To investigate which possibility is more likely, the researchers grew a network of tiny blood vessels from a solution of human umbilical-cord endothelial cells. They injected a solution containing vascular cells into a small microfluidic device containing a reservoir of hydrogel, along with growth factors normally present in the developing circulatory system. Within days, an intricate system of microvessels took shape, with each about one millimeter long and 10 to 100 microns in diameter -- dimensions similar to the body's small capillaries.
The group then pumped tumor cells through the vascular network, using a line of breast cancer cells known to be particularly invasive. Using high-resolution confocal microscopy, the team watched as tumor cells flowed through the miniature circulatory system. They observed that the majority of cells that arrested along a vessel did so due to entrapment -- that is, they simply became stuck.
A tumor cell finds a way out
With time-lapse images, the researchers took a closer look at the progression of events following cell arrest. Once a tumor cell becomes trapped, they observed that it sends out long, thin filaments that push against a vessel wall, eventually creating a small hole in the endothelial lining. More and more of the cell squeezes through as the holes give way, and eventually, even the cell's nucleus -- thought to be a relatively rigid, nondeformable structure -- is able to escape.
To their surprise, the researchers found that the nucleus made it through the vessel wall earlier and more quickly than they anticipated, squeezing through in about 15 minutes -- "a tiny chunk of the time it takes for this entire cell to extravasate," Chen notes.
Interestingly, Chen points out, once a tumor cell has completely exited a blood vessel, the endothelium app
|Contact: Andrew Carleen|
Massachusetts Institute of Technology