CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells
CXCR4 chemokine receptor and integrin signaling co-operate in mediating adhesion and chemoresistance in small cell lung cancer (SCLC) cells
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DOI：
10.1038/sj.onc.1208621
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发表时间：
2005-06-01
期刊：
影响因子：
8
通讯作者：
Burger, M
中科院分区：
文献类型：
--
作者：
Hartmann, TN;Burger, JA;Burger, M
小细胞肺癌（SCLC）是一种侵袭性、快速转移的肿瘤，具有高度的骨髓受累倾向。SCLC细胞表达高水平的趋化因子基质细胞衍生因子-1（SDF-1/CXCL 12）的功能性CXCR 4受体。SCLC细胞粘附于肿瘤微环境内的细胞外基质或辅助细胞，通过整合素信号传导赋予化疗耐药性，因此可能是SCLC中常见的残留疾病和复发的原因。我们研究了调节CXCL 12诱导的SCLC细胞与纤连蛋白、胶原和基质细胞粘附的信号机制以及对SCLC细胞化学抗性的影响。我们发现CXCL 12诱导的整合素活化导致SCLC细胞与纤连蛋白和胶原的粘附增加。这是由α 2、α 4、α 5和β 1整联蛋白沿着CXCR 4激活介导的，CXCR 4激活可被CXCR 4拮抗剂抑制。基质细胞保护SCLC细胞免于化疗诱导的凋亡，并且这种保护作用也可以被CXCR 4抑制剂拮抗。我们的结论是整合素和CXCR 4趋化因子受体的激活在介导从肿瘤微环境到SCLC细胞的粘附和存活信号中起协同作用。因此，应在SCLC中探索CXCR 4拮抗剂与细胞毒性药物的组合，以克服肿瘤微环境中CXCL 12介导的粘附和存活信号。
Small cell lung cancer (SCLC) is an aggressive, rapidly metastazising neoplasm with a high propensity for marrow involvement. SCLC cells express high levels of functional CXCR4 receptors for the chemokine stromal-cell-derived factor-1 (SDF-1/CXCL12). Adhesion of SCLC cells to extracellular matrix or accessory cells within the tumor microenvironment confers resistance to chemotherapy via integrin signaling and thus may be responsible for residual disease and relapses commonly seen in SCLC. We examined the signaling mechanisms that regulate CXCL12-induced adhesion of SCLC cells to fibronectin, collagen, and stromal cells and the effects on SCLC cell chemoresistance. We found that CXCL12-induced integrin activation which resulted in an increased adhesion of SCLC cells to fibronectin and collagen. This was mediated by alpha 2, alpha 4, alpha 5, and beta 1 integrins along with CXCR4 activation, which could be inhibited by CXCR4 antagonists. Stromal cells protected SCLC cells from chemotherapy-induced apoptosis, and this protection could also be antagonized by CXCR4 inhibitors. We conclude that activation of integrins and CXCR4 chemokine receptors co-operate in mediating adhesion and survival signals from the tumor microenvironment to SCLC cells. Therefore, CXCR4 antagonists in combination with cytotoxic drugs should be explored in SCLC to overcome CXCL12-mediated adhesion and survival signals in the tumor microenvironment.