Cell-surface interactions in a breast cancer model

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2017
Antmen, Ezgi
Breast cancer, is one of the most commonly diagnosed cancers, has a high mortality rate. One in every eight women (12.3%) develops breast cancer at some stage of their lives and this is the cause of about 15% of cancer deaths in women and 3% of total deaths. It is therefore important to study the behavior of breast cancer cells. Measurement of the mechanical properties of cancer cells leads to new insights such as that cancer cells are softer than healthy cells. Also, metastatic cancer cells were found to be more than 70% softer than benign cells. In summary, the more deformable the cells are, the more aggressive and invasive they are. This deformation is a result of the inherent properties of the cell and also influenced by the topography of their environment. Topographical cues on a surface influence cell morphology, migration and differentiation. It was found that cancer cells and healthy cells placed on micropatterned surfaces showed differences in their attachment, migration, proliferation and nucleus deformation. The crucial point in cancer studies is to understand the deformation mechanism of cells. Actin fibers of the cytoskeleton and LINC complex proteins are very important for the maintenance of the nuclear shape. In this study, the main assumption was that the difference in mechanical properties of malignant and benign breast cancer cells could be used as a simple and direct tool in cancer detection. We aimed to compare benign (MCF10A), malignant but noninvasive (MCF7), and malignant and highly invasive (MDAMB231) breast cells in the ability of their nuclei to deform when seeded on surfaces decorated with micro level physical cues. For this purpose, square prism shaped micropillars of poly(methyl methacrylate) (PMMA) with a specific dimension and gaps (4x4 µm2 widths with 4 µm gap size) which is optimal for the highest nucleus deformation were used. Quantification of the extent of deformation of cell nuclei was achieved on microscale substrate topography with the help of image analysis software, ImageJ (NIH), and its distribution Fiji. The relation between the nuclear envelope protein Lamin A/C, LINC complex protein Nesprin-2 and deformability of the nucleus was determined on micropatterned surfaces and expression levels of these proteins were quantified by real time quantitative PCR method. It was shown that there was an increase of nucleus deformation by the decrease of Lamin A/C and Nesprin-2. Moreover, the mechanism of the nucleus and cell deformation were studied by using drugs such as cytochalasin D which inhibits actin polymerization. We showed that the deformation of the nucleus of both benign and malignant cells was in a relation with actin filaments and inhibition of the actin polymerization caused a decrease in the deformation capability of the nucleus. Finally, the relation between the inhibition of actin filaments and expression levels of mechanotransduction proteins (Lamin A/C and Nesprin-2) were studied on micropatterned surfaces by using immunocytochemical staining method. It was shown that loss of actin filaments after drug treatment caused increased level of these two proteins and a decrease in the deformation capacity of the nucleus. In summary, it can be said that biomechanical properties (rigidity, elasticity, deformability) of cells can provide useful information about cancer state and they can be viewed as biological markers, which suggest an alternative identification to current proteomic techniques.

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Citation Formats
E. Antmen, “Cell-surface interactions in a breast cancer model,” Ph.D. - Doctoral Program, Middle East Technical University, 2017.