Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis
Pharmacological activation of estrogen receptor beta augments innate immunity to suppress cancer metastasis
复制标题
雌激素受体β的药理激活可增强先天免疫力，抑制癌症转移
DOI：
10.1073/pnas.1803291115
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发表时间：
2018-04-17
影响因子：
11.1
通讯作者：
Zhou, Shengtao
中科院分区：
文献类型：
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作者：
Zhao, Linjie;Huang, Shuang;Zhou, Shengtao
转移是癌症死亡的最大原因。然而，对于具有转移的癌症患者，目前不存在有效的治疗选择。雌激素受体β（ER β）作为核受体超家族的一员，在许多癌症中显示出有效的肿瘤抑制活性。为了研究ER β的调节是否可以作为癌症转移的治疗策略，我们检查了选择性ER β激动剂LY 500307是否可以抑制三阴性乳腺癌（TNBC）和黑色素瘤的肺转移。从机制上讲，虽然我们观察到LY 500307在体内有效诱导转移到肺的癌细胞的细胞死亡，但它在体外不介导癌细胞的凋亡，表明LY 500307的细胞死亡诱导作用可能是由肿瘤微环境介导的。病理学检查结合流式细胞术分析表明，LY 500307治疗诱导的转移龛中的中性粒细胞的显著浸润。功能实验证明，LY 500307处理的癌细胞显示出对中性粒细胞的趋化作用，并且通过Ly 6 G抗体施用的体内中性粒细胞消耗可以逆转LY 500307介导的转移抑制的作用。RNA测序分析显示，LY 500307可诱导TNBC和黑素瘤细胞中IL-1 β的上调，从而进一步触发抗肿瘤中性粒细胞趋化性。然而，LY 500307治疗抑制肺转移的治疗效果在IL 1B（-/-）鼠模型中减弱，这是由于未能在转移性小生境中诱导抗肿瘤嗜中性粒细胞浸润。总的来说，我们的研究表明，ER β的药理学激活可以增强先天免疫，以抑制癌症转移到肺部的定植，从而为转移的癌症患者提供替代治疗选择。
Metastases constitute the greatest causes of deaths from cancer. However, no effective therapeutic options currently exist for cancer patients with metastasis. Estrogen receptor beta(ER beta), as a member of the nuclear receptor superfamily, shows potent tumor-suppressive activities in many cancers. To investigate whether modulation of ER beta could serve as a therapeutic strategy for cancer metastasis, we examined whether the selective ER beta agonist LY500307 could suppress lung metastasis of triple-negative breast cancer (TNBC) and melanoma. Mechanistically, while we observed that LY500307 potently induced cell death of cancer cells metastasized to lung in vivo, it does not mediate apoptosis of cancer cells in vitro, indicating that the cell death-inducing effects of LY500307 might be mediated by the tumor microenvironment. Pathological examination combined with flow cytometry assays indicated that LY500307 treatment induced significant infiltration of neutrophils in the metastatic niche. Functional experiments demonstrated that LY500307-treated cancer cells show chemotactic effects for neutrophils and that in vivo neutrophil depletion by Ly6G antibody administration could reverse the effects of LY500307-mediated metastasis suppression. RNA sequencing analysis showed that LY500307 could induce up-regulation of IL-1 beta in TNBC and melanoma cells, which further triggered antitumor neutrophil chemotaxis. However, the therapeutic effects of LY500307 treatment for suppression of lung metastasis was attenuated in IL1B(-/-) murine models, due to failure to induce antitumor neutrophil infiltration in the metastatic niche. Collectively, our study demonstrated that pharmacological activation of ER beta could augment innate immunity to suppress cancer metastatic colonization to lung, thus providing alternative therapeutic options for cancer patients with metastasis.