Microfluidic chip-based systems for monitoring cancer therapy

Abstract

In tumor microenvironment, cancer cells are exposed to a range of fluid shear stresses (FSS); yet, current in vitro three-dimensional (3D) models have limitations to investigate the impact of biophysical stimuli on cancer mechanism and chemoresistance in a dynamic manner. In the past few decades, vital demand for exploring biological significance of mechanical forces has led to the development of several innovative approaches. One of these approaches is the integration of microfluidic systems into cancer studies. The use of microfluidic chips has garnered increasing attention since they offer ease-of-manipulation, high-throughput, less material/reagent consumption, and low-cost. On the other hand, the researches have stated explicitly that tumor-derived extracellular vesicles (EVs) regulate local and systemic milieu to drive the development and spread of cancer through nano- and micron-sized vesicles they carry. In this thesis, breast cancer cells (MCF-7) have been utilized as a model cancer system, and accordingly, they are cultivated through SF-coated microfluidic systems in order to mimic tumor microenvironment, exhibiting a more dynamic condition. Simultaneously, traditional static culture of MCF-7 cells is also performed as a control group in order to understand the impact of flow conditions. The effects of FSS on gene expression—in particular, EpCAM and CK-18 genes, which are highly expressed in MCF-7 cells— have been examined at the end of cell culturing process. In addition, cancer cells developing any resistance to anti-cancer drugs on the course of FSS have been investigated. In this regard, the cells are treated with either doxorubicin or docetaxel (anti-cancer drugs) in the cases of dynamic (microfluidic system) and static (tissue culture flask) culture conditions. Multi-Drug Resistance 1 (MDR-1) and Breast Cancer Resistance Protein (BCRP) gene expression levels have been assessed once anti-cancer treatment has been finalized. The final step of this study relies on the isolation and analysis of EVs from both static and dynamic conditions with the presence and absence of anti-cancer drug treatment. The utility of EVs has been evaluated deliberately as biomarkers for real-time monitoring of treatment efficacy.