文章：

肿瘤侵袭和转移中的细胞运动：来自简单模式生物的见解

Cell motility in cancer invasion and metastasis: insights from simple model organisms

原文发布日期：2018-03-16

DOI: 10.1038/nrc.2018.15

类型: Review Article

开放获取: 否

要点：

1. The motility of both tumour and normal host cells contributes to tumour metastasis at several steps, including breaching of basement membrane, escape from the primary tumour, migration to blood and lymphatic vessels, intravasation and extravasation and movement into distant organs. The ability to migrate towards favourable environments is a fundamental and evolutionarily conserved cellular behaviour from unicellular organisms to humans.
2. Both normal and cancer cells migrate using diverse modes including amoeboid, mesenchymal, epithelial, collective and individual. Simple model organisms also exhibit these diverse modes of motility and offer experimental advantages such as low cost, amenability to large-scale genetic and pharmacological screening and live imaging of cells interacting within their native environments.
3. Studies of the social amoeba Dictyostelium discoideum have unravelled the complex signalling networks that mediate chemokine-directed cell migration, which is also observed with human immune and tumour cells.
4. The combination of high-resolution live imaging and genetic screening in the nematode has revealed that cells can breach a basement membrane by pushing the matrix aside and also by degrading it. This potentially offers a new mechanism to target cancer invasion therapeutically.
5. Cooperative, collective cell motility appears to contribute to tumour metastasis. Border cells in the Drosophila melanogaster ovary serve as a simple model that is genetically tractable and amenable to live imaging. This model has revealed that some mechanisms of cooperative, collective cell migration, such as the requirement for E-cadherin, differ from those of single-cell motility.
6. Direct modelling of metastasis can be carried out in both flies and fish. Work in flies has resulted in the identification and optimization of kinase inhibitors for metastatic thyroid cancer. The fish offers the lowest-cost vertebrate model for intravasation and extravasation studies and is amenable to live imaging as well as genetic and pharmacological manipulation.

要点翻译：

1. 肿瘤和正常宿主细胞的运动能力在多个步骤中促进肿瘤转移，包括基底膜的破坏、原发肿瘤的逃逸、向血液和淋巴管的迁移、内渗和外渗以及向远处器官的移动。向有利环境迁移的能力是从单细胞生物到人类的一种基本且进化上保守的细胞行为。
2. 正常细胞和癌细胞均采用多种迁移模式，包括阿米巴样、间充质、上皮、集体和个体迁移。简单的模型生物也展现出这些多样的运动模式，并具有实验优势，如低成本、适合大规模遗传和药物筛选，以及在其原生环境中进行细胞相互作用的实时成像。
3. 对社交阿米巴盘基网柄菌的研究揭示了介导趋化因子导向的细胞迁移的复杂信号网络，这也与人类免疫细胞和肿瘤细胞的迁移机制相似。
4. 通过线虫的高分辨率实时成像和遗传筛选相结合，研究发现细胞可以通过推开基质或降解基质来突破基底膜。这为靶向癌症侵袭的治疗提供了新的潜在机制。
5. 协作性集体细胞运动似乎对肿瘤转移有贡献。黑腹果蝇卵巢中的边界细胞作为一个简单的模型，具有遗传易操作性和适合实时成像的特点。该模型揭示了协作性集体细胞迁移的某些机制（如对E-钙黏蛋白的需求）与单细胞运动机制不同。
6. 转移的直接模拟可以在果蝇和鱼类中进行。果蝇研究已经鉴定并优化了用于转移性甲状腺癌的激酶抑制剂。鱼类为内渗和外渗研究提供了最低成本的脊椎动物模型，并且适合实时成像以及遗传和药物操作。

英文摘要：

Metastasis remains the greatest challenge in the clinical management of cancer. Cell motility is a fundamental and ancient cellular behaviour that contributes to metastasis and is conserved in simple organisms. In this Review, we evaluate insights relevant to human cancer that are derived from the study of cell motility in non-mammalian model organisms. Dictyostelium discoideum, Caenorhabditis elegans, Drosophila melanogaster and Danio rerio permit direct observation of cells moving in complex native environments and lend themselves to large-scale genetic and pharmacological screening. We highlight insights derived from each of these organisms, including the detailed signalling network that governs chemotaxis towards chemokines; a novel mechanism of basement membrane invasion; the positive role of E-cadherin in collective direction-sensing; the identification and optimization of kinase inhibitors for metastatic thyroid cancer on the basis of work in flies; and the value of zebrafish for live imaging, especially of vascular remodelling and interactions between tumour cells and host tissues. While the motility of tumour cells and certain host cells promotes metastatic spread, the motility of tumour-reactive T cells likely increases their antitumour effects. Therefore, it is important to elucidate the mechanisms underlying all types of cell motility, with the ultimate goal of identifying combination therapies that will increase the motility of beneficial cells and block the spread of harmful cells.

摘要翻译： 

转移仍是癌症临床治疗中的最大难题。细胞运动是一种基本且古老的细胞行为，它促进转移，并在简单生物中高度保守。在本综述中，我们评估了利用非哺乳动物模型研究细胞运动所获得的对人类癌症具有启示意义的成果。盘基网柄菌、秀丽隐杆线虫、黑腹果蝇和斑马鱼可直接观察细胞在复杂原生环境中迁移，并适合大规模遗传和药理学筛选。我们重点总结了从这些模型中获得的洞见，包括：趋化因子趋化的详细信号网络、基底膜侵袭的新机制、E-钙黏蛋白在集体方向感知中的正向作用、基于果蝇工作筛选并优化用于转移性甲状腺癌的激酶抑制剂，以及斑马鱼在活体成像尤其是血管重塑和肿瘤细胞与宿主组织相互作用研究中的价值。虽然肿瘤细胞和某些宿主细胞的运动促进转移扩散，但肿瘤反应性T细胞的运动可能增强其抗肿瘤效应。因此，阐明所有类型细胞运动的机制至关重要，最终目标是找到联合疗法，既能增强有益细胞的运动，又能阻断有害细胞的扩散。

原文链接：

Cell motility in cancer invasion and metastasis: insights from simple model organisms