Farmaki Elena, Kaza Vimala, Papavassiliou Athanasios G, Chatzistamou Ioulia, Kiaris Hippokratis
Department of Drug Discovery and Biomedical Sciences, University of South Carolina, SC, USA.
Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece.
Cancer Lett. 2017 Mar 28;389:49-58. doi: 10.1016/j.canlet.2016.12.028. Epub 2016 Dec 29.
The induction of localized pro-inflammatory niches in the periphery is instrumental in metastasis. In order to better understand how tumors engage distal sites and activate a pro-inflammatory response we utilized syngeneic breast cancers as a model and showed that soluble factors from the neoplastic epithelium activate the expression of the monocyte chemoattractive protein (MCP) chemokines of the mouse 11C cluster that include Ccl1, Ccl2, Ccl7, Ccl8, Ccl11 and Ccl12. Tissues such as the lungs and the brain, that are more prone to colonization by breast cancer cells, were more sensitive to MCP cluster chemokine induction than others such as the liver. Subsequent analyses involving chemokine arrays in breast cancer cells and media followed by functional validation assays in in vitro and in vivo identified the cytokine Ccl3 as the principle mediator of the communication between the neoplastic epithelium and the peripheral tissues in terms of MCP cluster chemokine induction. Our results show that MCP chemokines are activated in peripheral tissues of breast cancer-bearing mice, by a mechanism that involves breast cancer cell-derived Ccl3. Interference with the expression of cancer cell-derived Ccl3 may find application in the management of breast cancer metastases.
外周局部促炎微环境的诱导在转移过程中起重要作用。为了更好地理解肿瘤如何影响远端部位并激活促炎反应，我们利用同基因乳腺癌作为模型，发现肿瘤上皮细胞分泌的可溶性因子可激活小鼠11C簇单核细胞趋化蛋白（MCP）趋化因子的表达，这些趋化因子包括Ccl1、Ccl2、Ccl7、Ccl8、Ccl11和Ccl12。与肝脏等其他组织相比，肺和脑等更容易被乳腺癌细胞定植的组织对MCP簇趋化因子的诱导更为敏感。随后，通过对乳腺癌细胞和培养基进行趋化因子阵列分析，并在体外和体内进行功能验证试验，确定细胞因子Ccl3是肿瘤上皮细胞与外周组织之间就MCP簇趋化因子诱导进行通信的主要介质。我们的研究结果表明，MCP趋化因子在荷乳腺癌小鼠的外周组织中被激活，其机制涉及乳腺癌细胞衍生的Ccl3。干扰癌细胞衍生的Ccl3的表达可能在乳腺癌转移的治疗中得到应用。
