The role of cysteine and serine proteases in colorectal carcinoma.
BACKGROUND
Cathepsin B (CATB) and cathepsin L (CATL), which are cysteine proteases, 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. The 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 free area (NORMAL) to compare their respective prognostic roles in patients with CRC.


METHODS
CANCER and NORMAL samples were obtained from 60 CRC patients undergoing surgery (36 males and 24 females; mean age, 63.8 years [range, 27-85 years]). The antigen concentrations were measured using an enzyme-linked immunoadsorbent assay method. The CANCER tissue also was examined in terms of major histomorphologic parameters such as differentiation, vascular invasion, degree of necrosis, and mucus production.


RESULTS
Significantly higher antigen levels were found: 1) in CANCER versus NORMAL (with respect to CATL, UPA, and PAI-1, with significantly lower levels for TPA); 2) in CRC with versus without metastasis (CATB, CATL, and PAI-1); 3) in poorly versus well differentiated CRC (UPA and PAI-1); and 4) in advanced Dukes stages (PAI-1). CATB and CATL significantly correlated with 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 vascular invasion (P = 0.03) had a significant prognostic impact.


CONCLUSIONS
The simultaneous up-regulation of cysteine and serine proteases in CRC confirms their role in colorectal tumor biology and particularly in the process of invasion and metastasis. Together with Dukes stage, determinations of CATL, UPA, and PAI-1 have a major prognostic impact in patients with CRC.
Herszènyi
L
L
Second Department of Medicine, Semmelweis University Medical School, Budapest, Hungary.
Plebani
M
M
Carraro
P
P
De Paoli
M
M
Roveroni
G
G
Cardin
R
R
Tulassay
Z
Z
Naccarato
R
R
Farinati
F
F
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D002401:Cathepsin B / Q000378:metabolism; D056668:Cathepsin L; D002403:Cathepsins / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000401:mortality / Q000473:pathology; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D010450:Endopeptidases; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011379:Prognosis; D012697:Serine Endopeptidases / Q000378:metabolism*; D015996:Survival Rate; D010959:Tissue Plasminogen Activator / Q000378:metabolism; D015854:Up-Regulation; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D014408:Biomarkers, Tumor; D017395:Plasminogen Activator Inhibitor 1; D002403:Cathepsins; D010450:Endopeptidases; D012697:Serine Endopeptidases; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; C534281:CTSL protein, human; D056668:Cathepsin L