High-resolution imaging of the dynamic tumor cell-vascular interface in transparent zebrafish
High-resolution imaging of the dynamic tumor cell-vascular interface in transparent zebrafish
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DOI：
10.1073/pnas.0703446104
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发表时间：
2007-10-30
影响因子：
11.1
通讯作者：
Klemke, Richard
中科院分区：
文献类型：
--
作者：
Stoletov, Konstantin;Montel, Valerie;Klemke, Richard
细胞转移是一个高度动态的过程，分多个步骤发生。由于无法使用动物模型实时可视化肿瘤细胞行为，因此对这一过程的理解受到限制。在这里，我们采用半透明斑马鱼和高分辨率共聚焦显微镜来研究人类癌细胞如何侵入组织、诱导血管生成以及与新形成的血管相互作用。我们利用这个系统来研究人类转移基因 RhoC 如何促进转移的初始步骤。我们发现 RhoC 表达诱导原始变形虫样细胞入侵，其特征是形成动态膜突起和气泡。令人惊讶的是，这些结构仅在血管重塑部位穿透血管壁，而不是在现有完整血管的区域。这个过程需要肿瘤细胞分泌 VEGF，从而诱导血管开口，而血管开口又充当孔洞，允许表达 RhoC 的细胞进入血液系统。我们的结果支持一个模型，其中内渗和转移的早期步骤需要两个独立的事件：（i）肿瘤细胞内肌动蛋白/肌球蛋白细胞骨架的动态调节以形成突出结构和（h）血管通透和血管重塑。斑马鱼转基因技术与人类癌症生物学的整合可能有助于开发针对肿瘤内特定器官、组织或细胞类型的癌症模型。斑马鱼还可以为快速开发旨在阻止人类癌症进展和肿瘤诱导的血管生成的治疗剂提供一种经济有效的方法。
Cell metastasis is a highly dynamic process that occurs in multiple steps. Understanding this process has been limited by the inability to visualize tumor cell behavior in real time by using animal models. Here, we employ translucent zebrafish and high-resolution confocal microscopy to study how human cancer cells invade in tissues, induce angiogenesis, and interact with newly formed vessels. We use this system to study how the human metastatic gene RhoC promotes the initial steps of metastasis. We find that RhoC expression induces a primitive amoeboid-like cell invasion characterized by the formation of dynamic membrane protrusions and blebs. Surprisingly, these structures penetrate the blood vessel wall exclusively at sites of vascular remodeling and not at regions of existing intact vessels. This process requires tumor cells to secrete VEGF, which induces vascular openings, which in turn, serve as portholes allowing access of RhoC-expressing cells to the blood system. Our results support a model in which the early steps in intravasation and metastasis require two independent events: (i) dynamic regulation of the actin/myosin cytoskeleton within the tumor cell to form protrusive structures and (h) vascular permeablization and vessel remodeling. The integration of zebrafish transgenic technology with human cancer biology may aid in the development of cancer models that target specific organs, tissues, or cell types within the tumors. Zebrafish could also provide a cost-effective means for the rapid development of therapeutic agents directed at blocking human cancer progression and tumorinduced angiogenesis.