Feng Tang, Fang Fei, Zhang Chunhe, Li Tiantian, He Jia, Shen Yang, Yu Hongchi, Liu Xiaoheng
Institute of Biomedical Engineering, West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, 610041 Chengdu, Sichuan, China.
Front Biosci (Landmark Ed). 2022 Mar 17;27(3):104. doi: 10.31083/j.fbl2703104.
Cancer-associated fibroblasts (CAFs) are of considerable importance in tumor progression by interacting with the tumor microenvironment. However, the hidden mechanism explaining how tumor cells interact with CAFs in the tumor mechanical microenvironment remains largely unknown.
We highlighted exosomes as the mediator modulating the interaction between liver cancer cells and CAFs under mechanical conditions. The normal hepatic stellate cells LX2 were exposed to the medium or exosomes from the HepG2 cells with or without fluid shear stress subjection, and the CAFs activation markers were checked. To further explore the potential role of PI3K, which is active in liver fibrosis, the PI3K inhibitor was used.
The specific markers of CAFs, FAP, and α-SMA, increased in LX2 with subjection to the fluid shear stress-induced exosomes from HepG2 cells. In turn, the enriched IGF2 in the exosomes activated the IGF2-PI3K signaling pathway in LX2 cells.
These findings reveal that fluid shear stress-induced liver cancer cells possess a stronger capacity to convert normal fibroblasts to CAFs than statically cultured liver cancer cells, and tumor-derived exosomes mediated the intercellular cross-talk between liver cancer cells and fibroblasts.
癌症相关成纤维细胞（CAFs）通过与肿瘤微环境相互作用在肿瘤进展中具有相当重要的意义。然而，解释肿瘤细胞在肿瘤机械微环境中如何与CAFs相互作用的潜在机制在很大程度上仍不清楚。
我们强调外泌体作为在机械条件下调节肝癌细胞与CAFs之间相互作用的介质。将正常肝星状细胞LX2暴露于有或无流体剪切应力作用的HepG2细胞的培养基或外泌体中，并检测CAFs激活标志物。为了进一步探讨在肝纤维化中活跃的PI3K的潜在作用，使用了PI3K抑制剂。
CAFs的特异性标志物FAP和α-SMA在LX2中随着受到来自HepG2细胞的流体剪切应力诱导的外泌体作用而增加。反过来，外泌体中富集的IGF2激活了LX2细胞中的IGF2-PI3K信号通路。
这些发现揭示，流体剪切应力诱导的肝癌细胞比静态培养的肝癌细胞具有更强的将正常成纤维细胞转化为CAFs的能力，并且肿瘤来源的外泌体介导了肝癌细胞与成纤维细胞之间的细胞间相互作用。
