Tissue Stiffness Can Increase Cell Mutation Rate

Multiple tissues across the body become stiffer with age, and according to new research cells in tougher tissue like bone may actually be more vulnerable to mutation

Progressive stiffening of tissue as you get older occurs due to a combination of factors including muscle loss and dehydration, but a large contributor is the accumulation of material your body can't remove. Sugars and compounds taken in through your diet lead to things called advanced glycation end products (AGEs) that form cross-links with connective tissue. All of these changes slowly but surely lead to a stiffening of many tissue types which may in itself squeeze and damage cell integrity according to the latest finding.

A tighter squeeze can create more mutations

Researchers at the University of Pennsylvania first conducted a meta-analysis on the varying tumour mutation rates in different organs. They discovered that cancerous cells in stiffer regions like bone and lung tissue surprisingly displayed mutation rates and chromosomal abnormalities around 100 times higher than those in soft tissue - like the brain and marrow.

"Basically, we hypothesize that stiffer tissues with their denser matrix and smaller constrictions cause more nucleus deformation that damages the nucleus"

Age-related stiffening and loss of tissue flexibility could cause higher mutation risk

To examine this intriguing finding further, the team designed an experiment involving two cancer cell lines from bone and lung tissue. They then coaxed them to migrate through tiny filters with 3 micrometre holes, which is much smaller than a cell. Just as mice can squeeze themselves through unbelievably small spaces, the cells can condense and travel through the restricted space.

At a cost

The experiment revealed that while larger 8 micrometre holes had no effect, squeezing through such a restricted space led to DNA damage accumulation. This was observed through an increased presence of DNA repair proteins.

"Imagine modeling the DNA as threads in a small cottonball that is squeezed into a small see-through straw. We think that such compaction reduces porosity and severely limits the mobility of protein to follow the DNA. This nuclear constriction - with local deficits in DNA repair factors - should reduce the repair rate, and thus increase mutation rates. What we are addressing right now is whether this constricted migration with molecular damage and segregation will translate to genomic instability, which is a 'hallmark' of cancer. Cancer needs to invade to spread, and that invasion could itself cause mutations"

While the study has important implications, the findings were established from already cancerous cell lines so more work would have to be conducted on ordinary cells to see whether a similar effect is observed in age-related stiffening for example.

Read more at MedicalXpress