Expression of heparanase, Mdm2, and erbB2 in ovarian cancer

Ovarian cancer is the most lethal of gynecological malignancies. Yet early diagnosis and prognosis are far from being satisfactory. Degradation of hep aran sulfate proteoglycans by heparanase appears to play an important role in the invasiveness of tumor cells through the basement membrane and into t he extracellular matrix. Recent cloning of the heparanase gene and generati on of monoclonal antibodies against the enzyme permit to examine tumor cell expression of the enzyme. The aim of the present study was to assess hepar anase activity and localization in various subtypes of epithelial ovarian c ancer in correlation with oncogene expression. Histologically confirmed mal ignant ovarian tissue from ten women and tissue from 2 benign ovarian tumor s and 4 normal ovaries were assessed for heparanase presence, activity and localization, incidence of apoptosis and expression of the oncogenes erbB2 and Mdm2. Heparanase immunohistostaining and activity were present in mucin ous carcinomas and were more intense than in endometrioid and in serous car cinomas. The lowest activity was observed in benign ovarian tumors and norm al ovaries. In ovarian carcinomas the enzyme was intensely concentrated in the cytoplasm of the cancerous cells. In contrast, in normal ovaries and be nign tumors the enzyme was predominantly localized in endothelial cells lin ing blood capillaries. The rate of apoptosis was considerably higher in muc inous and endometrioid carcinomas, and was lower in serous and primary peri toneal carcinomas. Extremely high concentration of heparanase was often dem onstrated in apoptotic cells. Endometrioid and serous carcinomas showed hig h expression of Mdm2 and erbB2 while mucinous carcinomas showed low express ion. In benign ovarian tumors and normal ovaries the expression of both onc oproteins was extremely low. In conclusion ovarian carcinomas demonstrate h igher levels of heparanase than benign tumors and normal ovaries suggesting that the enzyme may play an important role in metastatic spread of the can cerous cells. Apoptosis may be a significant part of the mechanism of the e nzyme release into the extacellular space. Although heparanase activity see ms to play an essential role in tumor progression, expression of oncogenes, such as erbB2 and Mdm2 seems to play the dominant role in the development of ovarian cancer.