title: Combined analysis of biomarkers of proliferation and apoptosis in colon cancer: an immunohistochemistry-based study using tissue microarray.
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.
  
  
  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.
authors.affiliation: Department of Surgical Oncology, Leiden University Medical Center, P.O Box 9600, 2300 RC, Leiden, The Netherlands.
authors.forename: M S
authors.initials: MS
authors.lastname: Reimers
authors.forename: E C M
authors.initials: EC
authors.lastname: Zeestraten
authors.forename: T C
authors.initials: TC
authors.lastname: van Alphen
authors.forename: J W T
authors.initials: JW
authors.lastname: Dekker
authors.forename: H
authors.initials: H
authors.lastname: Putter
authors.forename: S
authors.initials: S
authors.lastname: Saadatmand
authors.forename: G J
authors.initials: GJ
authors.lastname: Liefers
authors.forename: C J H
authors.initials: CJ
authors.lastname: van de Velde
authors.forename: P J K
authors.initials: PJ
authors.lastname: Kuppen
mesh_terms: D000368:Aged; D000704:Analysis of Variance; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis*; D053148:Caspase 3 / Q000032:analysis; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D053842:Microsatellite Instability; D009367:Neoplasm Staging; D012189:Retrospective Studies; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D019394:Ki-67 Antigen; D053148:Caspase 3