小细胞肺癌（SCLC）具有向脑特异性转移的病理特点，具体机制尚不清楚。前期发现，SCLC产生分泌因子改变脑微血管内皮细胞屏障功能，促进其迁移入脑。我们从寻找影响SCLC"脑转移微环境"形成的因子入手，利用肿瘤脑转移动物模型获得SCLC脑转移细胞株，基因芯片比较具有不同脑转移能力的SCLC细胞间差异表达基因，获得候选基因-膜联蛋白A1（Annexin A1），可以被SCLC细胞分泌到细胞外促进细胞间粘附。本项目拟研究：①解析Annexin A1与SCLC脑转移关系；②探明SCLC 分泌的Annexin A1如何调控血脑屏障微环境，适宜SCLC穿过血脑屏障迁移入脑及作用机制③尝试干预Annexin A1及相关分子功能，观察是否可以抑制SCLC脑转移发生。本项目的完成可为SCLC脑转移研究提供新的实验证据,有望为防治SCLC脑转移提供潜在作用靶点，丰富肿瘤器官特异性转移的"转移微环境"学说。

Small cell lung cancer (SCLC) is the most aggressive histologic subtype of lung cancer, with a strong predilection for metastasizing early. However, the cellular and molecular basis of SCLC brain metastasis is poorly known. Some recent studies revealed that brain microvasculature was the primary soil for metastatic tumor cell attachment and growth in the brain. We previously found that SCLC cells acted on human brain microvascular endothelial cells (HBMEC) to induce disassembly of TJ that leading to increased endothelial permeability and SCLC cells transendothelial migration. These data suggested that brain microvasculature might play an important role in the SCLC extravasation into the brain parenchyma. Therefore, we compare the gene expression profile of SCLC cell and SCLC cell co-cultured with HBMEC by DNA microarray and Annexin A1 was identified as a significant up-regulated gene. Further results showed that Annexin A1 was associated with SCLC metastasis to the brain. Based on these results, our projects will be focused in the role of Annexin A1 in migration across the blood brain barrier and metastasis to the brain, including Annexin A1 potential clinical relevance, the detailed mechanisms of Annexin A1 in the SCLC metastasis to brain. Finally, we will use the mice model to analyze whether the occurrence of SCLC metastasis to brain is blocked by prevention the effect of Annexin A1. These works are necessary to improve a better understanding of the mechanisms of SCLC brain metastasis and provide a potential therapeutic target for SCLC brain metastasis. More importantly, these studies will provie the strong evidence to verify the theory of the metastasis niche.