Functional expression of CXCR4 (CD184) on small-cell lung cancer cells mediates migration, integrin activation, and adhesion to stromal cells
Functional expression of CXCR4 (CD184) on small-cell lung cancer cells mediates migration, integrin activation, and adhesion to stromal cells
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DOI：
10.1038/sj.onc.1207097
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发表时间：
2003-11-06
期刊：
影响因子：
8
通讯作者：
Burger, JA
中科院分区：
文献类型：
--
作者：
Burger, M;Glodek, A;Burger, JA
小细胞肺癌（SCLC）是一种侵袭性、快速转移的肿瘤。趋化因子基质细胞衍生因子-1（SDF-1/CXCL 12）由骨髓基质细胞组成性分泌，在造血细胞归巢至骨髓中起关键作用。在这里，我们报道了小细胞肺癌患者的肿瘤细胞表达高水平的趋化因子CXCL 12的功能性CXCR 4受体。逆转录-聚合酶链反应和流式细胞术显示CXCR 4 mRNA和CXCR 4表面表达在SCLC细胞系。来自SCLC患者的原发性肿瘤样品的免疫组织化学显示CXCR 4的高表达。CXCL 12在SCLC细胞中引起CXCR 4受体内吞、肌动蛋白聚合和磷酸化p44/42丝裂原活化蛋白激酶的强烈活化。CXCL 12还能诱导SCLC细胞向细胞外基质的侵袭和与骨髓基质细胞的粘附。特异性CXCR 4拮抗剂T140、百日咳毒素、抗血管细胞粘附分子-1（VCAM-1）抗体和CS-1肽可显着抑制SCLC细胞的基质细胞粘附，这分别证明了CXCR 4趋化因子受体激活和α 4 β 1整合素结合的重要性。此外，CXCL 12增强了SCLC细胞与固定化VCAM-1的粘附，表明CXCR 4趋化因子受体可以诱导SCLC细胞上的整合素活化。由于小细胞肺癌有很高的骨髓受累倾向，我们的研究结果表明，CXCR 4趋化因子受体和α 4 β 1整合素在肿瘤微环境中小细胞肺癌细胞与基质细胞的相互作用中起着关键作用。
Small-cell lung cancer (SCLC) is an aggressive, rapidly metastasizing neoplasm. The chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) is constitutively secreted by marrow stromal cells and plays a key role for homing of hematopoietic cells to the marrow. Here, we report that tumor cells from patients with SCLC express high levels of functional CXCR4 receptors for the chemokine CXCL12. Reverse transcriptase-polymerase chain reaction and flow cytometry demonstrated CXCR4 mRNA and CXCR4 surface expression in SCLC cell lines. Immunohistochemistry of primary tumor samples from SCLC patients revealed high expression of CXCR4. CXCL12 elicited CXCR4 receptor endocytosis, actin polymerization, and a robust activation of phospho-p44/42 mitogen-activated protein kinase in SCLC cells. Furthermore, CXCL12 induced SCLC cell invasion into extracellular matrix and firm adhesion to marrow stromal cells. Stromal cell adhesion of SCLC cells was significantly inhibited by the specific CXCR4 antagonist T140, pertussis toxin, antivascular cell adhesion molecule-1(VCAM-1) antibodies, and CS-1 peptide, demonstrating the importance of CXCR4 chemokine receptor activation and alpha4beta1 integrin binding, respectively. In addition, CXCL12 enhanced the adhesion of SCLC cells to immobilized VCAM-1, demonstrating that CXCR4 chemokine receptors can induce integrin activation on SCLC cells. As SCLC has a high propensity for bone marrow involvement, our findings suggest that CXCR4 chemokine receptors and alpha4beta1 integrins play a critical role in the interaction of SCLC cells with stromal cells in the tumor microenvironment.