A microchip for studying cancer metastasis

February 7, 2014

A three-dimensional reconstruction of a confocal image of a bone-mimicking microenvironment (green). Endothelial cells (red) mimic blood vessels; breast cancer cells (blue) are passing through the endothelial wall, into the bone-like matrix. (Credit: Jessie Jeon)


(Nearly 70 percent of patients with advanced breast cancer experience skeletal metastasis, in which cancer cells migrate from a primary tumor into bone — a painful development that can cause fractures and spinal compression. Not much is known about how and why certain cancers spread to specific organs, such as bone, liver, and lungs.)

The microchip contains several channels in which the researchers grew endothelial cells (that line the interior surface of blood vessels) and bone cells to mimic a blood vessel and bone side-by-side. They then injected a highly metastatic (tend to spread in the body) line of breast cancer cells into the fabricated blood vessel.

Rapid spread of cancer cells into bone

Cancer cells quickly metastsize (spread) through the blood vessel wall and into the bonelike environment (credit: Simone Bersini et al./Biomaterials)




Jeon says the experiments demonstrate that the microchip may be used in the future to test drugs that might block metastasis, and also as a platform for studying cancer’s spread to other organs.



The next stage of metastasis


Jeon and her colleagues captured images of the metastatic process: Cancer cells pushed through the vessel wall, spread into the bonelike environment, and clustered deep in the bone matrix to form tiny tumors. They found that twice as many cancer cells spread to the bonelike environment compared to a standard collagen matrix; these also spread deeper into the bone matrix, forming microclusters of up to 60 cells after five days.




In the future, such a platform may be used in personalized medicine to determine the best cancer therapy for a given patient. “One might envision using cells from the cancer patient to produce models of different organs, then using these models to determine the optimal therapy from a variety of available drugs,” Kamm says.

This research was supported by the National Cancer Institute and the Italian Ministry of Health.

Abstract of Biomaterials paper

Cancer metastases arise following extravasation of circulating tumor cells with certain tumors exhibiting high organ specificity. Here, we developed a 3D microfluidic model to analyze the specificity of human breast cancer metastases to bone, recreating a vascularized osteo-cell conditioned microenvironment with human osteo-differentiated bone marrow-derived mesenchymal stem cells and endothelial cells. The tri-culture system allowed us to study the transendothelial migration of highly metastatic breast cancer cells and to monitor their behavior within the bone-like matrix. Extravasation, quantified 24 h after cancer cell injection, was significantly higher in the osteo-cell conditioned microenvironment compared to collagen gel-only matrices (77.5 ± 3.7% vs. 37.6 ± 7.3%), and the migration distance was also significantly greater (50.8 ± 6.2 μm vs. 31.8 ± 5.0 μm). Extravasated cells proliferated to form micrometastases of various sizes containing 4 to more than 60 cells by day 5. We demonstrated that the breast cancer cell receptor CXCR2 and the bone-secreted chemokine CXCL5 play a major role in the extravasation process, influencing extravasation rate and traveled distance. Our study provides novel 3D in vitro quantitative data on extravasation and micrometastasis generation of breast cancer cells within a bone-like microenvironment and demonstrates the potential value of microfluidic systems to better understand cancer biology and screen for new therapeutics.