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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells
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Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells

机译：雌激素促进结核菌素空细胞的存活和肺转移

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摘要

Lymphangioleiomyomatosis (LAM) is an often fatal disease primarily affecting young women in which tuberin (TSC2)-null cells metastasize to the lungs. The mechanisms underlying the striking female predominance of LAM are unknown. We report here that 17-β-estradiol (E_2) causes a 3- to 5-fold increase in pulmonary metastases in male and female mice, respectively, and a striking increase in circulating tumor cells in mice bearing tuberin-null xenograft tumors. E_2-induced metastasis is associated with activation of p42/44 MAPK and is completely inhibited by treatment with the MEK1/2 inhibitor, CM 040. In vitro, E_2 inhibits anoikis of tuberin-null cells. Finally, using a bioluminescence approach, we found that E_2 enhances the survival and lung colonization of intravenously injected tuberin-null cells by 3-fold, which is blocked by treatment with CI-1040. Taken together these results reveal a new model for LAM pathogenesis in which activation of MEK-depdhdent pathways by E_2 leads to pulmonary metastasis via enhanced survival of detached tuberin-null cells.
机译：淋巴管平滑肌瘤病（LAM）是一种常见的致死性疾病，主要影响年轻女性，其中结核菌素（TSC2）无效细胞转移到肺部。 LAM在女性中占主导地位的机制尚不清楚。我们在这里报告17-β-雌二醇（E_2）分别导致雄性和雌性小鼠肺转移3到5倍增加，以及在携带结核菌素无异种移植肿瘤的小鼠中循环肿瘤细胞的显着增加。 E_2诱导的转移与p42 / 44 MAPK的激活有关，并通过MEK1 / 2抑制剂CM 040的治疗被完全抑制。在体外，E_2抑制结核菌素无效细胞的失神经。最后，使用生物发光方法，我们发现E_2通过3倍提高了静脉注射的结核菌素无效细胞的存活率和肺部定植，而CI-1040可以阻止这种作用。总之，这些结果揭示了LAM发病机理的新模型，其中E_2对MEK依赖性途径的激活通过增加的游离管蛋白-空细胞的存活导致肺转移。

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