TGF-beta 3 expression correlates with epithelial cell death in normal, hyperplastic and malignant prostate

Abstract

Cytokines of the TGF beta family are thought to be involved in cellular growth control and are therefore likely candidates to regulate homeostasis of the prostate. We have analyzed immunohistochemically the expression of TGF-beta 3 in normal prostate (NP), benign prostate hyperplasia (BPH) and prostate cancer (PCa). Its expression was correlated to cell death and cell proliferation using double labeling techniques with terminal transferase and anti-Ki67 antibodies, respectively. TGF-beta 3 expression, localized to the basal cell layer of glandular epithelium, was found in NP and BPH. In TGF-beta 3 positive regions cell death was frequently detected, while proliferating cells were only observed in TGF-beta 3 negative areas. Moreover, cell death was not observed in the absence of TGF-beta 3. PCa was characterized by high cell proliferation and the absence of cell death. TGF-beta 3 expression could not be detected in PCa. Hormonal ablation is the main therapeutic protocol used today suffering, however, from a high relapse rate. We have used the rat as a model system to show that castration, resulting in massive cell death of glandular epithelial cells, induces overall expression of TGF-beta 3 in the basal cell layers. Interestingly, investigation of tumor material from patients received after hormonal ablation revealed the simultaneous presence of TGF-beta 3 positive, hyperplastic regions undergoing cell death and TGF-beta 3 negative highly proliferating malignant foci. Our results suggest that the expression of TGF-beta 3 strictly correlates with cell death in normal and hyperplastic prostate and that disappearance of TGF-beta 3 indicates high cell proliferation and the establishment of the malignant phenotype.