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 heparan sulfate proteoglycans by heparanase appears to play an important role in the invasiveness of tumor cells through the basement membrane and into the extracellular matrix. Recent cloning of the heparanase gene and generation of monoclonal antibodies against the enzyme permit to examine tumor cell expression of the enzyme. The aim of the present study was to assess heparanase activity and localization in various subtypes of epithelial ovarian cancer in correlation with oncogene expression. Histologically confirmed malignant ovarian tissue from ten women and tissue from 2 benign ovarian tumors 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 mucinous carcinomas and were more intense than in endometrioid and in serous carcinomas. The lowest activity was observed in benign ovarian tumors and normal ovaries. In ovarian carcinomas the enzyme was intensely concentrated in the cytoplasm of the cancerous cells. In contrast, in normal ovaries and benign tumors the enzyme was predominantly localized in endothelial cells lining blood capillaries. The rate of apoptosis was considerably higher in mucinous and endometrioid carcinomas, and was lower in serous and primary peritoneal carcinomas. Extremely high concentration of heparanase was often demonstrated in apoptotic cells. Endometrioid and serous carcinomas showed high expression of Mdm2 and erbB2 while mucinous carcinomas showed low expression. In benign ovarian tumors and normal ovaries the expression of both oncoproteins was extremely low. In conclusion ovarian carcinomas demonstrate higher levels of heparanase than benign tumors and normal ovaries suggesting that the enzyme may play an important role in metastatic spread of the cancerous cells. Apoptosis may be a significant part of the mechanism of the enzyme release into the extracellular space. Although heparanase activity seems 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.
Ginath
S
S
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Menczer
J
J
Friedmann
Y
Y
Aingorn
H
H
Aviv
A
A
Tajima
K
K
Dantes
A
A
Glezerman
M
M
Vlodavsky
I
I
Amsterdam
A
A
D002288:Adenocarcinoma, Mucinous / Q000201:enzymology* / Q000473:pathology; D000328:Adult; D017209:Apoptosis; D015153:Blotting, Western; D018269:Carcinoma, Endometrioid / Q000201:enzymology* / Q000473:pathology; D018284:Cystadenocarcinoma, Serous / Q000201:enzymology* / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D015870:Gene Expression; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008875:Middle Aged; D009367:Neoplasm Staging; D009687:Nuclear Proteins; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2; D015347:RNA Probes; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000099175:Heparanase
D005966:Glucuronidase; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D051736:Proto-Oncogene Proteins c-mdm2; D015347:RNA Probes; D018719:Erb-b2 Receptor Tyrosine Kinases; D000099175:Heparanase; C497206:MDM2 protein, human