Study Says Cancer Cells Get More Aggressive After Squeezing Through Tight Spaces
Elizabeth Morey
Researchers are always working to learn more about the mechanics behind the development and spread of cancer so that they have more possible routes to treat and cure it. Now a new study has demonstrated a new characteristic not previously known about cancer cells, namely that the stress of squeezing through tight spaces contributes to them becoming more aggressive and harder to treat.
Cancer cells often undergo a tight squeeze when they're exiting their tumor of origin or entering a very tiny capillary. To get through these spaces, the cells must change shape in a process called confined migration, which can cause mutations. Scientists wondered if confined migration might change cancer cells in other ways too.
The study, published in eLife, set out to determine what effects the physical stress of being squeezed had on cancer cells and whether it had anything to do with metastasis.
"Mechanical stress can cause cancer cell mutations, as well as an uncontrolled increase in cell numbers and greater tissue invasion," says Deborah Fanfone, first author of the study and postdoctoral fellow at the Cancer Research Center of Lyon, France. "We wanted to know if the mechanical stress of confined migration makes cancer cells more likely to metastasise, and how this happens."
To accomplish this task, Fanfone and her colleagues isolated human breast cancer cells and forced them through holes in a membrane only three micrometers wide.
After going through the holes just one time, the breast cancer cells became more mobile and less prone to attack by immune cells. They were notably more resistant to a type of programmed cell death called anoikis, which occurs when cells detach from their tumor and no longer have an extracellular matrix to help sustain them.
The experimentation also showed that inhibitory-of-apoptosis proteins (IAPs) were capable of increasing cancer cells' resistance to anoikis. Treatment with a SMAC mimetic, however, degraded the IAPs and removed the resistance to anoikis.
The team then studied how breast cancer cells that had been through confined migration acted when they were given to immune-suppressed mice. The mice that were given cells that had undergone confined migration developed more lung metastases than those that were given normal breast cancer cells.
Overall, researchers learned that mechanical stress from confined migration improves a cell's ability to evade the immune system and avoid cell death. They also become more aggressive and more likely to metastasize after passing through small spaces.
"By mimicking confined migration, we've been able to explore its multifaceted effects on cancer aggressiveness," says senior author Gabriel Ichim, leader of the Cancer Cell Death team at Lyon's Cancer Research Center. "We've shown how the process boosts survival in cancer cells and makes them more prone to forming deadly metastases."
Because metastasis is the main cause of most cancer-related deaths, being able to prevent cells from metastasizing could save countless lives. The results of this study could help researchers develop new approaches to treating and preventing metastasis. Future therapies may include those that block IAPs (like SMAC mimetics) or soften tumors to reduce mechanical stress on cancerous cells.
