PLASMINOGEN-ACTIVATOR ACTIVITIES IN SHORT-TERM TISSUE-CULTURES OF BENIGN PROSTATIC HYPERPLASIA AND PROSTATIC-CARCINOMA

The high prevalence of prostatic carcinoma (PRCA) and the limited ther apeutic possibilities provide a strong stimulus for exploring new appr oaches in experimental research that ultimately may lead to improved t herapy. Indeed, methods for assessing carcinoma prognosis, such as cli nical staging (clinical examination, ultrasound, and plasmatic levels of prostatic acid phosphatase and prostate specific antigen) and histo pathological grading according to the Gleason score, usually fail to p rovide consistent predictive information regarding the clinical outcom e of single tumors. Increased plasminogen activator (PA) activities ha ve been associated with high-grade malignancies and with the potential for invasion/metastasis in many tumors. Urokinase-type plasminogen ac tivator (uPA) is present in prostatic secretion, and an increased uPA activity has been noted in human prostatic cell lines with metastatic behavior. Unfortunately, any study of uPA production or gene regulatio n in primary tumors is complicated by the inherent mixture of host str omal cells, infiltrating macrophages, and subpopulations of tumor cell s that may have variable metastatic capacity and ability to synthesize uPA. In shortterm tissue culture of prostatic samples, it is possible to grow in vitro cancer prostatic epithelial cells and thus exclude t he presence of contaminant cells. We have shown elsewhere that the lev els of a type TV collagenase, 92-kDa matrix metalloproteinase, a prote ase involved in tumor progression and invasion, are increased in PRCA primary cell cultures if compared with benign prostatic hyperplasia (B PH) cell cultures (C. Festuccia et at, manuscript in preparation). Act ivation of matrix metalloproteinases also can be correlated with uPA e xpression; therefore we studied the expression of uPA in serum-free cu lture media of primary cultures of PRCA or BPH tissue samples. We have cultured 38 tissue samples obtained from transurethral resections, fi ne needle biopsies, or prostatectomies; 25 cases of PRCA; 1 case of pr ostatic intraepithelial neoplasia; and 12 cases of BPH. A statisticall y significant elevation (P < 0.01) in PA levels was noted in cultures of metastatic (stage D) as compared to nonmetastatic (stages B and C) PRCA tissue samples (1.310 and 0.360 mU/mu g protein, respectively). T he average PA activity was also significantly higher (P < 0.05) in PRC A primary cultures of all stages when compared with BPH cultures (0.58 0 and 0.031 mU/mu g protein, respectively). Zymogram analysis showed t hat PA activity is primarily due to uPA. Indeed, enzyme-linked immunoa ssay determinations for uPA revealed higher amounts in culture media o f metastatic as compared to nonmetastatic PRCA samples (128.10 and 42. 52 ng/mu g protein, respectively). Analogously, uPA was statistically higher (P < 0.01) in PRCA primary cultures when compared with BPH cult ures (61.44 vs. 2.59 ng/mu g protein). PA activity and uPA levels were not dependent on Gleason histological classification. This finding ma y contribute to recognizing the different biological features of singl e cases of PRCA to improve clinical evaluation and the choice of thera peutic options.