Study on Proteolytic Enzymes(uPA, PAI-1 and Type 4 Collagenase) Involved in Invasion and Metastasis of Gastric Carcinoma

Cho, J Y; Chung, H C; Noh, S H; Kim, H K; Park, J O; Lee, J I; Yoo, N C; Kim, J H; Roh, J K; Kim, B S; Kang, J K; Min, J S

Abstract

OBJECTIVES
Prognosis of gastric cancer is related to invasion and metastasis. Evidence has accumulated that invasion and metastasis in solid tumors require the action of tumor associated proteases, which promote the dissolution of the surrounding tumor matrix and the basement membrane. The serine protease [(urokinase-type plasminogen activator and plasminogen activator inhibitor-1 (PAI-1)] and type IV collagenase(MMP-9 and MMP-2) appear to play a key role in these processes. Recent reports have demonstrated that expression of these proteolytic enzymes are elevated in breast and colon cancer and that it can be associated with invasiveness and poor prognosis. We therefore evaluated whether the expression and activation of uPA, PAI-1 and type IV collagenase might be of clinical value in gastric cancer as a tumor/biologically defined risk factor.
METHODS
In a consecutive series of 160 gastric cancer patients who were enrolled in the Yonsei Cancer Center Study Group, the expression of uPA, PAI-1 and type IV collagenase was determined by ELISA, zymography and mmunohistochemical method. The results were as follows.
RESULTS
1) Both uPA and PAI-1 levels were significantly higher in cancer tissues than no rmal (uPA; 9.4 +/- 8.7vs 5.3 +/- 3.1 ng/mg protein cytosol, PAI-1;10.9 +/- 9.1vs 5.8 +/- 2.9 ng/mg protein cytosol), (p<0.001 respectively). Both high uPA and PAI-1 levels were associated with differentiation of the tumor(p=0.04, p=0.004), and a high PAI-1 level was associated with lymph nodes metastasis at an advanced stage (p=0.003, p=0.04). There was a correlation between the levels of uPA and PAI-1 expression in cancer tissues(r=0.57). 2) The activation ratio of MMP-9 and MMP-2 in cancer tissues 0.32 +/- 0.25, 0.27 +/- 0.34 were significantly higher than in normal tissue 0.19 +/- 0,27, 0.06 +/- 0.16(p<0.001). The MMP-9 activation was associated with lymphnode metastasis and the MMP-2 activation was associated with distant metastasis(p=0.011, p=0.041). 3) In univariate analysis all of the proteolytic enzymes were associated with short relapse free survival, but in multivariate analysis only the high uPA expression was an independent prognostic parameter for short relapse free survival of the gastric cancer patients.
CONCLUSION
These data indicate that uPA, PAI-1 and type IV collagenase were involved in the progression of gastric cancer at different points of time by different mechanisms. The combined expression and activation of these proteolytic enzymes were poor prognostic factors in gastric cancer patients, so new therapy based on these biologic behavior of the tumor in the same stage are clinically applicable. In particular, uPA is a new independent variable for the identification of patients at high risk, therefore therapy targetting uPA can be applied as a new treatment modality for gastric cancer.