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Keywords:

  • prostate cancer;
  • invasion;
  • type IV collagenases;
  • urokinase, retinoids

Abstract

We propose that, in prostate cancer, serine proteases occupy the apex of the proteolytic cascade and initiate the process of matrix degradation. Subsequently, collagenases are recruited after activation of procollagenases by another serine protease plasmin, which is formed by the activation of plasminogen by urokinase (u-PA). We show that u-PA alone can degrade fibronectin but not laminin. Serum free-conditioned medium (SF-CM) from DU-145 human prostatic carcinoma cells can degrade both fibronectin and laminin. Urokinase and gelatinase secretion was compared and correlated with the invasive ability of several human prostatic epithelial cell lines. DU-145 and LNCaP carcinoma cell lines and the following cell lines developed in our laboratories were used: PWR-1E (Ad12-SV40 immortalized, nontumorigenic), RWPE-1 (HPV-18 immortalized, nontumorigenic), and RWPE-2 (HPV-18 immortalized, Ki-ras-transformed, tumorigenic). Secreted urokinase levels were markedly increased in the malignant DU-145 and RWPE-2 cells and correlated with their invasive ability in vitro. Secreted gelatinase activity was undetectable in SF-CM from DU-145, trace in LNCaP, but detectable in the other three cell lines. The tumorigenic RWPE-2 cells secrete higher levels of gelatinases than their parent RWPE-1 cells. all-trans Retinoic acid (RA) caused a decrease in the extracellular u-PA and gelatinase activity and invasive ability of DU-145 and RWPE-2 cells. Treatment of cultures with RA reduced the ability of SF-CM to degrade fibronectin and laminin. These results may explain one mechanism by which retinoids inhibit invasion and metastasis. These studies have important translational value in the chemoprevention of prostatic intraepithelial neoplasia (PIN) and intervention in the progression of human prostate cancer. © 1995 Wiley-Liss, Inc.