There's apparently safety in numbers, even for cancer cells.

New research in mice suggests that cancer cells rarely form metastatic tumours on their own, preferring to travel in groups since collaboration seems to increase their collective chances of survival, according to researchers at Johns Hopkins.

In a report on the study, published online the week of Feb. 1 in the Proceedings of the National Academy of Sciences, the investigators say they also found evidence that travelling cells differ from those multiplying within a primary tumour, and that difference may make them naturally resistant to chemotherapy.

"We found that cancer cells do two things to increase their chances of forming a new metastasis," says Andrew Ewald, Ph.D., associate professor of cell biology at the Johns Hopkins University School of Medicine.

"They turn on a molecular programme that helps them travel through a diverse set of environments within the body, and they travel in groups."

According to Ewald, conventional wisdom holds that cancer cells leave tumours one by one to colonise other areas of the body, but clinical and genetic evidence has mounted over the last 10 years to suggest otherwise.

He and his team set out to settle the question using mice with a form of mammary gland cancer, which consistently metastasises to the lungs, making it a favoured research tool.

In their first experiments, Ewald and his team removed tumours from mice whose cells were genetically engineered to glow either red or green under special lights.

They then implanted those red and green tumours in the mammary glands of mice whose cells did not glow and looked for metastases in the lungs.

If single cells colonised new metastases, the cell clumps would only ever glow one colour or the other.

Instead, the researchers found many multicoloured clumps and, using computer modelling of this pattern, discovered that most of the single-coloured clumps had also arisen from multiple cells that happened to glow the same colour.

In all, they estimate that less than 3 percent of the metastases came from a single cell.

To catch sight of the cell clumps before they reached their destination in the lungs, the researchers looked for them in the tissue just outside the primary tumours, in the blood vessels surrounding the tumours and in circulating blood.

At each step, they found multicoloured clusters of cells.

Next, to figure out if group travel gave the cells an advantage, the team compared the ability of single cells and clusters to form colonies.

They began with two test groups with equal numbers of cells in dishes filled with a gelatine-like commercial product that mimics the tissue surrounding mammary tumours.

They found that clusters were more than 15 times better at forming colonies than single tumour cells and, when they repeated the test in mice, the clusters were more than 100 times better at creating large metastases.

"You can think of metastasis as The Amazing Race," says Ewald.

"The cells encounter many different challenges as they attempt to grow and spread, and some cells are better at different events than others, so travelling in a group makes sense."

Ewald says his team also looked at whether travelling cells showed any particular molecular hallmarks that could be used to predict and ultimately prevent tumour spread.

Previous work in his laboratory showed that cells are usually 'led' out of tumours by cells decorated with the protein K14, so they started there.

Indeed, he says, the team found that K14 levels are quite low in primary tumours and large metastases but high in small, travelling clusters of cells.

Experiments in petri dishes showed that the cells switched between two molecular programmes - one for proliferation and one for metastasis - and that the level of K14 revealed which programme was 'on' in any given cell.

"Because most chemotherapeutic drugs target proliferating cells, metastasising cells won't be killed by them, leaving patients vulnerable to new tumours," explains Ewald.

"Our discoveries add to knowledge that could help overcome that vulnerability."

The team, he adds, was able to use K14 to separate the two types of cells and compare their gene activity.

"We found that the activity of dozens of genes differs between proliferating and metastasising cells," says Ewald.

"Since many of those genes encode cell surface proteins, we hope these findings might eventually be used to develop new drugs that target metastasising cells."

Source: Johns Hopkins Medicine