Interplay between CCR7 and Notch1 axes promotes stemness in MMTV-PyMT mammary cancer cells.
Interplay between CCR7 and Notch1 axes promotes stemness in MMTV-PyMT mammary cancer cells.
复制标题
CCR7和Notch1轴之间的相互作用促进了MMTV-PYMT乳腺癌细胞中的干性。
DOI：
10.1186/s12943-017-0592-0
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发表时间：
2017-01-31
期刊：
影响因子：
37.3
通讯作者：
Kochetkova M
中科院分区：
文献类型：
--
作者：
Boyle ST;Gieniec KA;Gregor CE;Faulkner JW;McColl SR;Kochetkova M
乳腺癌是女性癌症相关死亡的主要原因。据认为，实体肿瘤中静止的干细胞样细胞负责癌症的维持、进展和最终的转移。我们最近报道了趋化因子受体CCR7，一种多功能的乳腺癌调节因子，维持干细胞样细胞的数量。本研究采用分子和细胞分析相结合的方法对MMTV-PYMT转基因小鼠乳腺肿瘤细胞进行检测，以检测CCR7和Notch信号通路之间的信号串扰。我们首次证明了CCR7在功能上与Notch信号通路相交，以调节乳腺癌干细胞样细胞。在这个细胞亚群中，CCR7的刺激激活了Notch信号通路，而CCR7的缺失显著降低了激活的裂解Notch1的水平。此外，阻断Notch活性可阻止特定配体诱导的CCR7信号转导和乳腺癌干细胞样细胞功能的增强。CCR7和Notch1之间的串扰促进了乳腺癌细胞的干性，并可能最终促进乳腺肿瘤的进展。因此，CCR7受体和Notch1信号轴的双重靶向可能是特异性抑制乳腺癌干细胞功能的潜在治疗途径。本文的在线版本(doi：10.1186/s12943-0170592-0)包含补充材料，授权用户可以使用。
Breast cancer is the major cause of cancer-related mortality in women. It is thought that quiescent stem-like cells within solid tumors are responsible for cancer maintenance, progression and eventual metastasis. We recently reported that the chemokine receptor CCR7, a multi-functional regulator of breast cancer, maintains the stem-like cell population. This study used a combination of molecular and cellular assays on primary mammary tumor cells from the MMTV-PyMT transgenic mouse with or without CCR7 to examine the signaling crosstalk between CCR7 and Notch pathways. We show for the first time that CCR7 functionally intersects with the Notch signaling pathway to regulate mammary cancer stem-like cells. In this cell subpopulation, CCR7 stimulation activated the Notch signaling pathway, and deletion of CCR7 significantly reduced the levels of activated cleaved Notch1. Moreover, blocking Notch activity prevented specific ligand-induced signaling of CCR7 and augmentation of mammary cancer stem-like cell function. Crosstalk between CCR7 and Notch1 promotes stemness in mammary cancer cells and may ultimately potentiate mammary tumor progression. Therefore, dual targeting of both the CCR7 receptor and Notch1 signaling axes may be a potential therapeutic avenue to specifically inhibit the functions of breast cancer stem cells. The online version of this article (doi:10.1186/s12943-017-0592-0) contains supplementary material, which is available to authorized users.