Ma Di, Liang Rui, Luo Qing, Song Guanbin
Key Laboratory of Biorheological Science and Technology, Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400044, China.
J Cell Physiol. 2025 Jan;240(1):e31451. doi: 10.1002/jcp.31451. Epub 2024 Oct 2.
Cancer stem cells (CSCs) are considered the major cause of the occurrence, progression, chemoresistance/radioresistance, recurrence, and metastasis of cancer. Increased interstitial fluid pressure (IFP) is a key feature of solid tumors. Our previous study showed that the distribution of liver cancer stem cells (LCSCs) correlated with the mechanical heterogeneity within liver cancer tissues. However, the regulation of liver cancer's mechanical microenvironment on the LCSC stemness is not fully understood. Here, we employed a cellular pressure-loading device to investigate the effects of normal IFP (5 mmHg), as well as increased IFP (40 and 200 mmHg) on the stemness of LCSCs. Compared to the control LCSCs (exposure to 5 mmHg pressure loading), the LCSCs exposed to 40 mmHg pressure loading exhibited significantly upregulated expression of CSC markers (CD44, EpCAM, Nanog), enhanced sphere and colony formation capacities, and tumorigenic potential, whereas continuously increased pressure to 200 mmHg suppressed the LCSC characteristics. Mechanistically, pressure loading regulated Yes-associated protein (YAP) activity and Bcl-2 modifying factor (BMF) expression. YAP transcriptionally regulated BMF expression to affect the stemness of LCSCs. Knockdown of YAP and overexpression of BMF attenuated pressure-mediated stemness and tumorgenicity, while YAP-deficient and BMF-deletion recused pressure-dependent stemness on LCSCs, suggesting the involvement of YAP/BMF signaling axis in this process. Together, our findings provide a potential target for overcoming the stemness of CSCs and elucidate the significance of increased IFP in cancer progression.
癌症干细胞（CSCs）被认为是癌症发生、发展、化疗耐药/放疗抵抗、复发和转移的主要原因。间质液压力（IFP）升高是实体瘤的一个关键特征。我们之前的研究表明，肝癌干细胞（LCSCs）的分布与肝癌组织内的力学异质性相关。然而，肝癌的力学微环境对LCSC干性的调控尚未完全明确。在此，我们使用细胞压力加载装置来研究正常IFP（5 mmHg）以及升高的IFP（40和200 mmHg）对LCSCs干性的影响。与对照LCSCs（暴露于5 mmHg压力加载）相比，暴露于40 mmHg压力加载的LCSCs表现出癌症干细胞标志物（CD44、EpCAM、Nanog）的表达显著上调，球体和集落形成能力增强，以及致瘤潜力增加，而持续将压力升高至200 mmHg则抑制了LCSC的特征。从机制上讲，压力加载调节Yes相关蛋白（YAP）活性和Bcl-2修饰因子（BMF）表达。YAP转录调节BMF表达以影响LCSCs的干性。敲低YAP和过表达BMF减弱了压力介导的干性和致瘤性，而YAP缺陷和BMF缺失则挽救了LCSCs上的压力依赖性干性，表明YAP/BMF信号轴参与了这一过程。总之，我们的研究结果为克服CSCs的干性提供了一个潜在靶点，并阐明了IFP升高在癌症进展中的意义。
