antigen
  • Caspase 3