Circulatory shear stress induces molecular changes and side population enrichment in primary tumor-derived lung cancer cells with higher metastatic potential.
Circulatory shear stress induces molecular changes and side population enrichment in primary tumor-derived lung cancer cells with higher metastatic potential.
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DOI：
10.1038/s41598-021-82634-1
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发表时间：
2021-02-02
影响因子：
4.6
通讯作者：
Chaichana KL
中科院分区：
文献类型：
--
作者：
Alvarado-Estrada K;Marenco-Hillembrand L;Maharjan S;Mainardi VL;Zhang YS;Zarco N;Schiapparelli P;Guerrero-Cazares H;Sarabia-Estrada R;Quinones-Hinojosa A;Chaichana KL
癌症是世界范围内死亡和疾病的主要原因。然而，虽然原发性癌症患者的生存率正在提高，但预防转移性癌症的能力却没有提高。一旦患者发生转移，其预后是令人沮丧的。转移的关键步骤是癌细胞在循环系统中的转运。在这种恶劣的微环境中，压力和流量的变化可以改变细胞的行为。然而，循环对癌细胞和转移过程的影响仍不清楚。为了进一步理解这一过程，我们设计了一个闭环流体系统来分析由原发性肿瘤来源的肺腺癌细胞的流速和压力变化引起的分子变化。我们发现癌细胞过度表达上皮-间充质转化标志物TWIST 1和SNAI 2，以及干细胞样标志物CD 44（但不表达CD 133、SOX 2和/或NANOG）。此外，这些细胞显示侧群细胞的百分比增加了四倍，并且具有增加的迁移倾向。在体内，存活的循环细胞导致啮齿动物存活率降低。这些结果表明，表达特定循环转变表型并富含侧群细胞的癌细胞能够在延长的循环应激中存活，并导致转移性疾病增加和生存期缩短。
Cancer is a leading cause of death and disease worldwide. However, while the survival for patients with primary cancers is improving, the ability to prevent metastatic cancer has not. Once patients develop metastases, their prognosis is dismal. A critical step in metastasis is the transit of cancer cells in the circulatory system. In this hostile microenvironment, variations in pressure and flow can change cellular behavior. However, the effects that circulation has on cancer cells and the metastatic process remain unclear. To further understand this process, we engineered a closed-loop fluidic system to analyze molecular changes induced by variations in flow rate and pressure on primary tumor-derived lung adenocarcinoma cells. We found that cancer cells overexpress epithelial-to-mesenchymal transition markers TWIST1 and SNAI2, as well as stem-like marker CD44 (but not CD133, SOX2 and/or NANOG). Moreover, these cells display a fourfold increased percentage of side population cells and have an increased propensity for migration. In vivo, surviving circulatory cells lead to decreased survival in rodents. These results suggest that cancer cells that express a specific circulatory transition phenotype and are enriched in side population cells are able to survive prolonged circulatory stress and lead to increased metastatic disease and shorter survival.
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