文章：

癌症的趋化性

Chemotaxis in cancer

原文发布日期：2011-07-22

DOI: 10.1038/nrc3078

类型: Review Article

开放获取: 否

要点：

1. Chemotaxis is the phenomenon by which cell movement is directed in response to an extracellular chemical gradient. Factors that mediate chemotaxis are frequently mutated in cancer. Although most of the factors have dual roles in cell growth and survival, they also mediate cytoskeletal dynamics that results in chemotaxis, thus suggesting a potentially important role of chemotaxis in cancer.
2. Tumour cells in vivo can move both randomly and directionally. However, invasion, migration and dissemination are most efficient when the cell is involved in directed migration. Different modes of directed migration have been described for tumour cells (amoeboid migration or mesenchymal migration for single cells and collective or streaming migration for groups of cells). The occurrence and frequency of these modes of migration in cancer is dependent on the type of cancer and the surrounding factors within the tumour microenvironment.
3. Despite the various patterns of directed migration during tumour cell dissemination, the intracellular processes that direct the cell motility cycle in response to the chemoattractant are probably similar and are comprised of three steps: chemosensing, polarization and locomotion. First, polarized intracellular signals lead to asymmetric actin polymerization resulting in extension of the cell membrane in the direction of movement, thus creating the leading-edge protrusion. This is followed by integrin-mediated adhesion to the substrate on which the cell is moving, and then by detachment from the substrate and contraction of the trailing edge of the cell.
4. In addition to cancer cells, directional migration to a chemokine source is observed in stromal cells, which frequently shape the tumour microenvironment to a more pro-metastatic state. A complex network of chemokines and growth factors is involved in the communication of tumour cells with stromal cells. This leads to several major events of cancer progression, such as immune evasion, angiogenesis, invasion and dissemination.
5. Despite the strong experimental evidence for the involvement of chemotaxis signalling pathways in tumour cell dissemination, therapeutics under development are tested only for their ability to reduce the tumour size in patients with late-stage disease. A lack of relevant therapeutic end points in clinical practice, together with the current belief that dissemination occurs early in tumour progression, before clinical presentation, have brought scepticism to the development of anti-invasion and anti-dissemination drugs.
6. We speculate that dissemination is not only a feasible but also a necessary therapeutic target if efficient long-term management of minimal residual disease is a goal in cancer treatment. The identification of therapeutic end points relevant to tumour cell dissemination will facilitate the development and appropriate use of therapeutics.

要点翻译：

1. 趋化性是细胞运动响应细胞外化学梯度而定向引导的现象。介导趋化性的因子在癌症中常发生突变。尽管大多数因子在细胞生长和存活中具有双重作用，但它们也介导导致趋化性的细胞骨架动力学，从而提示趋化性在癌症中可能具有重要作用。
2. 体内肿瘤细胞既可以随机运动，也可以定向运动。然而，当细胞参与定向迁移时，侵袭、迁移和播散最为有效。肿瘤细胞具有不同的定向迁移模式（单细胞的阿米巴样迁移或间充质迁移，以及细胞群的集体迁移或流式迁移）。这些迁移模式在癌症中的发生频率取决于癌症类型和肿瘤微环境中的周围因素。
3. 尽管肿瘤细胞播散过程中的定向迁移模式多种多样，但指导细胞运动周期响应化学吸引物的细胞内过程可能相似，并包括三个步骤：化学感应、极化和运动。首先，极化的细胞内信号导致不对称肌动蛋白聚合，从而使细胞膜向运动方向延伸，形成前缘突起。随后是整合素介导的细胞附着于运动底物的粘附，然后是细胞从底物脱离及尾缘收缩。
4. 除癌细胞外，基质细胞也观察到向趋化因子源的定向迁移，这常常使肿瘤微环境塑造为更促转移的状态。趋化因子和生长因子的复杂网络参与了肿瘤细胞与基质细胞的通讯。这导致了癌症进展的几个主要事件，如免疫逃逸、血管生成、侵袭和播散。
5. 尽管有强有力的实验证据表明趋化信号通路参与肿瘤细胞播散，但正在开发的治疗方法仅在晚期疾病患者中测试其缩小肿瘤大小的能力。临床实践中缺乏相关的治疗终点，加上目前认为播散发生在肿瘤进展早期（即临床表现出现之前），导致人们对开发抗侵袭和抗播散药物持怀疑态度。
6. 我们推测，如果有效长期管理微小残留病是癌症治疗的目标，那么播散不仅是一个可行的治疗靶点，而且是一个必要的治疗靶点。鉴定与肿瘤细胞播散相关的治疗终点将有助于治疗方法的开发及合理应用。

英文摘要：

Chemotaxis of tumour cells and stromal cells in the surrounding microenvironment is an essential component of tumour dissemination during progression and metastasis. This Review summarizes how chemotaxis directs the different behaviours of tumour cells and stromal cells in vivo, how molecular pathways regulate chemotaxis in tumour cells and how chemotaxis choreographs cell behaviour to shape the tumour microenvironment and to determine metastatic spread. The central importance of chemotaxis in cancer progression is highlighted by discussion of the use of chemotaxis as a prognostic marker, a treatment end point and a target of therapeutic intervention.

摘要翻译： 

肿瘤细胞及微环境中基质细胞的趋化作用，是肿瘤在进展和转移过程中扩散的关键环节。本文综述了趋化作用如何调控体内肿瘤细胞与基质细胞的不同行为、相关分子通路如何调节肿瘤细胞的趋化性，以及趋化作用如何协调细胞行为以塑造肿瘤微环境并决定转移播散。通过讨论将趋化作用用作预后标志、治疗终点及干预靶点，进一步凸显其在癌症进展中的核心地位。

原文链接：

Chemotaxis in cancer