HUMAN PROSTATIC TUMOR-CELLS IN CULTURE PRODUCE GROWTH AND DIFFERENTIATION FACTORS ACTIVE ON OSTEOBLASTS - A NEW BIOLOGICAL AND CLINICAL-PARAMETER FOR PROSTATIC-CARCINOMA

Prostate cancer (PRCA) cells metastasize to bone with high frequency, inducing typical osteosclerotic lesions. To establish if local stimuli on the bone tissue may derive from metastatic colonies of prostatic o rigin, we evaluated the biologic activities secreted by human prostati c epithelium and effective on osteoblast-like cells in vitro. Supernat ant from short-term tissue cultures of human prostatic tissue samples obtained from PRCA (35 cases) and benign prostatic hyperplasia (BPH, 1 2 cases) patients were applied to three models of cells with osteoblas tic phenotype: two normal [rabbit osteoblasts (OB) and rat periosteal cells (PO)] and one transformed (human osteosarcoma cell line, MG63). Proliferative activity was monitored through enzymatic reduction of te trazolium salts and expressed as relative mitogenic activities (RMA). Analysis of proliferation and alkaline phosphatase (ALP) activity, a m arker of osteoblast function, demonstrates that conditioned media (CM) from PRCA cultures stimulate both growth and activity of osteoblast-l ike cells to a greater extent compared to CM from BPH. Furthermore, ce ll growth and activity of osteoblast-like cells are progressively incr eased by CM derived from patients with stage B (tumor confined within the prostate capsule), stage C (locally invasive tumor), and stage D ( invasive tumor with distant metastasis) disease. One of the mechanisms potentially underlying the CM-stimulated effects on bone cells is ass ociated with the urokinase (uPA) enzyme route, whose release progressi vely increases with the stage of disease. However, antibodies against uPA and p-aminobenzamidine (a low molecular weight urokinase inhibitor ) treatment, which both inhibit the proliferative and differentiative effects induced by exogenous urokinase, partially slow down the effect s of CM from PRCA tissue cultures, suggesting that additional factors are secreted by prostatic tumor cells in vitro. In conclusion, we show that the mitogenic and differentiative activities for osteoblasts pro duced by prostatic tumor cells in short-term tissue cultures are relat ed to PRCA stage and may predict the behavior of skeletal metastases i n single cases of tumor. In addition, the culture methods used may rep resent a valid model to study prostatic and bone cellular interactions , which may indicate new therapeutic approaches in metastatic prostate tumors.