Level differentials of proteolytic factors uPA, PAI-1 and human kallikreins (hK) 5,6,7,8,10,11,13 in primary ovarian carcinoma tissues and corresponding omentum metastases impact on disease outcome

Abstract

Proteolytic factors of the plasminogen activation system and human tissue kallikreins hK4–15 are involved in tumor progression in ovarian cancer. 142 primary ovarian cancer patients FIGO I-IV were operated on at Dept OB&GYN, TU Munich (median follow-up 33 months). Antigen levels of uPA, PAI-1 and 7 tissue kallikreins (hK5,6,7,8,10,11,13) were determined in primary carcinoma and corresponding omentum metastasis and related to total protein content. Level in metastases minus level in primary tumor tissue was defined as level differential. Significant increases in metastasis levels compared to primary tumor levels were found for uPA (148% of mean) and hK5 (84% of mean). Regarding progression-free survival (PFS), differences in uPA, hK6,7 and 10 had significant impact in all patients, including those with residual tumor. In univariate Cox models with fractionally ranked level differentials, larger differentials were associated with disease progression. Hazard ratios for the 75th percentile of these differentials compared to the median were: 1.50 for uPA (1.14–1.97); 1.66 for hk6 (1.16–2.39); 1.36 for hk7 (1.00–1.86); and 1.65 for hk10 (1.16–2.34). In the group of patients with no macroscopical residual tumor, only level differentials of hk5,7,8, and 11 had a significant impact on PFS. Larger differentials were linked to disease progression: according to univariate Cox models with fractionally ranked level differentials, hazard ratios for the 75th percentile of these differentials compared to the median were as follows: 2.18 (1.03–4.60) for hk5; 2.38 for hk7 (1.08–5.27); 2.6 for hk8 (1.15–6.01); and 2.03 for hk11 (1.02–4.05). The impact for uPA, hk6, and hk10 on disease progression in all patients may be attributable to poorer debulking results obtainable in patients with increased levels in their metastases. Our results show that serine proteases such as uPA and some of the tissue kallikreins play a clinically meaningful role in primary ovarian cancer.