Combined role of tumor angiogenesis, bcl-2, and p53 expression in the prognosis of patients with colorectal carcinoma.
BACKGROUND
The objective of this study was to evaluate intratumoral neoangiogenesis in Dukes Stage B and Stage C (AJCC/UICC Stage I and III) colorectal adenocarcinoma and its correlation with nuclear p53 oncoprotein accumulation and cytoplasmic bcl-2 expression as well as to assess the prognostic significance of these features in patient outcome.


METHODS
Paraffin embedded specimens from 55 patients with Dukes Stage B (AJCC/UICC Stage I) and 51 patients with Dukes Stage C (AJCC/UICC Stage III) colorectal adenocarcinoma who were treated with surgery were assessed. Patients with lymph node involvement (Dukes Stage C [AJCC/UICC Stage III]) also were treated with postoperative pelvic radiotherapy and adjuvant chemotherapy with 5-fluorouracil and leucovorin with or without interferon-alpha. Immunohistochemistry was performed using the anti-CD31 monoclonal antibody (MoAb) for vessel staining, the DO7 MoAb for nuclear p53 expression, and the clone 124 for cytoplasmic/perinuclear bcl-2 expression. Patient follow-up ranged from 4-70 months (median, 28 months).


RESULTS
High vascular grade (microvessel score [MS] >/= 40) was observed in 39 of 106 specimens (37%), a medium MS (16-39) was observed in 29 of 106 cases (27%), and a low MS (7-15) was observed in 38 of 106 cases (36%). Positive expression of the bcl-2 protein in > 10% of cells was observed in 33 of 106 cases (31%), whereas p53 nuclear oncoprotein accumulation in > 10% of cells occurred more frequently (44 of 106 cases [42%]). No correlation among p53 expression, bcl-2 expression, and vascular grade was observed. Stroma infiltration by CD31 positive lymphocytes was associated strongly with increased vessel density (P = 0.0001). In univariate analysis Dukes stage was the only significant prognostic parameter (P = 0.02), whereas p53 and vascular grade showed marginal prognostic significance (P = 0.07 and P = 0.09, respectively). In Dukes Stage C (AJCC/UICC Stage III) patients, high vascular grade was the only parameter that predicted a worse overall survival (P = 0.04). Double stratification showed that patients with high vascular grade and positive p53 expression had a poorer survival (P = 0.03).


CONCLUSIONS
The results of the current study suggest that p53 mutations, loss of bcl-2 expression, and tumor angiogenesis are events linked to the processes of metastases and local invasion in patients with colorectal carcinoma. Increased vascularization appears to be the most important prognostic factor in patients with Dukes Stage C (AJCC/UICC Stage III) colorectal adenocarcinoma.
Giatromanolaki
A
A
Laboratory of Cancer Biology, University Hospital of Iraklion, Iraklion, Crete, Greece.
Stathopoulos
G P
GP
Tsiompanou
E
E
Tsiobanou
E
E
Papadimitriou
C
C
Georgoulias
V
V
Gatter
K C
KC
Harris
A L
AL
Koukourakis
M I
MI
D000230:Adenocarcinoma / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis / Q000096:biosynthesis* / Q000502:physiology; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000096:biosynthesis* / Q000502:physiology
D019408:Platelet Endothelial Cell Adhesion Molecule-1; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53