|M.Sc Student||Maayan Lia Yizraeli|
|Subject||The Effects of Electric Fields on Micromechanics of Breast|
Cancer Cells and Associated Fibroblasts
|Department||Department of Biomedical Engineering||Supervisor||Professor Weihs Daphne|
|Full Thesis text|
The application of direct-current (DC) low-intensity electric-fields (LIEF) has been suggested as a minimally-invasive method for treating various types of cancer, especially when other more conventional methods are not applicable. DC-LIEF is a localized treatment, which induces death of cancer cells and reduces their proliferation. Previous in vitro studies have focused on cancer cells alone. However, cancer cells in vivo are surrounded by an interconnected "reactive" microenvironment, which may affect the outcome of any treatment applied to the region. The tumor microenvironment, and fibroblasts as its key component, plays an important role in tumor initiation and progression. Thus, we study the influence of LIEFs on the entire cancer microenvironment, an important but as of yet not well-studied process.
In the current study, we co-culture human, epithelial, breast-cancer cells (MDA-MB-231) with primary, human fibroblasts from a breast tumor-adjacent site, as a simplified model for the in vivo tumor microenvironment. When treated separately, the cancer cells exhibit death and reduced metabolic activity. The non-cancerous fibroblasts, conversely, continue to grow with minimal cell death. Cell-internalized fluorescent 200-nanometer particles are tracked to evaluate the native and treatment-related intracellular dynamics and mechanics. The cells undergo various morphological, structural and mechanical changes following treatment. The cancer cells transiently lose their stress fibers and round-up immediately following treatment, indicating reduced tension and adhesion. Concurrently, there is a transient change in the typical particle-motion in the cancer cells, most likely related to microtubules dynamics and their associated motor-proteins. Conversely, in the fibroblasts, there is no visible change in particle motion, which is typically more hindered than in the untreated cancer cells. However, the cytoskeleton is transiently affected. In both cell types, cell-activity drives particle motion, however they exhibit dissimilar innate intracellular trafficking and responses to treatment. Interestingly, co-culturing the cancer cells with fibroblasts delays their responses, such as cell death and rounding. In addition, it reduces observed differences in particle motion after treatment. Thus, co-culturing cancer cells within the fibroblast model-microenvironment seems to protect them and reduce treatment effects. To conclude, this research underscores the importance of taking the cancer cell microenvironment into account when examining such a treatment. In addition, it provides insight into the innate mechanics and transport mechanisms of cancer cells and fibroblasts, as well as their dynamic responses to treatment in an attempt to develop better cancer therapies.