Multiple direct and indirect mechanisms drive estrogen-induced tumor growth in high grade serous ovarian cancers.
Multiple direct and indirect mechanisms drive estrogen-induced tumor growth in high grade serous ovarian cancers.
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DOI：
10.18632/oncotarget.6943
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发表时间：
2016-02-16
期刊：
影响因子：
--
通讯作者：
Gallo D
中科院分区：
文献类型：
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作者：
Ciucci A;Zannoni GF;Buttarelli M;Lisi L;Travaglia D;Martinelli E;Scambia G;Gallo D
更年期雌激素替代治疗增加了卵巢癌的风险，但仅适用于两种更常见的类型(即浆液性和子宫内膜样癌)，同时可能降低透明细胞肿瘤的风险，这一观点强烈暗示了因果关系。然而，雌二醇(E_2)是否具有致瘤作用或促进隐匿性既往疾病的发展尚不清楚。本研究探讨了E2调控高级别浆液性卵巢癌(HGSOC)生长的分子和细胞机制。结果表明，在体外模型中，ERα的表达是诱导HGSOC细胞生长的必要条件和充分条件。相反，体内实验研究表明，增加循环雌激素水平也会显著加速ERα阴性的HGSOC异种移植的生长。雌二醇组小鼠的肿瘤增殖率、血管生成和肿瘤相关巨噬细胞()密度显著高于去卵巢的雌性小鼠。相应地，对HGSOC患者ERα阴性组织标本的免疫组织化学分析显示，绝经前患者的浸润率明显高于绝经后女性。这项研究描述了E2对肿瘤微环境的影响，独立于其对肿瘤细胞生长的直接影响，从而支持了多种直接和间接机制推动雌激素诱导的HGSOC肿瘤生长的观点。
The notion that menopausal estrogen replacement therapy increases ovarian cancer risk, but only for the two more common types (i.e. serous and endometrioid), while possibly decreasing risk for clear cell tumors, is strongly suggestive of causality. However, whether estradiol (E2) is tumorigenic or promotes development of occult preexisting disease is unknown. The present study investigated molecular and cellular mechanisms by which E2 modulates the growth of high grade serous ovarian cancer (HGSOC). Results showed that ERα expression was necessary and sufficient to induce the growth of HGSOC cells in in vitro models. Conversely, in vivo experimental studies demonstrated that increasing the levels of circulating estrogens resulted in a significant growth acceleration of ERα-negative HGSOC xenografts, as well. Tumors from E2-treated mice had significantly higher proliferation rate, angiogenesis, and density of tumor-associated macrophage (TAM) compared to ovariectomized females. Accordingly, immunohistochemical analysis of ERα-negative tissue specimens from HGSOC patients showed a significantly greater TAM infiltration in premenopausal compared to postmenopausal women. This study describes novel insights into the impact of E2 on tumor microenvironment, independently of its direct effect on tumor cell growth, thus supporting the idea that multiple direct and indirect mechanisms drive estrogen-induced tumor growth in HGSOC.