title: High levels of cleaved caspase-3 in colorectal tumour stroma predict good survival.
abstract: OBJECTIVE
  The primary aim was to determine the prognostic significance of apoptosis in colorectal tumour cells and tumour-associated stroma. A secondary aim was to determine whether apoptosis was related to immune surveillance.
  
  
  METHODS
  Immunohistochemistry was performed using monoclonal antibodies recognising cleaved caspase-3 (CC3), cleaved poly (ADP-ribose) polymerase (PARP), p53, Bcl2, MHC-II, B cells (CD16), macrophages (CD68) and T cells (CD3), on a tissue microarray of 462 colorectal tumours.
  
  
  RESULTS
  Kaplan-Meier analysis demonstrated that patients with high expression of CC3 in the tumour or CC3 or cleaved PARP in tumour-associated stroma have a good prognosis. This suggests that tumour stroma is promoting tumourigenesis and that high levels of death within the stroma breaks this link. CC3 levels in the tumour correlated with cleaved PARP and MHC-II expression but not with CD16, CD68, CD3, p53 or Bcl2 expression. CC3 levels on tumour-associated stroma also correlated with cleaved PARP and MHC-II expression but not with CD16, CD68, CD3, p53 or Bcl2 expression. Tumour cells express MHC-II in response to IFN-γ, suggesting that this may be one of the initiators of apoptosis within the good prognosis tumours. Although 73% of the MHC-II-positive tumour had high levels of apoptosis, many tumours had high levels of apoptosis in the absence of MHC-II, implying that this is only one of many causes of apoptosis within tumours. On multivariate analysis, using Cox's proportional hazards model, tumour stage, vascular invasion and expression of CC3 in tumour-associated stroma were shown to be independent markers of prognosis.
  
  
  CONCLUSIONS
  This study shows that a high level of apoptosis within colorectal tumour-associated stroma is an independent marker of good prognosis.
authors.affiliation: Academic Department of Clinical Oncology, University of Nottingham, City Hospital Campus, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: P
authors.initials: P
authors.lastname: Noble
authors.forename: M
authors.initials: M
authors.lastname: Vyas
authors.forename: A
authors.initials: A
authors.lastname: Al-Attar
authors.forename: S
authors.initials: S
authors.lastname: Durrant
authors.forename: J
authors.initials: J
authors.lastname: Scholefield
authors.forename: L
authors.initials: L
authors.lastname: Durrant
mesh_terms: D000368:Aged; D017209:Apoptosis / Q000502:physiology; D014408:Biomarkers, Tumor / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism*; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000401:mortality* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D011379:Prognosis; D016016:Proportional Hazards Models; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D011498:Protein Precursors; C505407:CASP3 protein, human; D053148:Caspase 3