Vessel-guided collective cancer invasion in vivo: molecular mechanisms and fate

血管引导的体内癌症集体侵袭：分子机制和命运

• 批准号: 22053007
• 负责人: Professor Dr. Peter Friedl
• 金额: --
• 依托单位: Department of Cell Biology
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2011-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/22053007?language=en
• 关键词: Vessel; guided; collective; cancer; invasion

Cancer invasion and metastasis are the result of promigratory activity in tumor cells which is in part induced and directed by structural and molecular signals provided by the tumor microenvironment. The tumor vasculature represents both, a structural and molecular scaffold for tumor cell invasion. Structurally, vessels provide aligned fibrillar and basemement membrane ECM structures together with elongated endothelial cell bodies for direct engagement of tumor cells. The molecular proinvasive elements are ECM domains engaging integrins, released MMPs and other proteases for receptor processing, and cell surface molecules supporting heterophilic cellular interactions, including ephrin-B2/EphB4, N-/VE-cadherin, or NCAM. We will investigate how tumor vessels and neovessels contribute to tumor cell invasion by using dynamics imaging in 3D ECM based confrontation assays as well as intravital multiphoton microscopy of GFP/RFP expressing tumor cells in the nestin/GFP nude mouse. Using time-resolved topographic reconstruction and interference with soluble antagonists or RNAi, target functions will be ECM remodeling for guided migration and the provision of basement membrane and other aligned ECM structures. A key focus will aim at direct heterologous tumor cell-EC interactions via Ephrin/EphB pathways mediating dynamic cell-cell contacts. Concepts will be established using ECM in vitro confrontation assays and then validated by intravital multiphoton microscopy. These studies will provide new concepts on molecular switches of tumor invasion beyond integrin-mediated cell-matrix interactions.

癌症侵袭和转移是肿瘤细胞中促迁移活性的结果，其部分由肿瘤微环境提供的结构和分子信号诱导和指导。肿瘤脉管系统代表肿瘤细胞侵袭的结构和分子支架。在结构上，血管提供对齐的纤维状和基底膜ECM结构以及伸长的内皮细胞体，用于直接接合肿瘤细胞。分子促侵袭元件是接合整联蛋白的ECM结构域、释放的MMP和用于受体加工的其他蛋白酶，以及支持嗜异性细胞相互作用的细胞表面分子，包括肝配蛋白-B2/EphB 4、N-/VE-钙粘蛋白或NCAM。我们将研究如何肿瘤血管和新生血管有助于肿瘤细胞的侵袭，通过使用动态成像在3D ECM为基础的对抗试验，以及在nestin/GFP裸鼠的GFP/RFP表达肿瘤细胞的活体多光子显微镜。使用时间分辨的地形重建和可溶性拮抗剂或RNAi的干扰，靶功能将是ECM重塑，用于引导迁移和提供基底膜和其他对齐的ECM结构。一个关键的焦点将旨在通过Ephrin/EphB途径介导动态细胞-细胞接触直接异源肿瘤细胞-EC相互作用。将使用ECM体外对抗试验建立概念，然后通过活体多光子显微镜进行验证。这些研究将为整合素介导的细胞-基质相互作用之外的肿瘤侵袭分子开关提供新的概念。