Squeezing through narrow spaces increases cancer cells'' potential potential to become more aggressive and assists them in avoiding cell death, according to a study published today ineLife.
Mechanical stress increases cancer cell proliferation, but there are currently no treatments to prevent metastasis.
Cancer cells may be forced to escape their tumour or enter tiny blood vessels, called capillaries, to spread through the body. In a process called confined migration, the cells must also avoid detection and destruction by the immune system.
Mechanical stress is causing cancer cell failures, as well as an uncontrolled increase in cell numbers and even greater tissue invasion, according to first author Deborah Fanfone, a postdoctoral researcher at the Cancer Research Center of Lyon, France. We wanted to see if cancer cells are more likely to metastasise, and how this unfolds.
To answer these questions, Fanfone and colleagues forced human breast cancer cells to a membrane with tiny, three-micrometre-sized holes to simulate a confined migration environment. After only one passage through the membrane, they discovered that the cells became more responsive to anoikis, a form of programmed cell death that occurs when cells become detached from the surrounding network of proteins and other molecules that support them (the extracellular matrix). The cells were also able to escape destruction by immune natural killer cells.
Further experiments showed that the expression of inhibitory-of-apoptosis proteins (IAPs) increased the resistance of cancer cells to anoikis. Taking the cancer cells with a new type of cancer medication called a SMAC mimetic, which degrades IAPs, altered this protection.
The researchers studied how breast cancer cells that had undergone confined migration developed when administered to immune-suppressed mice. These mice found that lung metastases were greater than those that were administered with breast cancer cells that had not been exposed to confined migration.
Despite the impact of restricted migration on cancer aggressiveness, we have able to investigate it, according to senior author Gabriel Ichim, who leads the Cancer Cell Death team at the Cancer Research Center of Lyon. Using the technique, we have shown how survival in cancer cells improves their survival and increase the risk of developing deadly metastases.
These findings suggest that further research may be conducted on potentially novel metastasis therapies, such as therapies that soften tumours to reduce mechanical stress on cancer cells, or that block IAPs. These include SMAC mimetics, which are currently being used in clinical trials as a potential new treatment approach.