Interdisciplinary Graduate Program in Cancer Biology, Seoul National University College of Medicine, Seoul, Korea.
Center for Medical Innovation, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
Sci Rep. 2021 Jan 14;11(1):1337. doi: 10.1038/s41598-020-80625-2.
To understand the potential effects of cancer cells on surrounding normal mammary epithelial cells, we performed direct co-culture of non-tumorigenic mammary epithelial MCF10A cells and various breast cancer cells. Firstly, we observed dynamic cell-cell interactions between the MCF10A cells and breast cancer cells including lamellipodia or nanotube-like contacts and transfer of extracellular vesicles. Co-cultured MCF10A cells exhibited features of epithelial-mesenchymal transition, and showed increased capacity of cell proliferation, migration, colony formation, and 3-dimensional sphere formation. Direct co-culture showed most distinct phenotype changes in MCF10A cells followed by conditioned media treatment and indirect co-culture. Transcriptome analysis and phosphor-protein array suggested that several cancer-related pathways are significantly dysregulated in MCF10A cells after the direct co-culture with breast cancer cells. S100A8 and S100A9 showed distinct up-regulation in the co-cultured MCF10A cells and their microenvironmental upregulation was also observed in the orthotropic xenograft of syngeneic mouse mammary tumors. When S100A8/A9 overexpression was induced in MCF10A cells, the cells showed phenotypic features of directly co-cultured MCF10A cells in terms of in vitro cell behaviors and signaling activities suggesting a S100A8/A9-mediated transition program in non-tumorigenic epithelial cells. This study suggests the possibility of dynamic cell-cell interactions between non-tumorigenic mammary epithelial cells and breast cancer cells that could lead to a substantial transition in molecular and functional characteristics of mammary epithelial cells.
为了了解癌细胞对周围正常乳腺上皮细胞的潜在影响，我们进行了非致瘤性乳腺上皮 MCF10A 细胞与各种乳腺癌细胞的直接共培养。首先，我们观察到 MCF10A 细胞与乳腺癌细胞之间的动态细胞-细胞相互作用，包括片状伪足或纳米管样接触以及细胞外囊泡的转移。共培养的 MCF10A 细胞表现出上皮-间充质转化的特征，并且显示出增强的细胞增殖、迁移、集落形成和 3 维球体形成能力。直接共培养显示出 MCF10A 细胞最明显的表型变化，其次是条件培养基处理和间接共培养。转录组分析和磷酸化蛋白阵列表明，与乳腺癌细胞直接共培养后 MCF10A 细胞中几个癌症相关途径显著失调。S100A8 和 S100A9 在共培养的 MCF10A 细胞中明显上调，并且在同基因小鼠乳腺肿瘤的原位移植中也观察到其微环境上调。当 MCF10A 细胞中诱导 S100A8/A9 过表达时，细胞在体外细胞行为和信号活性方面表现出与直接共培养 MCF10A 细胞相似的表型特征，表明 S100A8/A9 介导的非致瘤性上皮细胞中的过渡程序。这项研究表明非致瘤性乳腺上皮细胞与乳腺癌细胞之间可能存在动态的细胞-细胞相互作用，这可能导致乳腺上皮细胞的分子和功能特征发生实质性转变。
