Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow.
Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow.
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DOI：
10.1038/ncb3408
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发表时间：
2016-10
影响因子：
21.3
通讯作者：
Giaccia AJ
中科院分区：
文献类型：
--
作者：
Johnson RW;Finger EC;Olcina MM;Vilalta M;Aguilera T;Miao Y;Merkel AR;Johnson JR;Sterling JA;Wu JY;Giaccia AJ
乳腺癌细胞通常位于骨髓中，在形成骨转移之前，它们可能进入休眠状态。白介素6(IL-6)细胞因子家族的几个成员与乳腺癌的骨定植有关，但IL-6细胞因子白血病抑制因子(LIF)在这一过程中的作用尚不清楚。我们测试了LIF为骨骼中的乳腺癌细胞提供促进休眠信号的假设。在乳腺癌患者中，LIF受体(LIFR)水平随着骨转移的降低而降低，并且与患者预后和缺氧基因活性显著负相关。低氧还降低了乳腺癌细胞中的LIFR：STAT3：SOCS3信号通路。LIFR或STAT3的丢失使原本处于休眠状态的乳腺癌细胞能够下调休眠、静止和癌症干细胞相关基因，并在骨中增殖和特异性定植，这表明LIFR：STAT3信号在扩散到骨的乳腺癌细胞中赋予了休眠表型。
Breast cancer cells frequently home to the bone marrow, where they may enter a dormant state before forming a bone metastasis. Several members of the interleukin-6 (IL-6) cytokine family are implicated in breast cancer bone colonization, but the role for the IL-6 cytokine leukemia inhibitory factor (LIF) in this process is unknown. We tested the hypothesis that LIF provides a pro-dormancy signal to breast cancer cells in the bone. In breast cancer patients, LIF receptor (LIFR) levels are lower with bone metastases and are significantly and inversely correlated with patient outcome and hypoxia gene activity. Hypoxia also reduces the LIFR:STAT3:SOCS3 signaling pathway in breast cancer cells. Loss of the LIFR or STAT3 enables otherwise dormant breast cancer cells to down-regulate dormancy, quiescence, and cancer stem cell-associated genes, and to proliferate in and specifically colonize the bone, suggesting LIFR:STAT3 signaling confers a dormancy phenotype in breast cancer cells disseminated to bone.