Weitzenfeld Polina, Kossover Olga, Körner Cindy, Meshel Tsipi, Wiemann Stefan, Seliktar Dror, Legler Daniel F, Ben-Baruch Adit
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel;
Faculty of Biomedical Engineering, Technion-Israel Institute of Technology, Haifa, Israel;
J Leukoc Biol. 2016 Jun;99(6):1009-25. doi: 10.1189/jlb.3MA0815-373R. Epub 2016 Mar 2.
Chemokine axes have been shown to mediate site-specific metastasis in breast cancer, but their relevance to different subtypes has been hardly addressed. Here, with the focus on the CCR7-CCL21 axis, patient datasets demonstrated that luminal-A tumors express relatively low CCR7 levels compared with more aggressive disease subtypes. Furthermore, lymph node metastasis was not associated with high CCR7 levels in luminal-A patients. The metastatic pattern of luminal-A breast tumors may be influenced by the way luminal-A tumor cells interpret signals provided by factors of the primary tumor microenvironment. Thus, CCR7-expressing human luminal-A cells were stimulated simultaneously by factors representing 3 tumor microenvironment arms typical of luminal-A tumors, hormonal, inflammatory, and growth stimulating: estrogen + TNF-α + epidermal growth factor. Such tumor microenvironment stimulation down-regulated the migration of CCR7-expressing tumor cells toward CCL21 and inhibited the formation of directional protrusions toward CCL21 in a novel 3-dimensional hydrogel system. CCL21-induced migration of CCR7-expressing tumor cells depended on PI3K and MAPK activation; however, when CCR7-expressing cancer cells were prestimulated by tumor microenvironment factors, CCL21 could not effectively activate these signaling pathways. In vivo, pre-exposure of the tumor cells to tumor microenvironment factors has put restraints on CCL21-mediated lymph node-homing cues and shifted the metastatic pattern of CCR7-expressing cells to the aggressive phenotype of dissemination to bones. Several of the aspects were also studied in the CXCR4-CXCL12 system, demonstrating similar patient and in vitro findings. Thus, we provide novel evidence to subtype-specific regulation of the CCR7-CCL21 axis, with more general implications to chemokine-dependent patterns of metastatic spread, revealing differential regulation in the luminal-A subtype.
趋化因子轴已被证明可介导乳腺癌的位点特异性转移，但其与不同亚型的相关性却鲜有研究。在此，以CCR7-CCL21轴为重点，患者数据集显示，与侵袭性更强的疾病亚型相比，腔面A型肿瘤表达的CCR7水平相对较低。此外，腔面A型患者的淋巴结转移与高CCR7水平无关。腔面A型乳腺肿瘤的转移模式可能受腔面A型肿瘤细胞解读原发肿瘤微环境因子所提供信号方式的影响。因此，表达CCR7的人腔面A型细胞同时受到代表腔面A型肿瘤典型的三种肿瘤微环境因素的刺激：雌激素+肿瘤坏死因子-α+表皮生长因子。这种肿瘤微环境刺激下调了表达CCR7的肿瘤细胞向CCL21的迁移，并在一种新型三维水凝胶系统中抑制了向CCL21的定向突起形成。CCL21诱导的表达CCR7的肿瘤细胞迁移依赖于PI3K和MAPK激活；然而，当表达CCR7的癌细胞被肿瘤微环境因子预刺激时，CCL21无法有效激活这些信号通路。在体内，肿瘤细胞预先暴露于肿瘤微环境因子会限制CCL21介导的淋巴结归巢信号，并将表达CCR7的细胞的转移模式转变为向骨转移的侵袭性表型。在CXCR4-CXCL12系统中也研究了其中几个方面，显示出类似的患者和体外研究结果。因此，我们为CCR7-CCL21轴的亚型特异性调节提供了新证据，对趋化因子依赖性转移扩散模式具有更广泛的意义，揭示了腔面A型亚型中的差异调节。
