bromochloroacetic-acid and androstane-3-17-diol-dipropionate

The canine prostate has often been proposed as a model for abnormal growth of the human gland. Hyperplasia of the prostate is common in aging men and has been estimated to be present in 100% of old intact dogs. While prostatic carcinoma is common in older men it appears to be rare in dogs and unlike the disease in humans it occurs with relatively high frequency in castrated animals. Since basal cells are thought to be key participants in normal and abnormal growth of the human gland, we used immunohistochemistry to investigate the role that they may play in canine prostatic development, the evolution of hyperplasia and carcinoma, and the effects of sex hormones on these cells.. Prostate specimens were obtained at autopsy from seven sexually immature dogs, autopsy and biopsy samples from 14 sexually mature intact animals, from four castrates, and from 19 dogs with prostatic carcinoma. In addition, we also studied the prostates from two intact dogs treated with 5 alpha-dihydrotestosterone (DHT) for 6 months and two castrated dogs that were subsequently treated with 5 alpha-androstane-3 alpha diol and estradiol-17 alpha as well as specimens from two sexually ablated animals given DHT for 2 weeks. All specimens were immunostained for high molecular weight cytokeratin (HMC), Pancytokeratin, androgen receptor (AR), and the proliferative marker KI-67.. We find that basal cells are the major proliferative cell type in the neonatal and adult canine prostate and that the expression of HMC staining, which defines these cells, may be regulated by androgens. In the adult gland, ductal basal cells formed a contiguous layer whereas those lining acini were discontinuous. Populations of both basal cell types were variably AR positive but while HMC immunostaining was abolished in acinar cells following long-term castration, staining remained in ductal cell counterparts. Paralleling the histological development of hyperplasia, the acinar basal cell population increased with age and were the major cell type that expressed KI-67. In contrast, ductal basal cell populations did not expand in the prostates of older dogs and were seldom positively stained for KI-67. The numbers of HMC and KI-67-stained acinar basal cells were dramatically increased in the prostates of intact dogs treated with DHT when compared with glands of untreated controls. This was not the case with ductal basal cells. Androgens given alone or together with estrogen to castrated dogs induced widespread HMC and KI-67 immunostaining in both populations of basal cells. In addition, our results indicate that the majority of canine prostatic carcinomas likely arise exclusively from ductal epithelium. Only one of the 19 cases of carcinoma contained cells that expressed AR which suggests that androgens may not be required for the initiation or progression of these cancers.. Our findings indicate that two biologically distinct populations of basal cells may exist in the canine prostate. In this regard the age-related expansion of proliferating acinar basal cell populations, probably mediated by sex steroids, is a key factor in the pathogenesis of canine prostatic hyperplasia. Additionally we find that prostatic carcinoma in the dog likely arises from ductal cells. Taken together these findings may indicate that canine acinar basal cells and ductal epithelium have separate susceptibilities to factors that promote hyperplastic or neoplastic development. Prostate 47:149-163, 2001.

Topics: Adenocarcinoma; Androstane-3,17-diol; Animals; Cell Division; Dihydrotestosterone; Disease Models, Animal; Dog Diseases; Dogs; Estradiol; Gonadal Steroid Hormones; Immunohistochemistry; Keratins; Ki-67 Antigen; Male; Orchiectomy; Prostate; Prostatic Hyperplasia; Prostatic Neoplasms; Receptors, Androgen

To demonstrate a potential for multidirectional differentiation in mature prostatic epithelium, 17 beta-estradiol 17-cyclopentylpropionate (ECP) and 5 alpha-androstane-3 alpha, 17 beta-diol dipropionate (3 alpha-diol DP) were administered individually and in combination to castrated dogs. Quantitative ultrastructural and cytochemical methods were used to distinguish phenotypes of glandular cells in the various hormonal environments. Castration-induced glandular cell regression was accompanied by an increased nuclear to cytoplasmic ratio; by enhanced keratin positivity, expressed as dispersed immunolabeled tonofilaments; and by an absence of peanut agglutinin (PNA) binding sites on luminal membranes. Administration of ECP resulted in squamous metaplasia as well as hypertrophy of the glandular epithelium. The hypertrophied estrogen-modified glandular (EMG) cells were characterized by a new population of small (0.29 micron in diameter) secretory granules, bundles of tonofilaments, and PNA-positive luminal membranes. Treatment of castrated dogs with 3 alpha-diol DP produced a greater epithelial hypertrophy than ECP. These cells were characterized by larger (0.49 micron in diameter) secretory granules, dispersed tonofilaments, and no detectable PNA receptors. Joint administration of ECP and 3 alpha-diol DP caused a florid response including squamous metaplasia and hypertrophy of the glandular epithelium which was associated with the emergence of a novel phenotype in androgen-estrogen modified glandular (A-EMG) cells. In A-EMG cells, secretory granules were similar in size to those found in 3 alpha-diol DP-dominated epithelium whereas tonofilaments often appeared in bundles and luminal membranes were PNA positive, i.e., features found in EMG cells. Our results indicate that atrophic canine prostatic glandular cells possess pluripotentiality of response to sex hormones.

Topics: Androgens; Androstane-3,17-diol; Animals; Cytoplasmic Granules; Dogs; Epithelial Cells; Epithelium; Estradiol; Estrogens; Immunoenzyme Techniques; Keratins; Male; Microscopy, Electron; Orchiectomy; Phenotype; Prostate; Radioimmunoassay; Receptors, Mitogen; Tolonium Chloride