Hypoxia increases the metastatic ability of breast cancer cells via upregulation of CXCR4.
Hypoxia increases the metastatic ability of breast cancer cells via upregulation of CXCR4.
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DOI：
10.1186/1471-2407-10-225
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发表时间：
2010-05-21
期刊：
影响因子：
3.8
通讯作者：
Redmond HP
中科院分区：
文献类型：
--
作者：
Cronin PA;Wang JH;Redmond HP
趋化因子SDF 1 α及其独特的受体CXCR 4与包括乳腺癌在内的许多癌症的器官特异性转移有关。缺氧是实体瘤的常见特征，并且与其恶性表型相关。我们假设缺氧会上调CXCR 4的表达，并导致对其特异性配体SDF 1 α的趋化反应性增加。三种乳腺癌细胞系MDA-MB-231、MCF 7和4 T1经历48小时的缺氧或常氧。使用流式细胞术评估细胞表面受体表达。细胞外基质侵袭试验和微孔迁移试验用于评估趋化反应和转移能力。在暴露于缺氧后，两种人乳腺癌细胞系MDA-MB-231和MCF 7中CXCR 4表面表达显著增加。这种CXCR 4细胞表面表达的上调对应于SDF 1-α在体外应答的迁移和侵袭的显著增加。常氧和低氧处理的乳腺癌细胞系的转移潜能的增加通过用CXCR 4中和mAb MAB 172或CXCR 4拮抗剂AMD 3100中和CXCR 4而减弱，显示了CXCR 4过表达和增加的趋化反应性之间的关系。CXCR 4的表达可以通过组织微环境如缺氧来调节。CXCR 4的上调与增加的迁移和侵袭潜力相关，并且这种作用可以通过CXCR 4抑制来消除。趋化因子受体CXCR 4是乳腺癌辅助治疗的潜在靶点。
Chemokine SDF1α and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers including breast cancer. Hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. We hypothesized that hypoxia would upregulate CXCR4 expression and lead to increased chemotactic responsiveness to its specific ligand SDF1α. Three breast cancer cell lines MDA-MB-231, MCF7 and 4T1 were subjected to 48 hrs of hypoxia or normoxia. Cell surface receptor expression was evaluated using flow cytometry. An extracellular matrix invasion assay and microporous migration assay was used to assess chemotactic response and metastatic ability. CXCR4 surface expression was significantly increased in the two human breast cancer cell lines, MDA-MB-231 and MCF7, following exposure to hypoxia. This upregulation of CXCR4 cell surface expression corresponded to a significant increase in migration and invasion in response to SDF1-α in vitro. The increase in metastatic potential of both the normoxic and the hypoxic treated breast cancer cell lines was attenuated by neutralization of CXCR4 with a CXCR4 neutralizing mAb, MAB172 or a CXCR4 antagonist, AMD3100, showing the relationship between CXCR4 overexpression and increased chemotactic responsiveness. CXCR4 expression can be modulated by the tissue microenvironment such as hypoxia. Upregulation of CXCR4 is associated with increased migratory and invasive potential and this effect can be abrogated by CXCR4 inhibition. Chemokine receptor CXCR4 is a potential therapeutic target in the adjuvant treatment of breast cancer.
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