EMET:肿瘤转移新机制

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.

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。

本项目在发现CD146是肿瘤血管新靶分子（Blood 2003），通过诱导肿瘤细胞发生上皮-间质转化（EMT）（PNAS 2012），并通过与细胞骨架相互作用促进肿瘤转移的机制(Oncogene 2012)的基础上，根据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的发现，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。.本项目从肿瘤微环境水平入手，以CD146分子在肿瘤血管生成及肿瘤转移中的促进作用为切入点，系统研究肿瘤微环境中肿瘤细胞、血管内皮细胞及免疫细胞之间相互作用复杂网络，从网络水平阐明肿瘤血管生成及肿瘤发展的机制。发现了CD146通过介导EMET过程促进肿瘤血管生成和转移功能，阐明了CD146在EMET过程中调控肿瘤细胞迁移及血管新生的分子机制，发现CD146介导血管生成功能的配体Netrin-1，阐明肿瘤血管生成新机制，并阐明了CD146在肿瘤微环境复杂网络中的调控肿瘤血管生成、肿瘤迁移及肿瘤炎症的关键节点作用，为肿瘤的系统性靶向治疗策略奠定理论基础。.通过本项目的研究，除完成上述理论发现外，本项目在Cell Research及Nature Communications等高水平SCI期刊发表论文14篇，申请发明专利3项，并获得2014年北京市科学技术奖一等奖1项。全面完成计划书规定的指标。