To seed lethal secondary lesions, circulating tumor cells (CTCs) must survive all rate-limiting factors during hematogenous dissemination, including fluid shear stress (FSS) that poses a grand challenge to their survival. We thus hypothesized that CTCs with the ability to survive FSS in vasculature might hold metastasis-initiating competence. This study reported that FSS of physiologic magnitude selected a small subpopulation of suspended tumor cells with the traits of metastasis-initiating cells, including stemness, migration/invasion potential, cellular plasticity, and biophysical properties. These shear-selected cells generated local and metastatic tumors at the primary and distal sites efficiently, implicating their metastasis competence. Mechanistically, FSS activated the mechanosensitive protein CXCR4 and the downstream PI3K/AKT signaling, which were essential in shear-mediated selection of metastasis-competent CTCs. In summary, these findings conclude that CTCs with metastasis-initiating competence survive FSS during hematogenous dissemination through CXCR4-PI3K/AKT signaling, which may provide new therapeutic targets for the early prevention of tumor metastasis.

中文翻译：

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具有转移启动能力的循环肿瘤细胞通过 CXCR4-PI3K/AKT 信号传导在血行传播过程中承受流体剪切应力

为了播下致命的继发性病变，循环肿瘤细胞（CTC）必须在血行传播过程中克服所有限速因素，包括对其生存构成巨大挑战的流体剪切应力（FSS）。因此，我们假设能够在脉管系统中的 FSS 中存活的 CTC 可能具有启动转移的能力。这项研究报告称，生理量级的 FSS 选择了一小部分悬浮肿瘤细胞，具有转移起始细胞的特征，包括干性、迁移/侵袭潜力、细胞可塑性和生物物理特性。这些剪切选择的细胞在原发部位和远端部位有效地产生局部和转移性肿瘤，这表明它们的转移能力。从机制上讲，FSS 激活了机械敏感蛋白 CXCR4 和下游 PI3K/AKT 信号传导，这对于剪切介导的具有转移能力的 CTC 选择至关重要。总之，这些研究结果得出结论，具有转移启动能力的CTC在血行传播过程中通过CXCR4-PI3K/AKT信号传导在FSS中存活，这可能为早期预防肿瘤转移提供新的治疗靶点。