A microfluidic device for characterizing the invasion of cancer cells in 3‐D matrix

Abstract

A microfluidic device was developed for the study of directed invasion of cancer cells in 3-D matrix with concentration gradient. This device consists of two parallel perfusion channels connected by two cell culture chambers. To mimic extracellular matrix (ECM), gelled basement membrane extract (BME) was used to support 3-D distribution of breast cancer cells (MCF7) in cell culture chambers. A stable linear concentration gradient of epidermal growth factor (EGF) was generated across the chambers by continuous perfusion. Using the device, we investigated MCF7 cell invasion induced by different concentrations of EGF in 3-D matrix. It was found that cancer cells responded to EGF stimulation with forming cellular protrusions and migrating towards high EGF concentration. We further investigated the anti-invasion effect of GM 6001, a matrix metalloproteinase inhibitor. We identified that matrix metalloproteinase inhibition repressed both cellular protrusion formation and cell migration in 3-D matrix. These findings suggest that EGF is able to induce MCF7 cell invasion in 3-D extracellular matrix and this effect is dependent on proteolytic activity. This device is relatively simple to construct and operate. It should be a useful platform for elucidating the mechanism of cancer invasion and screening anti-invasion drugs for cancer therapy.

Migration of breast cancer cells into reconstituted type I collagen gels assessed via a combination of frozen sectioning and azan staining

“…Recently, various quantitative methods of assessing cell migration and invasion have been reported (8,(14)(15)(16)(17)(18)(19). Some of these methods facilitate the fl uorescenceassisted quantification or real-time observation of migrating cells.…”

Biomimetic tumor microenvironment on a microfluidic platform

“…Alternatively, by designing the microfluidic device with two parallel perfusion channels connected by elliptic cell culture chambers, a stable EGF gradient can be generated by diffusion of the molecules. 51 Based on protrusion index, the migration of tumor cell can be measured quantitatively, thus, facilitating the characterization of cell behaviors in response to chemical gradients in the tumor microenvironment.…”

Exploitation of physical and chemical constraints for three-dimensional microtissue construction in microfluidics

“…Cells inside the chamber became necrotic and apoptotic with the cells near to the flow appearing to be acidic and those farther away basic/alkaline. Some other chips were developed to model cancer cell migration or metastasis: ͑i͒ tumor cells were deformed when migrating across a microchannel lined with human microvascular endothelial cells; 201 ͑ii͒ invasion of cancer cells across a 3D matrix of basement membrane extract under the gradients of epidermal growth factor; 202 and ͑iii͒ motility of cancer cells in 3D under the constrains of mechanical confinement with a matrix-free environment. 203 Stroock et al 204 described the various engineering or biological challenges and opportunities for making a biomimetic microfluidic tumor model with a focus on embedding microvasculature structures.…”