Johnson Rachelle W, Finger Elizabeth C, Olcina Monica M, Vilalta Marta, Aguilera Todd, Miao Yu, Merkel Alyssa R, Johnson Joshua R, Sterling Julie A, Wu Joy Y, Giaccia Amato J
Department of Radiation Oncology, Division of Radiation and Cancer Biology, Stanford University, Stanford, California 94305, USA.
Department of Veterans Affairs: Tennessee Valley Healthcare System (VISN 9), Nashville, Tennessee 37212, USA.
Nat Cell Biol. 2016 Oct;18(10):1078-1089. doi: 10.1038/ncb3408. Epub 2016 Sep 19.
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 leukaemia 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 signalling pathway in breast cancer cells. Loss of the LIFR or STAT3 enables otherwise dormant breast cancer cells to downregulate dormancy-, quiescence- and cancer stem cell-associated genes, and to proliferate in and specifically colonize the bone, suggesting that LIFR:STAT3 signalling confers a dormancy phenotype in breast cancer cells disseminated to bone.
乳腺癌细胞常常归巢至骨髓，在那里它们可能在形成骨转移之前进入休眠状态。白细胞介素-6（IL-6）细胞因子家族的几个成员与乳腺癌骨定植有关，但IL-6细胞因子白血病抑制因子（LIF）在此过程中的作用尚不清楚。我们检验了LIF为骨中的乳腺癌细胞提供促休眠信号这一假设。在乳腺癌患者中，骨转移时LIF受体（LIFR）水平较低，且与患者预后和缺氧基因活性呈显著负相关。缺氧也会降低乳腺癌细胞中的LIFR:STAT3:SOCS3信号通路。LIFR或STAT3的缺失会使原本休眠的乳腺癌细胞下调与休眠、静止和癌症干细胞相关的基因，并在骨中增殖并特异性定植，这表明LIFR:STAT3信号赋予了播散至骨的乳腺癌细胞休眠表型。
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