Loss of ovarian function promotes angiogenesis in human ovarian carcinoma

被引:88
作者
Schiffenbauer, YS
Abramovitch, R
Meir, G
Nevo, N
Holzinger, M
Itin, A
Keshet, E
Neeman, M
机构
[1] WEIZMANN INST SCI,DEPT REGULAT BIOL,IL-76100 REHOVOT,ISRAEL
[2] MEIR HOSP,KEFAR SAVA,ISRAEL
[3] HEBREW UNIV JERUSALEM,HADASSAH MED SCH,DEPT MOL BIOL,IL-91010 JERUSALEM,ISRAEL
关键词
D O I
10.1073/pnas.94.24.13203
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
We show here that elevated levels of gonadotropins (luteinizing hormone and follicle stimulating hormone), as found in menopause or after ovariectomy, promote growth of human ovarian carcinoma by induction of tumor angiogenesis. Human epithelial ovarian cancer tumors progressed faster in ovariectomized mice. This induced growth could be attributed to the elevated levels of gonadotropins associated with loss of ovarian function because direct administration of gonadotropins also was effective in promoting tumor progression in vivo. On the other hand, gonadotropins had no direct effect on the proliferation of human ovarian cancer cells in vitro. Using MRI, we demonstrated that ovariectomy significantly (P < 0.02) induces neovascularization of human ovarian carcinoma spheroids implanted in nude mice. Moreover, conditioned medium of gonadotropin-treated human ovarian carcinoma cells showed increased mitogenic activity to bovine endothelial cells, and this activity could be blocked by neutralizing antibodies against luteinizing hormone and against vascular endothelial growth factor. Accordingly, gonadotropin stimulation resulted in a dose-dependent-induced expression of vascular endothelial growth factor in monolayer culture as well as in the outer proliferating cells of human ovarian cancer spheroids. These results demonstrate the significance of the elevated levels of gonadotropins, as found in menopause and in all ovarian cancer patients, on the progression of ovarian cancer and could explain the protective effect of estrogen replacement therapy. Based on these results, we suggest that hormonal therapy aimed at lowering the circulating levels of gonadotropins may possibly prolong remission in ovarian cancer by extending tumor dormancy.
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页码:13203 / 13208
页数:6
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