Loss of ovarian function promotes angiogenesis in human ovarian carcinoma
Loss of ovarian function promotes angiogenesis in human ovarian carcinoma
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DOI：
10.1073/pnas.94.24.13203
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发表时间：
1997-11-25
影响因子：
11.1
通讯作者：
Neeman, M
中科院分区：
文献类型：
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作者：
Schiffenbauer, YS;Abramovitch, R;Neeman, M
我们在此表明，在更年期或卵巢切除术后发现的促性腺激素（促黄体生成素和促卵泡激素）水平升高，通过诱导肿瘤血管生成来促进人类卵巢癌的生长。人上皮性卵巢癌肿瘤在切除卵巢的小鼠中进展更快。这种诱导生长可能归因于与卵巢功能丧失相关的促性腺激素水平升高，因为直接给药促性腺激素在体内也能有效促进肿瘤进展。另一方面，促性腺激素对体外培养的人卵巢癌细胞增殖无直接影响。通过MRI，我们发现卵巢切除术显著（P < 0.02）诱导裸鼠植入的人卵巢癌球体形成新生血管。此外，促性腺激素处理的人卵巢癌细胞在条件培养基中对牛内皮细胞的有丝分裂活性增强，这种活性可以被抗黄体生成素和抗血管内皮生长因子的中和抗体阻断。因此，促性腺激素刺激导致单层培养和人卵巢癌球体外增殖细胞中血管内皮生长因子的剂量依赖诱导表达。这些结果表明，在更年期和所有卵巢癌患者中发现的促性腺激素水平升高对卵巢癌的进展具有重要意义，并可以解释雌激素替代疗法的保护作用。基于这些结果，我们认为旨在降低促性腺激素循环水平的激素治疗可能通过延长肿瘤休眠来延长卵巢癌的缓解期。
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.