Disseminated Tumor Cells Persist in the Bone Marrow of Breast Cancer Patients through Sustained Activation of the Unfolded Protein Response
Disseminated Tumor Cells Persist in the Bone Marrow of Breast Cancer Patients through Sustained Activation of the Unfolded Protein Response
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DOI：
10.1158/0008-5472.can-14-3728
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发表时间：
2015-12-15
期刊：
影响因子：
11.2
通讯作者：
Pantel, Klaus
中科院分区：
文献类型：
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作者：
Bartkowiak, Kai;Kwiatkowski, Marcel;Pantel, Klaus
播散性肿瘤细胞（DTC）具有间充质和上皮特性，被认为是乳腺癌的转移起始细胞。然而，人们对支持 DTC 存活的机制知之甚少。低氧浓度可能会促进 DTC 外渗到骨髓，从而引发有助于 DTC 存活的代谢和分子改变。在这里，我们研究了未折叠蛋白反应（UPR）（缺氧诱导的一种重要的细胞保护程序）如何影响应激癌细胞的行为。从乳腺癌 (BC-M1)、肺癌 (LC-M1) 和前列腺癌 (PC-E1) 患者的骨髓中建立的 DTC 细胞系置于缺氧和低血糖条件下。 BC-M1 和 LC-M1 表现出间充质和上皮特性，易于适应缺氧和葡萄糖饥饿。 UPR蛋白（例如葡萄糖调节蛋白Grp78）的上调诱导丝状网络的形成，从而在完全葡萄糖剥夺下产生增殖优势和持续生存。 Grp78 高表达与乳腺癌和肺癌细胞的间质属性相关，并且与原发性乳腺癌和肺癌临床样本中的分化不良相关。在从乳腺癌患者的骨髓标本中分离出的 DTC 中，观察到 Grp78 阳性应激颗粒，这与这些细胞暴露于急性细胞应激的可能性一致。总体而言，我们的研究结果提供了第一个证据，表明癌症患者骨髓中的 DTC 中 UPR 被激活，值得进一步研究这种细胞应激途径作为复发转移性疾病的预测生物标志物。 (C)2015 AACR。 。
Disseminated tumor cells (DTC), which share mesenchymal and epithelial properties, are considered to be metastasis-initiating cells in breast cancer. However, the mechanisms supporting DTC survival are poorly understood. DTC extravasation into the bone marrow may be encouraged by low oxygen concentrations that trigger metabolic and molecular alterations contributing to DTC survival. Here, we investigated how the unfolded protein response (UPR), an important cytoprotective program induced by hypoxia, affects the behavior of stressed cancer cells. DTC cell lines established from the bone marrow of patients with breast cancer (BC-M1), lung cancer, (LC-M1), and prostate cancer (PC-E1) were subjected to hypoxic and hypoglycemic conditions. BC-M1 and LC-M1 exhibiting mesenchymal and epithelial properties adapted readily to hypoxia and glucose starvation. Upregulation of UPR proteins, such as the glucose-regulated protein Grp78, induced the formation of filamentous networks, resulting in proliferative advantages and sustained survival under total glucose deprivation. High Grp78 expression correlated with mesenchymal attributes of breast and lung cancer cells and with poor differentiation in clinical samples of primary breast and lung carcinomas. In DTCs isolated from bone marrow specimens from breast cancer patients, Grp78-positive stress granules were observed, consistent with the likelihood these cells were exposed to acute cell stress. Overall, our findings provide the first evidence that the UPR is activated in DTC in the bone marrow from cancer patients, warranting further study of this cell stress pathway as a predictive biomarker for recurrent metastatic disease. (C)2015 AACR. .