The transplantable human prostate tumor lines PC-82 and PC-EW regress after androgen depletion. The castration-induced decline in tumor volume was faster in the PC-EW tumor (half-life 6 days) than in the PC-82 tumor (half-life 18 days), despite similar castrate androgen levels of less than 3 pmol/g tissue. Androgen ablation of the PC-82 tumor induced a wave of apoptosis, whereas in the PC-EW tumor, necrotic cell death was predominantly observed. The proliferative activity (BrdU index) of PC-82 and PC-EW tumor tissue declined from 3% to less than 1% after castration. After androgen depletion, some proliferative activity remained, the major part of which was localized in the (murine) stromal compartment of the tumors. In contrast to the PC-EW tumors, regrowth of androgen-ablated PC-82 tumors was rapidly induced by androgen resubstitution. The differences in response of these tumor models to androgen depletion and repletion appear to be related to the putative involvement of different cell death pathways. The role of the stroma in these processes is unclear.

The study of stromal-epithelial interactions greatly depends on the ability to culture both cell types separately, in order to permit analysis of their interactions under defined conditions in reconstitution experiments. Here we report the establishment of explant cultures of human prostatic stromal cells and their immunocytochemical characterization. As determined by antibodies to keratin and prostate specific acid phosphatase, only small numbers (< 5%) of epithelial cells were present in primary cultures; subsequent passaging further reduced epithelial cell contamination. Antibodies against intermediate filament proteins (keratins, vimentin, and desmin) and smooth muscle actin microfilaments demonstrated that stromal cells from benign prostatic hyperplasia and prostate carcinoma differed in regard to their differentiation markers. Two contrasting phenotypes were identified in cultures derived from these two different lesions: One exhibiting fibroblastic features, was predominant in cultures derived from benign lesions and a second, showing varying degrees of smooth muscle differentiation, was more abundant in carcinoma-derived cultures. These findings are indicative of a remarkable divergence in the stromal-epithelial relationships associated with these pathological conditions and may provide us with a potential tool for studying these processes.

The potential of the adrenal androgens androstenedione (A) and dehydroepiandrosterone (DHEA) to stimulate prostate tumor growth was investigated in the hormone-dependent human prostate tumor model PC-82, propagated in nude mice. Substitution of castrated mice bearing growth-arrested tumors with DHEA for 28 days, resulting in peripheral levels of 9.2 +/- 1.7 nmol/liter (mean +/- SEM), led to a decline of tumor burden comparable to that observed in castrated controls. Intratumor testosterone (T) and 5 alpha-dihydrotestosterone were similar to those detected in the castrated group. In contrast, high-dose A supplementation (peripheral level of 13.5 +/- 1.3 nmol/liter) in androgen ablated tumor-bearing mice resulted in tumor growth, although less pronounced than in T-resubstituted mice (T level of 18.8 +/- 1.5 nmol/l). Intraprostatic levels of androgens were not different between both groups. Substitution of castrated PC-82 tumor-bearing mice with low-dose A (2.5 +/- 0.4 nmol/l) neither stimulated growth of tumors nor did it lead to regression of PC-82 tumors. Proliferative activity as estimated by BrdU incorporation (S-phase cells) was not induced in these tumors. In conclusion, DHEA does not have a stimulatory effect on growth of PC-82 tumor tissue, but A is capable of inducing PC-82 tumor growth, most likely through peripheral conversion of A into T and 5 alpha-dihydrotestosterone.

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