Department of Pathology, St. Vincent's Hospital, The Catholic University of Korea, 93-6 Chi-dong, Paldal-gu, Suwon, Korea.
J Neurooncol. 2012 Sep;109(2):219-27. doi: 10.1007/s11060-012-0890-8. Epub 2012 May 11.
It remains unclear whether patients with non-small-cell lung cancer (NSCLC) develop brain metastasis during or after standard therapy. We attempted to identify biological markers that predict brain metastasis, and investigated how to modulate expression of such markers. A case-control study of patients who were newly diagnosed with NSCLC and who had developed brain metastasis during follow-up was conducted between 2004 and 2009. These patients were compared with a control group of patients who had NSCLC but no evidence of brain metastasis. Immunohistochemical analysis of expression of Ki-67, p53, Bcl-2, Bax, vascular endothelial growth factor, epidermal growth factor receptor, caspase-3, and E-cadherin was conducted. The methylation status of the genes for O(6)-methylguanine-DNA-methyltransferase, tissue inhibitor of matrix metalloproteinase (TIMP)-2, TIMP-3, and death-associated protein-kinase was also determined, by use of a methylation-specific polymerase chain reaction. A significantly increased risk of developing brain metastasis was associated with the presence of primary tumors with low E-cadherin expression in patients with NSCLC. We also investigated the effects of pioglitazone, a peroxisome proliferator-activated receptor γ-activating drug, in tumor-bearing mouse models. We found that E-cadherin expression was proportional to pioglitazone exposure time. Interestingly, pioglitazone pretreatment before cancer cell inoculation prevented loss of E-cadherin expression and reduced expression of MMP9 and fibronectin, compared with the control group. E-cadherin expression could be a predictor of brain metastasis in patients with NSCLC. Preventive treatment with pioglitazone may be useful for modulating E-cadherin expression.
目前尚不清楚非小细胞肺癌（NSCLC）患者在标准治疗期间或之后是否会发生脑转移。我们试图确定预测脑转移的生物学标志物，并研究如何调节这些标志物的表达。2004 年至 2009 年期间进行了一项新诊断为 NSCLC 且在随访期间发生脑转移的患者的病例对照研究。将这些患者与一组无脑转移证据的 NSCLC 患者对照。对 Ki-67、p53、Bcl-2、Bax、血管内皮生长因子、表皮生长因子受体、半胱天冬酶-3 和 E-钙黏蛋白的表达进行了免疫组织化学分析。通过甲基化特异性聚合酶链反应确定 O(6)-甲基鸟嘌呤-DNA-甲基转移酶、基质金属蛋白酶抑制剂（TIMP）-2、TIMP-3 和死亡相关蛋白激酶基因的甲基化状态。在患有 NSCLC 的患者中，原发肿瘤中 E-钙黏蛋白表达降低与发生脑转移的风险显著增加相关。我们还研究了过氧化物酶体增殖物激活受体γ激活药物吡格列酮在荷瘤小鼠模型中的作用。我们发现 E-钙黏蛋白的表达与吡格列酮暴露时间成正比。有趣的是，与对照组相比，吡格列酮在癌细胞接种前进行预处理可防止 E-钙黏蛋白表达的丧失，并降低 MMP9 和纤维连接蛋白的表达。E-钙黏蛋白的表达可能是 NSCLC 患者脑转移的预测因子。吡格列酮的预防治疗可能有助于调节 E-钙黏蛋白的表达。
