The Expression Of Heparanase And It's Ralationship With Angiogenesis And Prognosis In Human Ovarian Carcinoma

Background and ObjectiveFor a malignant tumor cell to metastasize,it must break away from its neighbors,force its way through the surrounding stroma,and penetrate basement membranes to enter the circulation.A critical event in the process of cancer invasion and metastasis is therefore degradation of various constituents of the extra cellular matrix(ECM) including collagen, lamina,fibronectin,and heparin sulfate proteoglycans.The cell is able to accomplish this task through the concerted action of enzymes such as metalloproteinase,serine proteases, and endoglycosidases.Two essential processes required for metastasis are angiogenesis and tumor cell invasion of the basement membrane and ECM.H-S is an essential component of the extra cellular matrices of most tissues and is also a component of blood vessels,which is essential for insolubility of the extra cellular components,cell adhesion,and locomotion. Accordingly,cleavage of H-S by heparanase enzyme may play a decisive role in extravasations and invasion of tumor cells.So far,heparanase activity has been detected in various tumors and was found to correlate with their metastasis potentials.Meanwhile, heparanase may also contribute to angiogenesis by releasing the H-S-bound growth factors such as basic fibroblast growth factor(bFGF).bFGF is a potent antigenic growth factor that requires heparin or H-S for its biological activity mediated through tyrosine kinase signaling.The activity of bFGF is stringently controlled because it can be inactive in normal tissues and becomes activated upon tissue injury,inflammation,and tumor invasion. Heparanase enzyme possesses the ability to activate bFGF through structural modulation of the cell surface H-S proteoglycan.Accordingly,heparanase and bFGF could play complementary biological role in tumor angiogenesis and invasion.To our knowledge, expression of heparanase and its biological role in connection with bFGF expression in human ovarian carcinoma have not been evaluated so far.The present study,we tried to find out whether heparanase expression in the ovarian carcinoma was associated with the degree of tumor invasiveness,and whether the coexpression of heparanase and bFGF enhanced tumor angiogenesis compared with the expression of either factor alone,and whether the high expression of heparanase was associated with the poor prognosis of ovarian carcinoma.MethodsForty-one patients who had undergone ovary resection for ovarian carcinoma without preoperative treatment were included in the present study.In situ hybtidizatian and immunohistochemistry were used to study the expression of Hpa in 41 cases of ovarian carcinoma.We performed immunohistochemistry to detect the expression of bFGF and microvessel density(MVD),CD34 was used to explore the MVD as a marker of endothelial cells.Results1) The expression of heparanase mRNA increased in the ovarian carcinoma and the expression of heparanase protein was in consistent with the expression of heparanase mRNA in the same ovarian carcinoma tissue.The results of this study suggested that the Hpa expression in tumor tissue was remarkably higher than that in normal ovarian tissue,the positive rate of heparanase expression was 80.48%in ovarian carcinoma tissues and 10.00%in normal ovarian tissues(P＜0.05) The expression of heparanase was significantly higher in FIGO stageⅢandⅣthan inⅠandⅡ,and was significantly higher in low differentiated ovarian carcinoma tissues than in moderate-high differentiated tissues.There was no significant difference in expression of heparanase among each type of ovarian carcinoma tissues.2) Expression of heparanase and bFGF in ovarian carcinoma was positively correlated with MVD expression(P＜0.01).Carcinoma groups with the coexpression of heparanase and the growth factor bFGF showed a remarkably higher MVD than that showing heparanase and bFGF expression alone.3) 37 cases of the ovarian carcinoma was followed up,survival rates were calculated by the Kaplan-Meier method and differences were examined with the log-rank test.Our findings provide evidence that heparanase expression was not of value as a prognostic factor in ovarian carcinoma.Conclusions1) The results of this study suggest that the Hpa expression in ovarian carcinoma tissue was higher than that in normal ovarian tissue.The high expression of Hpa was related to the poor clinicopathologic features.Our findings provide evidence that the increased expression of heparanase may contribute to invasion and metastasis in ovarian carcinoma.2) The high expression of Hpa in ovarian carcinoma tissue contributes to tumor angiogenesis,and the coexpression of heparanase and bFGF could play complementary biological role in tumor angiogenesis.3) Our findings provide evidence that heparanase expression was not of value as a prognostic factor in ovarian carcinoma.The result may be influenced by the case quantities especially by the time of following up.