Cancer cells become more aggressive when migrating through small spaces
The findings of new research
suggest that squeezing through tight spaces makes cancer cells more
aggressive and helps them evade cell death.
The findings, published in 'eLife', reveal how mechanical stress makes cancer cells more likely to spread, or metastasis.
While metastasis is the cause of most cancer deaths, there are
currently no available cures. However, the new results may help
scientists develop novel approaches to treat or prevent metastasis. It
can be a tight squeeze for cancer cells to escape their tumour or enter
tiny blood vessels, called capillaries, to spread through the body. The
cells must collapse and change their shape to do this, in a process
called confined migration. As they spread, the cells must also avoid
detection and destruction by the immune system.
"Mechanical stress can cause cancer cell mutations, as well as an
uncontrolled increase in cell numbers and greater tissue invasion,"
explains first author Deborah Fanfone, 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 answer these questions, Fanfone and colleagues forced human
breast cancer cells through a membrane with tiny, three-micrometer-sized
holes to simulate a confined migration environment. After just one
passage through the membrane, they found that the cells became more
mobile and resistant 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 increased expression of
inhibitory-of-apoptosis proteins (IAPs) increased the resistance of
cancer cells to anoikis. Treating the cancer cells with a new type of
cancer drug called a SMAC mimetic, which degrades IAPs, removed this
protection.
The team then studied how breast cancer cells that had undergone
confined migration behave when administered to immune-suppressed mice.
They found these mice developed more lung metastases than mice that were
administered with breast cancer cells that had not been exposed to
confined migration.
"By mimicking confined migration, we've been able to explore its
multifaceted effects on cancer aggressiveness," says senior author
Gabriel Ichim, who leads the Cancer Cell Death team at the Cancer
Research Center of Lyon. "We've shown how the process boosts survival in
cancer cells and makes them more prone to forming deadly metastases."
The authors add that these results may lead to additional studies
of potential metastasis treatments, 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 tested in
clinical trials as a possible new treatment approach.