EphA2 Induces Metastatic Growth Regulating Amoeboid Motility and Clonogenic Potential in Prostate Carcinoma Cells
EphA2 Induces Metastatic Growth Regulating Amoeboid Motility and Clonogenic Potential in Prostate Carcinoma Cells
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DOI：
10.1158/1541-7786.mcr-10-0298
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发表时间：
2011-02-01
影响因子：
5.2
通讯作者：
Chiarugi, Paola
中科院分区：
文献类型：
--
作者：
Taddei, Maria Letizia;Parri, Matteo;Chiarugi, Paola
EphA 2激酶调节细胞形状、粘附和运动性，并且经常在几种癌症中过表达，包括黑素瘤、前列腺癌、乳腺癌和结肠癌以及肺癌。虽然已经提出了在肿瘤发病和转移中的功能，但EphA 2在肿瘤进展中所起的作用仍有争议。在黑色素瘤中，已经报道EphA 2影响细胞迁移和侵袭性，允许细胞通过蛋白水解独立的策略移动，通常称为变形虫运动。为了理解EphA 2在前列腺癌转移扩散中的作用，我们在侵袭性转移性前列腺癌模型中稳定沉默EphA 2表达。我们的研究结果表明，EphA 2驱动前列腺癌的转移程序，虽然其参与转移步骤之间有很大差异。事实上，EphA 2表达（i）极大地影响前列腺癌细胞运动方式，引导基于Rho介导的细胞变圆且独立于金属蛋白酶的变形虫运动，（ii）对跨内皮迁移、粘附到细胞外基质蛋白上以及对失巢凋亡的抗性无效，（iii）调节前列腺癌的克隆形成潜力，从而增加锚定非依赖性生长和自我更新、前列腺球形成，肿瘤发作、向骨的扩散和转移集落的生长。我们的发现表明EphA 2过表达的前列腺癌细胞从其变形虫运动方式中获得侵入性益处，以逃离原发性肿瘤，然后增强其克隆形成潜力，成功靶向骨并生长转移，从而确认EphA 2作为侵袭性前列腺癌抗转移治疗的靶标。Mol Cancer Res; 9（2）; 149-60. (C)2011年AACR。
EphA2 kinase regulates cell shape, adhesion, and motility and is frequently overexpressed in several cancers, including melanoma, prostate, breast, and colon cancers and lung carcinoma. Although a function in both tumor onset and metastasis has been proposed, the role played by EphA2 in tumor progression is still debated. In melanoma, EphA2 has been reported to affect cell migration and invasiveness allowing cells to move by a proteolysis-independent strategy, commonly referred as amoeboid motility. With the aim to understand the role of EphA2 in prostate cancer metastatic spreading, we stably silenced EphA2 expression in a model of aggressive metastatic prostate carcinoma. Our results show that EphA2 drives the metastatic program of prostate carcinoma, although its involvement greatly differs among metastatic steps. Indeed, EphA2 expression (i) greatly affects prostate carcinoma cell motility style, guiding an amoeboid movement based on Rho-mediated cell rounding and independent from metalloprotases, (ii) is ineffective on transendothelial migration, adhesion onto extracellular matrix proteins, and on resistance to anoikis, (iii) regulates clonogenic potential of prostate carcinoma, thereby increasing anchorage-independent growth and self-renewal, prostasphere formation, tumor onset, dissemination to bone, and growth of metastatic colonies. Our finding indicate that EphA2-overexpressing prostate carcinoma cells gain an invasive benefit from their amoeboid motility style to escape from primary tumors and then, enhancing their clonogenic potential successfully target bone and grow metastases, thereby acknowledging EphA2 as a target for antimetastatic therapy of aggressive prostate cancers. Mol Cancer Res; 9(2); 149-60. (C) 2011 AACR.