| Background and Objective HER-2 is a member of the epidermal growth factor receptor family, and its overexpression in ovarian cancer has been reported to be approximately 20~30%, which is involved in the carcinogenesis and progression of ovarian cancer. Research indicated that overexpression of HER-2 had significantly positive correlation with microvessel density (MVD) in tumor tissue, and activated HER-2 could up-regulate angiogenesis through signal pathways. Therefore, on the basic of exploring the correlations among HER-2, VEGF and MVD values in ovarian tumor, we investigated the effect of ChA21 combined with Herceptin on angiogenesis in ovarian cancer SKOV3 cells.Methods1) Forty-nine cases of epithelial serous ovarian tumors, including 17 case of serous cystadenoma, 7 cases of borderline serous cystadenoma and 25 cases of serous cystadenocarcinoma were collected, and immunohistochemical staining were used to detect the expression of HER-2,VEGF and MVD in 49 cases of epithelial serous ovarian tumors, and analyzed the correlations among them.2) Animal model with human ovarian cancer SKOV3 cells involved in nude mice was established and the mice were randomized into control group, ChA21 (30mg·kg-1) group, Herceptin (20mg·kg-1) group, ChA21 plus Herceptin (30mg·kg-1+ 20mg·kg-1) group. After administrated the antibodies which were injected twice a week for consecutive 3 weeks via caudal vein, the nude mice were killed. The tumor inhibition ratio were measured, and the expression of VEGF and MVD values in these groups were detected by immunohistochemistry.3)In vitro, the anti-HER-2 engineering antibody ChA21(5 mg.L-1)combined with Herceptin(5 mg.L-1)treated with ovarian cancer SKOV3 cells. MTS assay was used for the analysis of cell growth, ELISA assay was employed to observe secreted VEGF in SKOV3 supernate fluid. The change of invasion ability of SKOV3 was detected by Transwell assay, the expression of VEGF,Akt/pAkt were assayed by western blotting. The alteration of HUVECs proliferation and migration were also been detected by MTS and Transwell assay, respectively.Results1) The HER-2 overexpression rates, the positive rates of VEGF and MVD values in borderline tumor and carcinoma were significantly higher than those in serous cystadenoma (P<0.01); The expresson of HER-2,VEGF and MVD were significantly positive correlation in serous cystadenocarcinoma (P<0.01); The expresson of HER-2,VEGF and MVD were closely correlated with tumor size and peritoneal cavity metastasis, but were little correlated with patient's age and TNM stages(P>0.05).2) The growth of SKOV3 xenografts in nude mice was significantly inhibited by ChA21 plus Herceptin treatment group than control group, ChA21 or Herceptin treatment alone group. Both VEGF protein expression and MVD values in ChA21 plus Herceptin treatment group were lower than those in the control group, ChA21 or Herceptin treatment alone group.3) In vitro, the growth and invasion ability of human ovarian cancer cell line SKOV3 were significantly inhibited by treated with ChA21 plus Herceptin for 48 h. The SKOV3 cells treated with ChA21 plus trastuzumab for 12 h secreted less VEGF than the cells treated agent alone, and VEGF,pAkt were reduced more effectively by combined treatment compared with the treatment alone by western blotting. The combination group that stimulated less endothelial cell proliferation and migration were also been observed by MTS and Transwell assay, respectively.Conclusions The expresson of HER-2,VEGF and MVD were significantly positive correlation in serous cystadenocarcinoma, they may play important roles in the development and progression of serous cystadenocarcinoma. Combination of ChA21 with Herceptin better inhibited the expression of VEGF possibly through Akt/pAkt signal pathway, and then effected the HUVECs proliferation and migration, and final inhibited angiogenesis and growth of xenografts in human ovarian cancer SKOV3 cells.
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