Live Imaging of Innate Immune Cell Sensing of Transformed Cells in Zebrafish Larvae: Parallels between Tumor Initiation and Wound Inflammation
Live Imaging of Innate Immune Cell Sensing of Transformed Cells in Zebrafish Larvae: Parallels between Tumor Initiation and Wound Inflammation
复制标题
DOI：
10.1371/journal.pbio.1000562
复制
发表时间：
2010-12-01
期刊：
影响因子：
9.8
通讯作者：
Martin, Paul
中科院分区：
文献类型：
--
作者：
Feng, Yi;Santoriello, Cristina;Martin, Paul
以前不可能实时成像宿主环境和癌基因转化细胞之间的最早相互作用，因为它们在生物体内启动癌症的形成。在这里，我们利用斑马鱼幼虫的透明性，观察宿主先天免疫细胞的反应，作为癌基因转化的成黑色素细胞和杯状细胞内繁殖的幼虫皮肤。我们的研究表明，在携带转化细胞负荷的幼虫中，白细胞在非常早期的阶段被激活。在局部，我们看到中性粒细胞和巨噬细胞在受精后48小时的募集，此时转化细胞仍然只是单细胞或双细胞，在此之后不久，我们看到免疫细胞和转化细胞之间的密切联系，以及连接两种细胞类型的细胞质系链的频繁例子，以及中性粒细胞和巨噬细胞对转化细胞的吞噬。我们发现，将炎症细胞吸引到致癌HRAS（G12 V）转化细胞的信号的主要成分是H（2）O（2），这也是负责将中性粒细胞募集到伤口的关键损伤线索。我们的短期阻断实验表明，在这些早期阶段阻止免疫细胞的募集会导致转化细胞克隆的生长减少，并表明免疫细胞可能为转化细胞提供营养支持的来源，就像它们在组织修复部位所做的那样。对转化细胞的炎症反应和对伤口的炎症反应之间的这些相似之处加强了其他人的建议，即癌症类似于无法愈合的伤口。
It has not previously been possible to live image the earliest interactions between the host environment and oncogene-transformed cells as they initiate formation of cancers within an organism. Here we take advantage of the translucency of zebrafish larvae to observe the host innate immune cell response as oncogene-transformed melanoblasts and goblet cells multiply within the larval skin. Our studies indicate activation of leukocytes at very early stages in larvae carrying a transformed cell burden. Locally, we see recruitment of neutrophils and macrophages by 48 h post-fertilization, when transformed cells are still only singletons or doublets, and soon after this we see intimate associations between immune and transformed cells and frequent examples of cytoplasmic tethers linking the two cell types, as well as engulfment of transformed cells by both neutrophils and macrophages. We show that a major component of the signal drawing inflammatory cells to oncogenic HRAS(G12V)-transformed cells is H(2)O(2), which is also a key damage cue responsible for recruiting neutrophils to a wound. Our short-term blocking experiments show that preventing recruitment of immune cells at these early stages results in reduced growth of transformed cell clones and suggests that immune cells may provide a source of trophic support to the transformed cells just as they do at a site of tissue repair. These parallels between the inflammatory responses to transformed cells and to wounds reinforce the suggestion by others that cancers resemble non-healing wounds.