Heparanase expression correlates with poor survival in metastatic ovarian carcinoma

Abstract

Objective: To analyze the expression of Heparanase, an enzyme involved in cancer metastasis and angiogenesis, in ovarian and breast carcinoma cells in effusions.

Methods: Heparanase protein expression was analyzed in malignant effusions from ovarian (=200) and breast (=41) carcinoma patients using immunocytochemistry. The levels of secreted heparanase were analyzed in 45 effusion supernatants using a newly established ELISA test. Heparanase expression levels were analyzed for clinical significance.

Results: Heparanase was expressed at the cell membrane in 106/200 (53%) ovarian and 22/41 (54%) breast carcinomas. Cytoplasmic expression was found in 180/200 (90%) ovarian and 26/41 (63%) breast carcinomas. Reactive mesothelial cells showed frequent cytoplasmic, but not membrane expression. ELISA showed secreted heparanase in all 45 analyzed effusions. Higher levels were detected in peritoneal compared to pleural effusions (p=0.031). In univariate survival analysis of ovarian carcinoma patients with post-chemotherapy effusions, membrane expression in >5% of tumor cells correlated with shorter overall survival (OS, p=0.013). FIGO stage (p=0.03 for all patients, p=0.045 for those with post-chemotherapy specimens) and response to first-line chemotherapy (p<0.0001 for all patients, p=0.049 for those with post-chemotherapy specimens) were the clinical parameters related to OS. In Cox analysis of this subset of patients, heparanase expression (p=0.02) and response to chemotherapy (p=0.049) were independent predictors of poor OS. Heparanase expression did not correlate with survival in breast carcinoma.

Conclusions: Our data show that heparanase is frequently expressed in metastatic gynecologic adenocarcinomas, and that it is secreted into the effusion fluid in body cavities. The correlation between heparanase expression and poor survival in ovarian carcinoma suggests a role for this molecule in ovarian cancer metastasis and supports its role as a marker of aggressive clinical behavior at disease recurrence.