Prostate cancer induction in autoimmune rats and modulation of T cell apoptosis

In this study we present an experimental model of prostate gland cancer induced by long term hormonal treatment with testosterone in combination with a chemical carcinogenic agent in male Wistar rats with autoimmune prostatitis (AIP). This system is particularly attractive in order to study the factors involved in the transition from a non-invasive to an invasive carcinoma, decisive in the risk of human cancer. At first, autoimmune prostatitis was induced by immunization in 3 months-old male Wistar rats with autologous accessory glands. Then, rats were treated with continuous intradermal implants of testosterone propionate (TP) and with single doses of the chemical carcinogen 7, 12 dimethylbenz (alpha) anthracene (DMBA) by intraperitoneal injection. Histopathological studies of the prostate gland revealed the presence of pre-malignant lesions, particularly the so-called prostatic intraepithelial neoplasm (PIN) in 50% of animals. Moreover, we observed the development of carcinomas in 50% of treated-animals, which could be histologically discriminated in adenocarcinomas, carcinoma of epidermal origin and undifferentiated carcinoma. In autoimmune rats which did not receive any other treatment, exposure to autoantigens gave rise to an atypical hyperplasia of the prostatic gland which could be attributed to the hyperactive state of the gland. Control groups constituted by autoimmune rats treated with TP or DMBA, and normal rats which were exposed to TP and/or DMBA evidenced the presence of PINs at different degrees, but did not develop carcinomas. Moreover, serum acid phosphatase significantly increased as treatment was accomplished, reaching its maximum levels in animals with carcinoma, in which DNA content, determined by image cytometry, showed to be aneuploid. Finally, we provided biochemical and cytofluorometrical evidence of the induction of apoptosis of spleen T cells in carcinoma-bearing hosts, and to a lesser extent in animals with PIN, but not in autoimmune or normal controls, which could represent an alternative molecular mechanism for explaining host immunosuppression triggered by tumors.