Alteration of proliferation and apoptotic markers in normal and premalignant tissue associated with prostate cancer.
BACKGROUND
Molecular markers identifying alterations in proliferation and apoptotic pathways could be particularly important in characterizing high-risk normal or pre-neoplastic tissue. We evaluated the following markers: Ki67, Minichromosome Maintenance Protein-2 (Mcm-2), activated caspase-3 (a-casp3) and Bcl-2 to determine if they showed differential expression across progressive degrees of intraepithelial neoplasia and cancer in the prostate. To identify field effects, we also evaluated whether high-risk expression patterns in normal tissue were more common in prostates containing cancer compared to those without cancer (supernormal), and in histologically normal glands adjacent to a cancer focus as opposed to equivalent glands that were more distant.


METHODS
The aforementioned markers were studied in 13 radical prostatectomy (RP) and 6 cystoprostatectomy (CP) specimens. Tissue compartments representing normal, low grade prostatic intraepithelial neoplasia (LGPIN), high grade prostatic intraepithelial neoplasia (HGPIN), as well as different grades of cancer were mapped on H&E slides and adjacent sections were analyzed using immunohistochemistry. Normal glands within 1 mm distance of a tumor focus and glands beyond 5 mm were considered "near" and "far", respectively. Randomly selected nuclei and 40 x fields were scored by a single observer; basal and luminal epithelial layers were scored separately.


RESULTS
Both Ki-67 and Mcm-2 showed an upward trend from normal tissue through HGPIN and cancer with a shift in proliferation from basal to luminal compartment. Activated caspase-3 showed a significant decrease in HGPIN and cancer compartments. Supernormal glands had significantly lower proliferation indices and higher a-casp3 expression compared to normal glands. "Near" normal glands had higher Mcm-2 indices compared to "far" glands; however, they also had higher a-casp3 expression. Bcl-2, which varied minimally in normal tissue, did not show any trend across compartments or evidence for field effects.


CONCLUSIONS
These results demonstrate that proliferation and apoptosis are altered not only in preneoplastic lesions but also in apparently normal looking epithelium associated with cancer. Luminal cell expression of Mcm-2 appears to be particularly promising as a marker of high-risk normal epithelium. The role of apoptotic markers such as activated caspase-3 is more complex, and might depend on the proliferation status of the tissue in question.
Ananthanarayanan
Vijayalakshmi
V
Department of Pathology, University of Illinois, Chicago, USA. viju@uic.edu
Deaton
Ryan J
RJ
Yang
Ximing J
XJ
Pins
Michael R
MR
Gann
Peter H
PH
D000230:Adenocarcinoma / Q000737:chemistry / Q000473:pathology*; D017209:Apoptosis; D015415:Biomarkers; D053148:Caspase 3; D020169:Caspases / Q000032:analysis; D018797:Cell Cycle Proteins / Q000032:analysis; D002455:Cell Division; D004847:Epithelial Cells / Q000737:chemistry / Q000648:ultrastructure; D006801:Humans; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D064111:Minichromosome Maintenance Complex Component 2; D009363:Neoplasm Proteins / Q000032:analysis*; D009687:Nuclear Proteins / Q000032:analysis; D011467:Prostate / Q000737:chemistry / Q000473:pathology*; D019048:Prostatic Intraepithelial Neoplasia / Q000737:chemistry / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000737:chemistry / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D001749:Urinary Bladder Neoplasms / Q000737:chemistry / Q000473:pathology
D015415:Biomarkers; D018797:Cell Cycle Proteins; D019394:Ki-67 Antigen; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2