Cathepsins B and D activity and activity ratios in normal ovaries, benign ovarian neoplasms, and epithelial ovarian cancer

Objective: Cathepsins B (CB) and D (CD) belong to a family of proteases felt to be important in tumor metastasis and invasion. It has been suggested that bothe enzymes play a role the progression of epithelial ovarian cancer and they have been investigated as potential biomarkers for ovarian cancer. Our objective was to determine if activity ratios of these two isoforms might enhance their usefulness as biomarkers. Methods: Ovarian cancer cell lines and snap-frozen archived tissue samples were sonicated and cathepsin activities were assayed fluorometrically with cathepsin-specific peptide substrates in combination with specific inhibitors. Tissue specimens were divided into four groups: normal ovary, benign neoplasm, early-stage (I/II) cancer, and late-stage (III/IV) cancer. Median CB and CD activity and the ratio of CB to CD (CB/CD) were compared using the Wilcoxan rank sum test. Nonparametric Spearman correlation was used to determine association between cathepsin activity and malignancy. Results: In cell lines and tissue, CD activity remained relatively constant, while CB activity varied. CB activity was greatest in cancer tissue. Elevated serum CA-125 was associated with elevations in CB activity and CB/CD but not CD activity. Elevated CB activity and CB/CD as well as increasing CA-125 and age are all associated with malignancy. Multiple logistic regression shows that CB activity and age best predict malignancy status. Conclusions: CB activity is associated with invasive ovarian neoplasm. Our results do not suggest that the ratio of activity between CB and CD provides any additional information than CB activity alone. Both tissue CB activity abd CB/CD activity ratios correlate with serum levels of CA-125; however there is no correlation between CD activity and CA-125.