Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic.
Institute of Physiology, University of Zurich and Zurich Center for Integrative Human Physiology, Zurich, Switzerland.
Oncogene. 2018 Feb 22;37(8):1020-1030. doi: 10.1038/onc.2017.392. Epub 2017 Oct 30.
Metastasis accounts for most of cancer-related deaths. Paracrine signaling between tumor cells and the stroma induces changes in the tumor microenvironment required for metastasis. Transcription factor c-Myb was associated with breast cancer (BC) progression but its role in metastasis remains unclear. Here we show that increased c-Myb expression in BC cells inhibits spontaneous lung metastasis through impaired tumor cell extravasation. On contrary, BC cells with increased lung metastatic capacity exhibited low c-Myb levels. We identified a specific inflammatory signature, including Ccl2 chemokine, that was expressed in lung metastatic cells but was suppressed in tumor cells with higher c-Myb levels. Tumor cell-derived Ccl2 expression facilitated lung metastasis and rescued trans-endothelial migration of c-Myb overexpressing cells. Clinical data show that the identified inflammatory signature, together with a MYB expression, predicts lung metastasis relapse in BC patients. These results demonstrate that the c-Myb-regulated transcriptional program in BCs results in a blunted inflammatory response and consequently suppresses lung metastasis.
转移是癌症相关死亡的主要原因。肿瘤细胞与基质之间的旁分泌信号诱导转移所需的肿瘤微环境变化。转录因子 c-Myb 与乳腺癌（BC）的进展有关，但它在转移中的作用尚不清楚。在这里，我们表明，BC 细胞中 c-Myb 表达的增加通过损害肿瘤细胞的外渗来抑制自发性肺转移。相反，具有增加的肺转移能力的 BC 细胞表现出低水平的 c-Myb。我们确定了一个特定的炎症特征，包括趋化因子 Ccl2，它在肺转移细胞中表达，但在 c-Myb 水平较高的肿瘤细胞中受到抑制。肿瘤细胞衍生的 Ccl2 表达促进了肺转移，并挽救了过表达 c-Myb 的细胞的跨内皮迁移。临床数据表明，鉴定出的炎症特征，连同 MYB 表达，可预测 BC 患者的肺转移复发。这些结果表明，BC 中 c-Myb 调节的转录程序导致炎症反应减弱，从而抑制肺转移。
