Urokinase-type plasminogen activator and its receptor in colorectal cancer: Independent prognostic factors of metastasis and cancer-specific survivaland potential therapeutic targets

Urokinase-type plasminogen activator (uPA) and its receptor (uPAR), plasmin ogen (Plg), and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) have been observed in many cancers and may contribute to progression and m etastasis. In our study, we examined the expression of the 5 proteins by im munohistochemistry in 59 consecutive primary colorectal cancers (CRC) and c orrelated the protein expression with patient outcome. In addition, we dete rmined the effect of down-regulation of uPAR on the invasive/metastatic cap ability of CRC cells, by measuring antisense-uPAR transfected HCT116 and co ntrol cell lines, in terms of uPAR expression, uPA-binding activity, invasi veness through Matrigel in vitro and metastasis after cecal orthotopic impl antation in nude mice in vivo. We found that higher expression of uPA or uP AR in primary tumor tissues was positively correlated with distant metastas is of CRC (Mann-Whitney, p < 0.02) and negatively correlated with both pati ent overall survival (OS) and cancer-specific survival (CSS; Cox model. p < 0.04). The prognostic value of uPA and uPAR for both OS and CSS was indepe ndent of other variables (multivariate Cox model, p < 0.007). Antisense-uPA R transfected HCTI id cells, which expressed significantly lower levels of total cellular and cell surface uPAR proteins and uPA binding activity comp ared with either wild-type or cells transfected with vector alone (Bonferro ni, p < 0.05/3), consistently showed decreased invasiveness through Matrige l (Bonferroni, p < 0.05/3) and decreased metastasis formation in nude mice (Fisher, p < 0.05), Our data suggest that uPAR and uPA are independent prog nostic factors in CRC; anti-uPAR treatment, which affects both uPAR and uPA levels, may have potential for new treatment of the disease. (C) 2000 Wile y-Liss, Inc.