College of Life Science and Bioengineering, Beijing University of Technology, Beijing, China.
China-Japan Union Hospital, Jilin University, Changchun, China.
J Cell Physiol. 2019 Apr;234(4):3570-3582. doi: 10.1002/jcp.27011. Epub 2018 Nov 11.
Cell fusion plays a crucial role in cancer progression and leads to massive aberrant changes in chromosome and gene expression involved in tumor metastasis. Cancer cells can fuse with many cell types, including stromal cells, epithelial cells, macrophages, and endothelial cells. Mesenchymal stem cells (MSCs) have been reported to migrate and incorporate into tumor sites during cancer progression. However, the underlying mechanism of stem cell fusion in tumor metastasis has not been fully deciphered. In this research, we established a cell fusion model between lung cancer cells and MSCs in vitro. We found that the hybrid cells showed enhanced metastatic capacity with increased expression of MMP-2 and MMP-9, whereas the proliferation ability was inhibited and cell cycle was blocked in the G /G phase with elevated expression of p21, p27, and p53. Moreover, the hybrid cells lost epithelial morphology and exhibited an epithelial-mesenchymal transition (EMT) change with downregulation of E-cadherin and upregulation of N-cadherin, Vimentin, α-SMA and Fibronectin1. Meanwhile, the expressions of EMT transcription factors, including Snail1, Slug, Twist1, Zeb1, and Zeb2, were also increased in hybrid cells. More important, the fusion hybrids acquired stem cell-like properties, which exhibited increased expression stem cell transcription factors Oct4, Sox2, Nanog, Kif4 as well as Bmi1. Taken together, our results suggested that cell fusion between lung cancer cells and MSCs offered enhanced metastatic capacity and characteristics of cancer stem cell by undergoing EMT. This study will contribute to explaning the origin of lung cancer stem cells and to elucidate the role of cell fusion in cancer metastasis.
细胞融合在癌症进展中起着至关重要的作用，并导致涉及肿瘤转移的染色体和基因表达的大量异常变化。癌细胞可以与多种细胞类型融合，包括基质细胞、上皮细胞、巨噬细胞和内皮细胞。已经有报道称间充质干细胞 (MSC) 在癌症进展过程中迁移并整合到肿瘤部位。然而，干细胞融合在肿瘤转移中的潜在机制尚未完全阐明。在这项研究中，我们在体外建立了肺癌细胞和 MSC 之间的细胞融合模型。我们发现杂交细胞表现出增强的转移能力，MMP-2 和 MMP-9 的表达增加，而增殖能力受到抑制，细胞周期在 G1 期被阻断，p21、p27 和 p53 的表达升高。此外，杂交细胞失去上皮形态，并表现出上皮-间充质转化 (EMT) 变化，E-钙黏蛋白下调，N-钙黏蛋白、波形蛋白、α-SMA 和纤维连接蛋白 1 上调。同时，EMT 转录因子，包括 Snail1、Slug、Twist1、Zeb1 和 Zeb2 的表达也在杂交细胞中增加。更重要的是，融合杂种获得了干细胞样特性，表现出干细胞转录因子 Oct4、Sox2、Nanog、Kif4 以及 Bmi1 的表达增加。总之，我们的结果表明，肺癌细胞和 MSC 之间的细胞融合通过 EMT 提供了增强的转移能力和癌症干细胞特征。这项研究将有助于解释肺癌干细胞的起源，并阐明细胞融合在癌症转移中的作用。
