Breakthrough could prevent breast cancer spreading

Breakthrough could prevent breast cancer spreading

Breakthrough could prevent breast cancer spreading

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The way breast cancer cells spread to other parts of the body - increasing the risk of the patient dying - has been identified by scientists.

The spread of cancer cells from one part of the body to another - a process known as "metastasis" - is the leading cause of death among cancer patients.

Now new research reveals why some cancer cells may be more metastatic than others.

The findings, published in the journal Biophysical Journal, show that breast cancer cells spread to other parts of the body by "sliding" around other cells blocking their escape route out of the original tumour.

Senior study Doctor Anand Asthagiri, of Northeastern University, said: "We demonstrate a quantitative ruler for measuring how well a cell is able to slide.

"By putting numbers to this cellular behaviour, we can not only discern which pathways regulate sliding, but also how much. This opens the door to finding the most powerful

drivers of sliding behavior and strategies to curb this invasive behaviour."

To invade other tissues in the body, cancer cells migrate along collagen protein fibres that serve as a path out of the original tumour.

But these fibres are very narrow and the micro-environment is crowded with other cells, so it has not been clear how metastatic cancer cells get past obstacles and successfully navigate this spatially constrained environment.

Dr Asthagiri said: "Keep in mind that each cell is 10-15 micron wide and is finding a way to slide past a neighbour, also 10-15 micron wide.

"And they do all this on a track that is only 5 microns wide.

"How they physically squeeze, extend and wrap around is really remarkable and a fascinating biophysical problem.

"We were very interested in sorting out the mechanics and regulation of how cells accomplish this, and why cancer cells are particularly adept at it."

To answer the question, Dr Asthagiri and his colleagues stamped a glass surface with micropatterned lines of fibronectin protein, and then used time-lapse microscopy to study collisions between pairs of cells deposited on the adhesive fibres.

On micropatterns that were only 6 microns or 9 microns wide, mimicking conditions in the tumour environment, 99 per cent of normal breast cells stopped and reversed direction upon physical contact with another cell.

By contrast, about half of metastatic breast cancer cells responded to collisions by sliding past the other cell, maintaining their migratory path along the protein track.

However, Dr Asthagiri said the normal breast cells were much more likely to slide past other cells when the researchers either increased the micro-pattern width to 33 micron, or reduced levels of E-cadherin - a sticky membrane protein that binds cells together.

Meanwhile, increased levels of E-cadherin diminished the sliding behaviour of metastatic breast cancer cells.

Additional experiments revealed that proteins implicated in metastasis cooperate to regulate cell-sliding behaviour.

Taken together, Dr Asthagiri said the findings show the key role of cell sliding in supporting metastasis, and the molecular pathways that allow it to happen.

Now the researchers plan to further explore the underlying molecular mechanisms and test whether the system they developed can be used as a screening platform to find molecular targets that inhibit cell sliding.

Dr Asthagiri added: "Because our results provide a ruler to measure the extent to which genetic perturbations enable sliding, it offers a way to rank order molecular pathways and to identify combinations of genes that have synergistic effect on sliding potential.

"Sliding, and we believe invasiveness more broadly, is a property that's progressively accrued, with each cancer-promoting event measurably shifting the degree of invasiveness.

"Having a ruler allows us to quantify how far cells have transformed and how effective one therapy is versus another."

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