EMET:肿瘤转移新机制

申请者在国际上首次报道CD146是肿瘤血管新靶分子（Blood 2003），发现它还是肿瘤细胞发生上皮-间质转化（EMT）的诱导分子（PNAS 2012），并揭示其与细胞骨架相互作用促进肿瘤转移的机制(Oncogene 2012)。在上述工作的基础上，最新发现CD146诱导发生EMT的肿瘤细胞不仅侵袭能力增强促进肿瘤转移，而且还参与肿瘤血管拟态的形成。据此，申请者第一次提出肿瘤细胞通过上皮-间质-内皮转化（EMET）机制促进肿瘤恶性化的假设。本项目将以乳腺癌为研究对象，在细胞、动物和临床标本等不同层面探讨肿瘤细胞通过EMET形成肿瘤血管拟态的规律和机制，揭示CD146在其中的作用，并探讨EMET在肿瘤诊断和治疗中的临床意义, 为肿瘤靶向治疗提供新思路和新靶点，验证靶向肿瘤血管内皮、肿瘤EMT及肿瘤血管拟态"一石三鸟"的治疗效果。

We have found that CD146 was a novel marker for tumor angiogenesis (Blood 2003)and played key roles in this process as membrane receptor. Moreover, CD146 was an inducer of epithelial-mesenchymal transition (EMT) in invasive triple-negative breast cancer (PNAS 2012)and promoted cancer metastasis by interaction with cytoskeleton (Oncogene 2012). Recently we have found that with over-expression of CD146, the epithelial-mesenchymal transited tumor cells was endowed with capacity of forming vasculogenic mimicry. Based on this finding, here we for the first time raise a novel concept,epithelial-mesenchymal-endothelia transition, EMET. In this study, we are going to discover the mechanisms by which tumor cells were transformed to endothelia-like cells with blood vessel formation capacity via EMET, and elucidated the roles of CD146 in EMET and the signal transduction pathways involved. This study will put forward a new clue to illuminate the mechanisms for cancer progression and validate CD146 as a triple-potent therapeutic target for cancer due to its roles in tumor angiogenesis, invasion and vasculogenic mimicry.