Differential effects of EGF gradient profiles on MDA-MB-231 breast cancer cell chemotaxis (original) (raw)
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Bulletin of the American Physical Society, 2021
Epidermal growth factor (EGF), a potent cytokine, is known to promote tumor invasion both in vivo and in vitro. Previously, we observed that single breast tumor cells (MDA-MB-231 cell line) embedded within a 3D collagen matrix displayed enhanced motility but no discernible chemotaxis in the presence of linear EGF gradients using a microfluidic platform. Inspired by a recent theoretical development that clustered mammalian cells respond differently to chemical gradients than single cells, we studied tumor spheroid invasion within a 3D extracellular matrix (ECM) in the presence of EGF gradients. We found that EGF gradients promoted tumor cell detachment from the spheroid core, and the position of the tumor spheroid core showed a mild chemotactic response towards the EGF gradients. For those tumor cells detached from the spheroids, they showed an enhanced chemokinesis response in contrast to previous experimental results using single cells embedded within an ECM. No discernible chemotactic response towards the EGF gradients was found for the cells outside the spheroid core. This work demonstrates that a cluster of tumor cells responds differently than single tumor cells towards EGF gradients and highlights the importance of a tumor spheroid platform for chemotaxis studies.
The Migration of Cancer Cells in Gradually Varying Chemical Gradients and Mechanical Constraints
Micromachines, 2014
We report a novel approach to study cell migration under physical stresses by utilizing established growth factor chemotaxis. This was achieved by studying cell migration in response to epidermal growth factor (EGF) chemoattraction in a gradually tapered space, imposing mechanical stresses. The device consisted of two 5-mm-diameter chambers connected by ten 600 µm-long and 10 µm-high tapered microchannels. The taper region gradually changes the width of the channel. The channels tapered from 20 µm to 5 µm over a transition length of 50 µm at a distance of 250 µm from one of the chambers. The chemoattractant drove cell migration into the narrow confines of the tapered channels, while the mechanical gradient clearly altered the migration of cells. Cells traversing the channels from the wider to narrow-end and vice versa were observed using time-lapsed imaging. Our results indicated that the impact of physical stress on cell migration patterns may be cell type specific.
Epidermal growth factor promotes breast cancer cell chemotaxis in CXCL12 gradients
Biotechnology and Bioengineering, 2008
The chemokine receptor CXCR4 and its ligand CXCL12 play an important role in breast cancer invasion and metastasis, and induce the chemotaxis of various types of cancer cells. Previous studies of CXCL12-induced chemotaxis have, for the most part, relied on endpoint assays (e.g., transwell assays) that provide poor control over the cell microenvironment. Specifically, these assays lacked the ability to dissect the role that autocrine and paracrine growth factors play in chemokine-induced cancer cell chemotaxis. Here, we employ a microfluidic chemotaxis chamber that allows the effects of specific exogenous factors on cell migration to be directly characterized, without the interference of autocrine/paracrine signaling. Using this approach, we investigated the migration of MDA-MB-231 breast cancer cells in well-defined CXCL12 gradients. We found that CXCL12 alone failed to stimulate chemotaxis of these cells; however, when the CXCL12 gradient was supplemented with a uniform stimulus of either EGF or conditioned media, a directional response was induced. This dependence on growth factor signaling points to the importance of autocrine and paracrine factors in determining the migratory response of the cells, and may play an important role in cancer metastasis.
Journal of Clinical Medicine, 2019
Epithelial to mesenchymal transition (EMT) induces cell migration, invasion, and drug resistance, and consequently, contributes to cancer metastasis and disease aggressiveness. This study attempted to address crucial biological parameters to correlate EMT and drug-treated cancer cells traversing through microcapillaries, reminiscent of metastatic conditions. MDA-MB-468 breast cancer cells induced to undergo EMT by treatment with 20 ng/mL of epidermal growth factor (EGF) were initially passed through several blockages and then through a constricted microchannel, mimicking the flow of invasive metastatic cells through constricted blood microcapillaries. EMT cells acquired enhanced migratory properties and retained 50% viability, even after migration through wells 10–15 μm in size and a constricted passage of 7 μm and 150 μm in length at a constant flow rate of 50 μL/h. The hydrodynamic properties revealed cellular deformation with a deformation index, average transit velocity, and ent...
A new chemotaxis device for cell migration studies
Integr. Biol., 2010
This study presents the design and optimization for in vitro use of a new versatile chemotaxis device called the NANIVID (NANo IntraVital Imaging Device), developed using advanced nano/micro fabrication techniques. The device is fabricated using microphotolithographic techniques and two substrates are bonded together using a thin polymer layer creating a sealed device with one outlet. The main structure of the device consists of two Pyrex substrates: an etched chemoattractant reservoir and a top cover, with a final size of 0.2 Â 2 Â 3 mm. This reservoir contains a hydrogel blend with EGF which diffuses out through a small (B9 . 10 3 mm 2 ) outlet. This reservoir sustains a steady release of growth factor into the surrounding environment for several hours establishing a consistent concentration gradient from the device. The focus of this study was to design and optimize the new device for cell chemotaxis studies in breast cancer cells in cell culture. Our results show that we have created a flexible, cheap, miniature and autonomous chemotaxis device and demonstrate its usefulness in 2D and 3D cell culture. We also provide preliminary data for use of the device in vivo.
A 3D Microfluidic Model to Recapitulate Cancer Cell Migration and Invasion
Bioengineering
We have developed a microfluidic-based culture chip to simulate cancer cell migration and invasion across the basement membrane. In this microfluidic chip, a 3D microenvironment is engineered to culture metastatic breast cancer cells (MX1) in a 3D tumor model. A chemo-attractant was incorporated to stimulate motility across the membrane. We validated the usefulness of the chip by tracking the motilities of the cancer cells in the system, showing them to be migrating or invading (akin to metastasis). It is shown that our system can monitor cell migration in real time, as compare to Boyden chambers, for example. Thus, the chip will be of interest to the drug-screening community as it can potentially be used to monitor the behavior of cancer cell motility, and, therefore, metastasis, in the presence of anti-cancer drugs.
Chemokine gradient formation in microfluidic devices to investigate prostate cancer cell migration
Biomedical Applications of Micro- and Nanoengineering IV and Complex Systems, 2008
Metastasis of cancer requires adhesion and migration of cells. The effect of chemokine gradient on prostate cancer cells (PCC) is not well understood. A poly-dimethylsiloxane (PDMS) microfluidic device that enables time-lapse study of cell migration is presented. Photolithography and soft lithography processes were used to fabricate the PDMS devices from SU-8 molds. The device has two inlets, a cell reservoir and an outlet channel with a depth of 100μm. The microfluidic device is configured to provide fluid mixing leading to a gradient across the outlet channel. The inlets allow for introduction of different chemokines at different concentrations and flow rates. The cell migration in the presence of chemokine gradient and flow rate can thus be monitored in a time-lapse fashion. The gradient formations at different flow rates over different lengths of time have been analyzed. Flow rates of 2, 3, 6, 8, 10, 20 μl/min at 5-minute intervals for over an hour were monitored to determine optimum flow rates and times required to produce desired gradient profiles. Results suggest that gradients formed at lower flow rates have less variation over time. Moreover, lower flow rates do not affect cell movement making observation of cell migration towards gradients possible. Higher flow rates have better gradient definition but cells tend to flow away with the fluid.
Tumor spheroid invasion in epidermal growth factor gradients revealed by a 3D microfluidic device
Physical Biology
Epidermal growth factor (EGF), a potent cytokine, is known to promote tumor invasion both in vivo and in vitro. Previously, we observed that single breast tumor cells (MDA-MB-231 cell line) embedded within a 3D collagen matrix displayed enhanced motility but no discernible chemotaxis in the presence of linear EGF gradients using a microfluidic platform. Inspired by a recent theoretical development that clustered mammalian cells respond differently to chemical gradients than single cells, we studied tumor spheroid invasion within a 3D extracellular matrix (ECM) in the presence of EGF gradients. We found that EGF gradients promoted tumor cell detachment from the spheroid core, and the position of the tumor spheroid core showed a mild chemotactic response towards the EGF gradients. For those tumor cells detached from the spheroids, they showed an enhanced motility response in contrast to previous experimental results using single cells embedded within an ECM. No discernible chemotactic...
A study of cancer cell metastasis using microfluidic transmigration device
2012 IEEE 25th International Conference on Micro Electro Mechanical Systems (MEMS), 2012
Metastasis of cancer cell was studied using microfluidic device. Migration of cells in the microchannel array mimics their transmigration in tissue capillaries during in vivo metastasis. Details of the morphological changes were recorded through high resolution imaging. Results showed that the deformation of cell nucleus is critical for the transmigration of breast cancer cell MDA-MB-231. Condensation of chromatin by drug plicamycinon significantly impaired their deformation abilities and subsequently reduced the transmigration by 2 to 3 fold for microchannel smaller than 10 μm × 5 μm. As transmigration is critical for cancer metastasis, the results will be useful in designing new anti-cancer therapy.