International Research Centre for Nano Handling and Manufacturing of China, Changchun University of Science and Technology, Changchun 130022, China.
Centre for Opto/Bio-Nano Measurement and Manufacturing, Zhongshan Institute of Changchun University of Science and Technology, Zhongshan 528437, China.
Mol Pharm. 2023 Nov 6;20(11):5579-5592. doi: 10.1021/acs.molpharmaceut.3c00488. Epub 2023 Oct 16.
Hypoxic tumor cell-derived exosomes play a key role in the occurrence, development, and metastasis of tumors. However, the mechanism of hypoxia-mediated metastasis remains unclear. In this study, hypoxic hepatocellular carcinoma cell (HCC-LM3)-derived exosomes (H-LM3-exos) were used to induce hepatocytes (HL-7702) over a long term (40 passages in 120 days). A nude mouse experiment further verified the effect of H-LM3-exos on tumor growth and metastasis. The process of cancer development in hepatocytes induced by H-LM3-exos was analyzed using both biological and physical techniques, and the results showed that the proliferation and soft agar growth abilities of the transformed cells were enhanced. The concentration of tumor markers secreted by transformed cells was increased, the cytoskeleton was disordered, and the migration ability was enhanced and was accompanied by epithelial-mesenchymal transition (EMT). Transcriptome results showed that differentially expressed genes between transformed cells and hepatocytes were enriched in cancer-related signaling pathways. The degree of cancer development in transformed cells was enhanced by an increase in H-LM3-exos-induced passages. Nude mice treated with different concentrations of H-LM3-exos showed different degrees of tumor growth and liver lesions. The physical properties of the cells were characterized by atomic force microscopy. Compared with the hepatocytes, the height and roughness of the transformed cells were increased, while the adhesion and elastic modulus were decreased. The changes in physical properties of primary tumor cells and hepatocytes in nude mice were consistent with this trend. Our study linking omics with the physical properties of cells provides a new direction for studying the mechanisms of cancer development and metastasis.
缺氧肿瘤细胞衍生的外泌体在肿瘤的发生、发展和转移中发挥关键作用。然而，缺氧介导转移的机制仍不清楚。在这项研究中，使用缺氧肝癌细胞（HCC-LM3）衍生的外泌体（H-LM3-exos）长期诱导肝细胞（HL-7702）（120 天内 40 代）。裸鼠实验进一步验证了 H-LM3-exos 对肿瘤生长和转移的影响。使用生物和物理技术分析了 H-LM3-exos 诱导的肝细胞中癌症发展的过程，结果表明转化细胞的增殖和软琼脂生长能力增强。转化细胞分泌的肿瘤标志物浓度增加，细胞骨架紊乱，迁移能力增强，并伴有上皮-间充质转化（EMT）。转录组结果表明，转化细胞和肝细胞之间差异表达的基因在癌症相关信号通路中富集。通过增加 H-LM3-exos 诱导的传代数，增强了转化细胞的癌症发展程度。用不同浓度的 H-LM3-exos 处理的裸鼠显示出不同程度的肿瘤生长和肝损伤。原子力显微镜用于表征细胞的物理特性。与肝细胞相比，转化细胞的高度和粗糙度增加，而粘附力和弹性模量降低。裸鼠中原代肿瘤细胞和肝细胞的物理特性变化与这一趋势一致。我们将组学与细胞的物理特性联系起来的研究为研究癌症发展和转移的机制提供了新的方向。
