Cell Surface Tetraspanin CD9 Mediates Chemoresistance in Small Cell Lung Cancer
Cell Surface Tetraspanin CD9 Mediates Chemoresistance in Small Cell Lung Cancer
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DOI：
10.1158/0008-5472.can-10-0996
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发表时间：
2010-10-15
期刊：
影响因子：
11.2
通讯作者：
Kawase, Ichiro
中科院分区：
文献类型：
--
作者：
Kohmo, Satoshi;Kijima, Takashi;Kawase, Ichiro
小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，由于在其临床病程早期出现广泛转移和初始治疗后快速获得耐药性，死亡率极高。细胞粘附介导的耐药性理论被认为是细胞外基质蛋白提供抵抗细胞毒性药物诱导的细胞凋亡的存活优势的主要机制。我们发现，四跨膜蛋白家族成员CD 9优先表达于SCLC肿瘤和7例复发患者中的3例转移瘤，而16例化疗无效的原发性肿瘤仅1例为CD 9阴性。此外，CD 9在对顺铂或依托泊苷具有抗性的SCLC细胞系上高度表达，并且在暴露于这些化合物中的任一种后48小时内在亲本化学敏感细胞中上调。表达CD 9的化疗耐药SCLC细胞通过β 1整合素更紧密地粘附于纤连蛋白，但它们的运动性低于相应的化疗敏感亲本细胞系。值得注意的是，用趋化因子CXCL 12处理化学抗性细胞下调了CD 9并短暂恢复了运动性。此外，通过用特异性单克隆抗体ALB 6或小干扰RNA治疗来选择性靶向CD 9，触发了化学抗性细胞的凋亡。总之，我们的研究结果表明，CD 9参与了细胞粘附介导的耐药机制，突出了CD 9作为一个有吸引力的治疗靶点，以改善SCLC的治疗结果。Cancer Res; 70（20）; 8025-35. (C)2010年AACR。
Small cell lung cancer (SCLC) is an aggressive malignancy with extremely high mortality due to the appearance of widespread metastases early in its clinical course and rapid acquisition of chemoresistance after initial therapy. A theory of cell adhesion-mediated drug resistance is thought to be a principal mechanism in which extracellular matrix proteins provide a survival advantage against cytotoxic drug-induced apoptosis. We found that the tetraspanin family member CD9 was expressed preferentially in SCLC tumors and metastases from three of seven relapsed patients, whereas chemonaive primary tumors from 16 patients were CD9 negative with only one exception. Additionally, CD9 was highly expressed on SCLC cell lines rendered resistant to cisplatin or etoposide, and was upregulated in parental chemosensitive cells within 48 hours after exposure to either of these compounds. CD9-expressing chemoresistant SCLC cells adhered more tightly to fibronectin via beta 1 integrin, but they were less motile than the respective chemosensitive parental lines. Notably, treatment of the chemoresistant cells with chemokine CXCL12 downregulated CD9 and transiently restored motility. Moreover, selective targeting of CD9 by treatment with specific monoclonal antibody ALB6 or a small interfering RNA triggered apoptosis in the chemoresistant cells. Taken together, our findings implicate CD9 in the cell adhesion-mediated drug resistance mechanism, highlighting CD9 as an attractive therapeutic target to improve therapeutic outcomes in SCLC. Cancer Res; 70(20); 8025-35. (C) 2010 AACR.