ChemoCentryx, Inc., 850 Maude Avenue, Mountain View, CA 94043, USA.
Mol Cancer. 2011 Jun 14;10:73. doi: 10.1186/1476-4598-10-73.
Migration of metastatic tumor cells from the bloodstream into lymph nodes is thought to be facilitated by expression of the chemokine receptors CCR7, CXCR4 and, for B cell-derived tumors, CXCR5. Expression of their respective chemokine ligands (CCL19, CCL21, CXCL12 and CXCL13) by endothelial cells inside the lymph nodes facilitates the trans-endothelial migration (TEM) of these cells through high endothelial venules into the lymph node parenchyma. It is known that CXCR7, a second CXCL12 receptor, regulates TEM of CXCR4+CXCR7+ tumor cells towards a CXCL12 source. In this study, we set out to assess the potential stimulation by CXCL12 of tumor cell TEM towards other chemokines and whether CXCR7 might be able to regulate such effects.
The human Burkitt's lymphoma cell line NC-37, which expresses CXCR4, CXCR5, CXCR7 and CCR7, was selected as a model system. TEM of these cells through a human HUVEC endothelial cell monolayer was used as the main model system for these studies. Regulation of their TEM behavior by various concentrations of the various cognate chemokines for the above-mentioned receptors, placed in either the source or target wells of modified Boyden chamber migration plates, was assessed by quantifying the number of cells migrated under each experimental condition.
Exposure of CXCR4⁺CXCR7⁺ cancer cells to CXCL12 greatly potentiated their TEM towards the chemokines CCL19 and CXCL13. This CXCL12-potentiated TEM was inhibited by the second CXCR7 chemokine ligand, CXCL11, as well as CXCR7-specific small molecule antagonists and antibodies. In contrast, the CXCR4 antagonist AMD3100 was less effective at inhibiting CXCL12-potentiated TEM. Thus, CXCR7 antagonists may be effective therapeutic agents for blocking CXCL12-mediated migration of CXCR4⁺CXCR7⁺ tumor cells into lymph nodes, regardless of whether the cancer cells follow a CXCL12 gradient or whether serum CXCL12 stimulates their migration towards CCR7 and CXCR5 chemokines in the lymph nodes.
从血流中转移到淋巴结的转移性肿瘤细胞的迁移被认为是通过趋化因子受体 CCR7、CXCR4 和 B 细胞来源的肿瘤的 CXCR5 的表达来促进的。淋巴结内皮细胞内表达它们各自的趋化因子配体（CCL19、CCL21、CXCL12 和 CXCL13）有助于这些细胞通过高内皮小静脉穿过内皮迁移（TEM）到淋巴结实质中。已知第二个 CXCL12 受体 CXCR7 调节 CXCR4+CXCR7+肿瘤细胞向 CXCL12 源的 TEM。在这项研究中，我们着手评估 CXCL12 对肿瘤细胞 TEM 向其他趋化因子的潜在刺激作用，以及 CXCR7 是否能够调节这种作用。
选择人 Burkitt 淋巴瘤细胞系 NC-37 作为模型系统，该细胞系表达 CXCR4、CXCR5、CXCR7 和 CCR7。这些细胞通过人 HUVEC 内皮细胞单层的 TEM 被用作这些研究的主要模型系统。通过在改良 Boyden 室迁移板的源或靶孔中放置各种浓度的上述受体的各种同源趋化因子，评估各种趋化因子对其 TEM 行为的调节作用，通过量化每种实验条件下迁移的细胞数量来评估。
CXCR4+CXCR7+癌细胞暴露于 CXCL12 大大增强了它们对趋化因子 CCL19 和 CXCL13 的 TEM。这种 CXCL12 增强的 TEM 被第二个 CXCR7 趋化因子配体 CXCL11 以及 CXCR7 特异性小分子拮抗剂和抗体抑制。相比之下，CXCR4 拮抗剂 AMD3100 对抑制 CXCL12 增强的 TEM 效果较差。因此，CXCR7 拮抗剂可能是阻止 CXCL12 介导的 CXCR4+CXCR7+肿瘤细胞迁移到淋巴结的有效治疗药物，无论肿瘤细胞是否遵循 CXCL12 梯度，或者血清 CXCL12 是否刺激它们向淋巴结中的 CCR7 和 CXCR5 趋化因子迁移。
