The role of cysteine and serine proteases in colorectal carcinoma

BACKGROUND. Cathepsin B (CATB) and cathepsin L (CATL), which are cysteine p roteases, urokinase-(UPA) and tissue-type plasminogen activator (TPA), both serine proteases, and their inhibitor type-1 (PAI-1) are believed to play an important role in colorectal carcinoma (CRC) invasion and metastasis. Th e objective of this study was to measure CATB, CATL, UPA, TPA, and PAI-1 in the same cancerous tissue (CANCER) and in tissues obtained from a tumor fr ee area (NORMAL) to compare their respective prognostic roles in patients w ith CRC. METHODS. CANCER and NORMAL samples were obtained from 60 CRC patients under going surgery (36 males and 24 females; mean age, 63.8 years [range, 27-85 years]). The antigen concentrations were measured using an enzyme-linked im munoadsorbent assay method. The CANCER tissue also was examined in terms of major histomorphologic parameters such as differentiation, vascular invasi on, degree of necrosis, and mucus production. RESULTS. Significantly higher antigen levels were found: 1) in CANCER versu s NORMAL (with respect to CATL, UPA, and PAI-1, with significantly lower le vels for TPA); 2) in CRC with versus without metastasis (CATB, CATL, and PA I-1); 3) in poorly versus well differentiated CRC (UPA and PAI-1); and 4) i n advanced Dukes stages (PAI-1). CATB and CATL significantly correlated wit h UPA and PAI-1. Finally, CATL (P = 0.0001), UPA (P = 0.006), PAI-1 (P = 0. 006), Dukes stage (P = 0.0001), presence of metastases (P = 0.003), and vas cular invasion (P = 0.03) had a significant prognostic impact. CONCLUSIONS. The simultaneous up-regulation of cysteine and serine protease s in CRC confirms their role in colorectal tumor biology and particularly i n the process of invasion and metastasis. Together with Dukes stage, determ inations of CATL, UPA, and PAI-1 have a major prognostic impact in patients with CRC. Cancer 1999; 86:1135-42. (C) 1999 American Cancer Society.