TUMOR-ASSOCIATED PROTEASES AND INHIBITORS IN GASTRIC-CANCER - ANALYSIS OF PROGNOSTIC IMPACT AND INDIVIDUAL RISK PROTEASE PATTERNS

Expression of proteolytic parameters of the urokinase-type plasminogen activator (uPA) system [aPA receptor (uPA-R), plasminogen activator i nhibitor (PAI)-1] has been proven to be an independent prognostic para meter in cancer. However, it has not been considered that the uPA syst em is interacting with several other protease/inhibitor systems, neith er has a comparable prognostic role of these factors been investigated . Moreover, studies evaluating specific protease patterns indicating h igh individual risk are missing completely, Therefore, in a consecutiv e prospective series of 203 gastric cancer patients, the expression of activators (plasminogen, tPA, MMP-2 cathepsin D, antithrombin 3) and inhibitors (alpha-2-antiplasmin, alpha-2-macroglobulin, alpha-1-antitr ypsin, alpha-1-antichymotrypsin) of proteolysis was studied immunohist ochemically in the tumor epithelium semiquantitatively (score 0-3) in addition to the uPA system. Kaplan-Meier analysis (median time of foll ow-up 31 months) revealed a significant association of cathepsin D (P= 0.0042), alpha-2-macroglobulin (P = 0.0281) and antitrypsin (P = 0.037 2) with disease-free survival and of cathepsin D (P = 0.0018), antitry psin (P = 0.0112) and antichymotrypsin (P = 0.0002) with overall survi val. Multivariate Cox analysis performed to correct these results for relative impact of the uPA system and established prognostic factors s howed PAI-1 (disease-free survival: P = 0.002, relative risk 1.86; ove rall survival: P = 0.005, relative risk 1.39), pT and pN as independen t parameters. Cathepsin D was shown to have an independent impact on d isease-free survival (P = 0.020, relative risk 2.98). Comparative chi- square analysis of cases with poor and good prognoses revealed that in patients with good clinical outcome, inhibitors of proteolysis are co rrelated significantly, whereas in patients with poor prognosis activa tors of proteolysis are significantly associated preferentially and si gnificant correlations with the uPA-R are dominant. For detailed patte rn analysis, stepwise overall Kaplan-Meier analyses were performed in subgroups of high uPA-R-, uPA-, PAI-1- and cathepsin D expression for two additional proteases each. From these analyses, the combination of high (score 2/3) expression of uPA-R, PAI-1, antichymotrypsin and alp ha-2-macroglobulin was identified as a high-risk pattern, representing parameters known to be essential for uPA-R internalization and recycl ing. This suggests some of the uPA-associated proteases and inhibitors investigated as univariate prognostic parameters in gastric cancer. C athepsin D is a new independent parameter for disease-free survival. T he study further demonstrates that a protease pattern promoting uPA-R recycling in tumor cells especially indicates high individual risk tum ors in gastric cancer.