CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer
CXCR4 expression increases liver and lung metastasis in a mouse model of pancreatic cancer
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DOI：
10.1053/j.gastro.2005.06.056
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发表时间：
2005-10-01
期刊：
影响因子：
29.4
通讯作者：
Schmid, RM
中科院分区：
文献类型：
--
作者：
Saur, D;Seidler, B;Schmid, RM
背景和目标：最近，G1蛋白偶联趋化因子受体CXCR 4的表达与人胰腺癌细胞系的增殖、侵袭和迁移增加有关。然而，CXCR 4与器官特异性胰腺癌体内转移的相关性仍不清楚。在这里，我们研究了CXCR 4在体内的作用，在胰腺癌小鼠模型中使用非侵入性成像的靶向转移。研究方法：通过稳定转染鼠TD-2胰腺癌细胞实现趋化因子受体CXCR 4和CCR 7的功能性表达，并通过流式细胞术、钙通量、迁移和增殖测定进行分析。不同的稳定TD-2细胞克隆的转移潜力通过使用体内生物发光成像的裸鼠中的尾静脉转移测定来评估。结果：TD-2细胞在尾静脉注射后表现出非常低的CXCR 4和CCR 7表达，并且表现出较差的转移潜力。为了研究CXCR 4在胰腺癌转移中的作用，我们选择了与来自转移病灶的人胰腺癌细胞系具有相似CXCR 4表达水平的稳定TD-2细胞克隆。CXCR 4（而不是CCR 7）的表达显着增加了TD-2细胞的体内转移潜力，导致裸小鼠的肝和肺转移。选择性CXCR 4抑制剂AMD 3：100的全身给药有效地阻断了表达CXCR 4的胰腺癌细胞的增强的转移潜力。结论：这些结果表明，CXCR 4表达介导胰腺癌细胞的器官特异性转移，并提供了临床前证据，即阻断CXCL 12/CXCR 4轴是抗转移治疗的靶点。
Background & Aims: Expression of the Gi-protein-coupled chemokine receptor CXCR4 has recently been linked to increased proliferation, invasion, and migration of human pancreatic cancer cell lines. However, the relevance of CXCR4 for organ-specific pancreatic cancer metastasis in vivo remains unclear. Here, we have studied the role of CXCR4 in vivo using noninvasive imaging of targeted metastasis in a mouse model of pancreatic cancer. Methods: Functional expression of the chemokine receptors CXCR4 and CCR7 was achieved by stable transfection of murine TD-2 pancreatic cancer cells and analyzed by flow cytometry, calcium flux, migration, and proliferation assays. The metastatic potential of the different stable TD-2 cell clones was assessed by tail vein metastatic assays in nude mice using in vivo bioluminescent imaging. Results: Native TD-2 cells display very low abundant CXCR4 and CCR7 expression and show poor metastatic potential after tail vein injection. To study the role of CXCR4 in pancreatic cancer metastasis, we selected stable TD-2 cell clones with similar CXCR4 expression levels as human pancreatic cancer cell lines derived from metastatic lesions. CXCR4, but not CCR7, expression dramatically increased the in vivo metastatic potential of TD-2 cells, resulting in liver and lung metastasis in nude mice. Systemic administration of the selective CXCR4 inhibitor AMD 3:100 effectively blocked the enhanced metastatic potential of CXCR4-expressing pancreatic cancer cells. Conclusions: These, results indicate that CXCR4 expression mediates organ-specific metastasis of pancreatic cancer cells and provide preclinical evidence that blockade of the CXCL12/CXCR4 axis is a target for antimetastatic therapy.