文章：

cofilin通路在乳腺癌侵袭转移中的作用

The cofilin pathway in breast cancer invasion and metastasis

原文发布日期：2007-06-01

DOI: 10.1038/nrc2148

类型: Review Article

开放获取: 否

要点：

1. A pattern of changes in gene expression clustered in the cofilin pathway is consistently observed in mammary tumours and cells derived from them.
2. The cofilin pathway has emerged as having a central role in the generation of free actin filament ends resulting in actin filament remodelling by polymerization and depolymerization. Filament remodelling is essential during the formation and retraction of path-finding structures used in the chemotaxis, cell migration and invasion of tumour cells.
3. The spatial localization of cofilin activity is required for chemotaxis by tumour cells in response to epidermal growth factor, and fits a local excitation global inhibition (LEGI)-type model of chemotaxis.
4. A balance of the stimulatory and inhibitory branches of the cofilin pathway must be achieved for protrusion, cell migration and chemotaxis to occur optimally. Too much or too little activity will inhibit all of these essential steps in motility and invasion.
5. As there are four regulatory mechanisms for cofilin activity which seem to be uncoupled, the activity status of cofilin in a cell cannot be assessed by measuring the ratio of dephosphorylated cofilin to the total cofilin present.
6. An important implication of recent studies of the cofilin pathway is that looking at the expression status of a single gene can be misleading when interpreting phenotype, as it is the collective activity of multiple genes of the pathway that determines the integrated output of the pathway and therefore phenotype.
7. The rational design of inhibitors of the cofilin pathway is possible. Measuring the output of the cofilin pathway directly in living cells isolated from invasive tumours will be necessary to assess the efficacy of the inhibitors. New technologies for intravital imaging, invasive tumour cell collection and expression profiling, and for measuring cofilin pathway activity, make inhibitor design and testing possible.

要点翻译：

1. 在乳腺肿瘤及源自这些肿瘤的细胞中， consistently观察到一种集中在丝切蛋白信号通路中的基因表达变化模式。
2. 丝切蛋白通路通过聚合和解聚作用产生游离肌动蛋白丝末端，在肌动蛋白丝重塑过程中发挥核心作用。这种细丝重塑对于肿瘤细胞趋化、迁移和侵袭过程中路径寻找结构的形成与回缩至关重要。
3. 肿瘤细胞响应表皮生长因子的趋化作用需要丝切蛋白活性的空间定位，这符合局部激发全局抑制（LEGI）型趋化模型。
4. 必须实现丝切蛋白通路刺激支与抑制支的平衡，才能最优化地实现细胞伪足伸展、迁移和趋化作用。活性过高或过低都会抑制运动性和侵袭性的所有关键步骤。
5. 由于丝切蛋白存在四种看似互不关联的调节机制，仅通过测量去磷酸化丝切蛋白与总丝切蛋白的比值无法准确评估细胞内的丝切蛋白活性状态。
6. 近期丝切蛋白通路研究的重要启示在于：在解读表型时，仅观察单个基因的表达状态可能产生误导，因为决定通路整体输出乃至表型的是该通路多个基因的协同活性。
7. 丝切蛋白通路抑制剂的合理设计具有可行性。为评估抑制剂效能，必须直接检测从侵袭性肿瘤中分离的活细胞内丝切蛋白通路的输出。活体成像、侵袭性肿瘤细胞采集与表达谱分析、以及丝切蛋白通路活性测量等新技术的出现，使抑制剂的设计与测试成为可能。

英文摘要：

Recent evidence indicates that metastatic capacity is an inherent feature of breast tumours and not a rare, late acquired event. This has led to new models of metastasis. The interpretation of expression-profiling data in the context of these new models has identified the cofilin pathway as a major determinant of metastasis. Recent studies indicate that the overall activity of the cofilin pathway, and not that of any single gene within the pathway, determines the invasive and metastatic phenotype of tumour cells. These results predict that inhibitors directed at the output of the cofilin pathway will have therapeutic benefit in combating metastasis.

摘要翻译： 

最新证据表明，转移能力是乳腺肿瘤的内在特征，而非罕见的晚期获得性事件。这促使人们提出新的转移模型。在这些新模型的背景下对表达谱数据进行解读，已确定cofilin通路是转移的主要决定因素。近期研究表明，决定肿瘤细胞侵袭和转移表型的，是cofilin通路的整体活性，而非该通路中任一单个基因的活性。这些结果预示，靶向cofilin通路输出的抑制剂将在抗击转移中具有治疗益处。

原文链接：

The cofilin pathway in breast cancer invasion and metastasis