The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases
The stromal derived factor-1/CXCL12-CXC chemokine receptor 4 biological axis in non-small cell lung cancer metastases
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DOI：
10.1164/rccm.200301-071oc
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发表时间：
2003-06-15
影响因子：
24.7
通讯作者：
Strieter, RM
中科院分区：
文献类型：
--
作者：
Phillips, RJ;Burdick, MD;Strieter, RM
非小细胞肺癌的特征在于特定的转移模式。器官特异性转移的机制知之甚少，尽管有证据表明趋化因子基质衍生因子-1（CXCL 12）及其同源受体CXCR 4可能调节乳腺癌转移。我们假设CXCL 12-CXCR 4生物轴在介导非小细胞肺癌转移中是重要的。我们的研究结果表明，从患者切除的非小细胞肺癌肿瘤标本和非小细胞肺癌细胞系均表达CXCR 4，但不表达CXCL 12。CXCL 1/2-CXCR 4激活的非小细胞肺癌细胞系显示细胞内钙动员和丝裂原活化蛋白激酶激活，细胞外信号相关激酶-1/2磷酸化增强，而增殖或凋亡无变化。小鼠模型中的靶器官是人类非小细胞肺癌转移的首选目的地，其CXCL 12水平高于原发性肿瘤;并表明产生了趋化梯度。向表达人非小细胞肺癌的严重联合免疫缺陷小鼠施用特异性中和性抗CXCL 12抗体消除了器官转移，而不影响原发性肿瘤衍生的血管生成。这些数据表明，CXCL 12-CXCR 4生物轴参与调节非小细胞肺癌的转移。
Non-small cell lung cancer is characterized by a specific metastatic pattern. The mechanism for organ-specific metastasis is poorly understood, although evidence has suggested that the chemokine stromal derived factor-1 (CXCL12) and its cognate receptor CXCR4 may regulate breast cancer metastasis. We hypothesized that the CXCL12-CXCR4 biological axis is important in mediating non-small cell lung cancer metastases. Our results indicate that both non-small cell lung cancer tumor specimens resected from patients and non-small cell lung cancer cell lines express CXCR4, but not CXCL12. Non-small cell lung cancer cell lines undergo chemotaxis in response to CXCL12.CXCL12-CXCR4 activation of non-small cell lung cancer cell lines showed intracellular calcium mobilization and mitogen-activated protein kinase activation with enhanced extracellular signal-related kinase-1/2 phosphorylation without change in either proliferation or apoptosis. Target organs in a murine model that are the preferred destination of human non-small cell lung cancer metastases elaborate higher levels of CXCL12 than does the primary tumor; and suggest the generation of chemotactic gradients. The administration of specific neutralizing anti-CXCL12 antibodies to severe combined immunodeficient mice expressing human non-small cell lung cancer abrogated organ metastases, without affecting primary tumor-derived angiogenesis. These data suggest that the CXCL12-CXCR4 biological axis is involved in regulating the metastasis of non-small cell lung cancer.