Proinflammatory Adhesion Molecules Facilitate Polychlorinated Biphenyl-Mediated Enhancement of Brain Metastasis Formation
Proinflammatory Adhesion Molecules Facilitate Polychlorinated Biphenyl-Mediated Enhancement of Brain Metastasis Formation
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DOI：
10.1093/toxsci/kfr349
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发表时间：
2012-04-01
影响因子：
3.8
通讯作者：
Toborek, Michal
中科院分区：
文献类型：
--
作者：
Sipos, Eszter;Chen, Lei;Toborek, Michal
多氯联苯（PCBs）是一种环境毒物，可引起血管炎症并促进脑转移的发展。转移形成的关键事件是血液传播的肿瘤细胞粘附到血管内皮上，随后是它们的跨毛细血管迁移。本研究的目的是在血脑屏障水平上研究PCB 118诱导脑转移瘤形成的机制，重点是肿瘤细胞与脑内皮细胞的粘附。对野生型或细胞间粘附分子-1（ICAM-1）缺陷小鼠口服PCB 118，然后将刘易斯肺癌细胞注射到颈动脉中。用PCB 118治疗导致脑转移瘤的发展增强。注射肿瘤细胞诱导ICAM-1和血管内皮细胞粘附分子-1（VCAM-1）在脑内皮细胞中过度表达，在暴露于PCB 118的小鼠中进一步增强。PCB 118不影响ICAM-1缺陷小鼠中粘附和外渗的肿瘤细胞的数量。另外的体外研究表明，VCAM-1中和抗体可防止PCB 118诱导的肿瘤细胞与培养的脑内皮细胞的粘附。这些结果表明，暴露于选定的PCB同系物，如PCB 118，诱导肿瘤细胞的粘附和跨毛细血管迁移。这一过程是由促炎粘附分子促进的，并导致脑转移形成的增强。
Polychlorinated biphenyls (PCBs) are environmental toxicants that cause vascular inflammation and facilitate the development of brain metastases. The crucial event in metastasis formation is adhesion of blood-borne tumor cells to the vascular endothelium, followed by their transcapillary migration. The aim of the present study was to examine the mechanisms of PCB118-induced brain metastasis formation at the blood-brain barrier level with the focus on tumor cell adhesion to the brain endothelium. PCB118 was administered orally to wild-type or intercellular cell adhesion molecule-1 (ICAM-1)-deficient mice, followed by an injection of Lewis lung carcinoma cells into the carotid artery. Treatment with PCB118 resulted in enhanced development of brain metastases. Injection of tumor cells induced overexpression of ICAM-1 and vascular endothelial cell adhesion molecule-1 (VCAM-1) in brain endothelium that was further potentiated in mice exposed to PCB118. PCB118 did not affect the number of adhered and extravasated tumor cells in ICAM-1-deficient mice. Additional in vitro studies indicated that VCAM-1-neutralizing antibody protected against PCB118-induced adhesion of tumor cells to cultured brain endothelial cells. These results indicate that exposure to selected PCB congeners, such as PCB118, induces adhesion and transcapillary migration of tumor cells. This process is facilitated by proinflammatory adhesion molecules and results in potentiation of brain metastasis formation.