EphA2 Reexpression Prompts Invasion of Melanoma Cells Shifting from Mesenchymal to Amoeboid-like Motility Style
EphA2 Reexpression Prompts Invasion of Melanoma Cells Shifting from Mesenchymal to Amoeboid-like Motility Style
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DOI：
10.1158/0008-5472.can-08-1845
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发表时间：
2009-03-01
期刊：
影响因子：
11.2
通讯作者：
Chiarugi, Paola
中科院分区：
文献类型：
--
作者：
Parri, Matteo;Taddei, Maria Letizia;Chiarugi, Paola
Eph 酪氨酸激酶指示细胞进行排斥行为，调节细胞形状、粘附和运动。除了在胚胎发生、神经发生和血管生成过程中发挥作用外，EphA2 激酶在不同组织型的肿瘤细胞中经常上调，包括前列腺癌、乳腺癌、结肠癌、肺癌以及黑色素瘤。尽管已提出 EphA2 在肿瘤发生和转移中发挥作用，但其所发挥的作用仍存在争议。在这里，我们发现，B16 鼠黑色素瘤细胞中的 EphA2 重新表达，使用明确的间充质侵袭策略，将其迁移方式从间充质转化为阿米巴样，赋予肿瘤细胞侵袭的可塑性。事实上，响应 EphA2 的重新表达和激活，黑色素瘤细胞激活一种非蛋白水解侵入程序，该程序通过激活细胞骨架运动、收缩细胞突起、Rho 介导的细胞体变圆以及在三维基质中挤压来进行，从而成功实现肺和腹膜淋巴结转移。我们的结果表明，在肿瘤细胞穿透宿主组织的解剖屏障的冗余机制中，EphA2 在迁移模式和机制的适应性转换、定义和区分肿瘤细胞侵袭策略中发挥着关键作用。因此，靶向 EphA2 可能代表了治疗癌症扩散的未来方法。 [癌症研究 2009;69(5):2072-81]
Eph tyrosine kinases instruct cell for a repulsive behavior, regulating cell shape, adhesion, and motility. Beside its role during embryogenesis, neurogenesis, and angiogenesis, EphA2 kinase is frequently up-regulated in tumor cells of different histotypes, including prostate, breast, colon, and lung carcinoma, as well as melanoma. Although a function in both tumor onset and metastasis has been proposed, the role played by EphA2 is still debated. Here, we showed that EphA2 reexpression in B16 murine melanoma cells, which use a defined mesenchymal invasion strategy, converts their migration style from mesenchymal to amoeboid-like, conferring a plasticity in tumor cell invasiveness. Indeed, in response to reexpression and activation of EphA2, melanoma cells activate a nonproteolytic invasive program that proceeds through the activation of cytoskeleton motility, the retraction of cell protrusions, a Rho-mediated rounding of the cell body, and squeezing among three-dimensional matrix, giving rise to successful lung and peritoneal lymph node metastases. Our results suggest that, among the redundant mechanisms operating in tumor cells to penetrate the anatomic barriers of host tissues, EphA2 plays a pivotal role in the adaptive switch in migration pattern and mechanism, defining and distinguishing tumor cell invasion strategies. Thus, targeting EphA2 might represent a future approach for the therapy of cancer dissemination. [Cancer Res 2009;69(5):2072-81]