Abstract
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.
Highlights
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
We show that breast cancer cells and non-tumorigenic mammary epithelial cells undergo dynamic cell–cell interactions that lead to a substantial reprograming of molecular characteristics of the mammary epithelial cells
The time-lapse imaging of the cells showed that MDA-MB-231 cells had more frequent cell movements than the MCF10A cells and the cells showed various dynamic cell–cell interaction patterns (Supplementary Videos S1 and S2)
Summary
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. While the normal myoepithelial cells obtained from healthy human breast tissues contribute to the maintaining polarity of mammary epithelial cells and suppress aberrant growth, the myoepithelial cells derived from breast cancer tissues failed to restore physiologic polarity in mammary epithelial cells and showed increased expression of various chemokines such as C XCL1213,14. These reports suggest a potential functional transition of normal epithelial cells caused by adjacent malignant epithelial cells which may contribute the progression of solid tumors. Our data suggests that S100A8/A9 upregulation in non-tumorigenic mammary epithelial cells may play a critical role in the phenotype shifting induced by adjacent cancer cells
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