Apoptotic versus proliferative activities in human benign prostatic hyperplasia

Abstract

Cell growth in the normal prostate is regulated by a delicate balance between cell death and cell proliferation (ie, apoptotic v proliferative activity). Disruption of the molecular mechanisms that regulate these two processes may underline the abnormal growth of the gland leading to benign prostatic hyperplasia (BPH). In this study, the incidence of programmed cell death (apoptosis) and cell proliferation was comparatively analyzed among the various cell subpopulations in the normal and benign hyperplastic human prostate. The authors also examined the relative expression of two proteins involved in the regulation of prostate apoptosis: (1) transforming growth factor (TGF)- β 1, a negative growth factor able to induce prostate apoptosis under physiological conditions; and (2) bcl-2, a potent apoptosis suppressor. Analysis of the incidence of “spontaneous” apoptosis in situ, using the end-labeling terminal transferase staining technique for the detection of nucleosomal DNA fragmentation, revealed infrequent apoptotic staining in isolated basal and secretory prostate epithelial cells. The basal level of cell proliferation was determined on the basis of the Ki-67 nuclear antigen staining, a nuclear protein that appears primarily during the proliferative phases of the cell cycle. The Ki-67-positive nuclei were equally distributed among the basal and secretory epithelial cells of the hyperplastic prostatic acini. The apoptotic index of the secretory and basal cells of the prostate epithelium was higher in the normal prostate compared with BPH tissue, whereas there was a significant increase in the proliferative index of the respective cell populations in the hyperplastic prostate. Balancing the apoptotic versus the proliferative activities revealed a substantial net decrease (fourfold) in the total number of cells dying via apoptosis in both the glandular and basal epithelial cell compartments of the hypertrophic prostate (BPH) when compared with the normal gland. TGF-β staining was exclusively identified in the secretory epithelial cells, lining the prostatic lumen with minimal involvement of the basal cells and total lack of immunoreactivity among the stroma elements. Statistical analysis revealed a significant elevation in TGF-β expression in the epithelial cells of BPH tissue compared with the normal prostate ( P < .001). Expression of bcl-2 was topologically restricted to the glandular epithelium of the prostate. In the normal prostate, bcl-2 immunoreactivity was predominantly identified in the basal cell layer. An increase in both the intensity of immunoreactivity for bcl-2 and the number of positive epithelial cells (basal and secretory) was detected in BPH specimens relative to the normal prostate ( P < .02). These results suggest a potential involvement of enhanced expression of this antiapoptosis protein in deregulation of the normal apoptotic cell death mechanisms in the human prostate, thus resulting in a growth imbalance in favor of cell proliferation that might ultimately promote prostatic hyperplasia.