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Cancer cells, courtesy of the LRI EM Dept

Conventional wisdom says that if you put a good kid in a bad school full of troublemakers, the chances are they’ll make mischief. Put a bad kid in a school of little angels, and they’ll be more likely to toe the line and behave. Before you start thinking that this has become a child psychology blog, rest assured that it’s actually a metaphor for cancer.

For years, researchers have been investigating the ‘tumour microenvironment’ – the cells, signals and biological cues that immediately surround cancer cells. These can have a powerful impact on tumours, either encouraging them to grow aggressively – the good kid gone bad – or keeping them under control, like the reformed ruffian.

This is particularly important for metastasis – the process by which cancer spreads. Cells break away from the original (primary) tumour and travel through the bloodstream, setting up home elsewhere in the body to form secondary cancers. It’s usually these secondary cancers that actually end up being a major problem, and often lead to death as they are difficult to treat effectively.

To continue the analogy, if the travelling cells settle in a ‘good school’, they might never grow into tumours. But if they end up in a bad microenvironment, then trouble can start.

Now Robert Weinberg and his team at MIT have made a discovery that adds an extra twist to this situation – primary cancers can send signals around the body, ‘activating’ the growth of secondary tumours at a distance. Their results are published in this week’s edition of the journal Cell.


Instigators and responders
For their experiments, the team used two different types of human breast cancer cells, grown in the lab. The first are ‘instigator’ cells, which always form aggressive primary tumours when injected into mice, while the second are ‘responder’ cells, which are less likely to form tumours.

The scientists injected instigator cells into one side of a mouse, then injected responder cells into the other. Effectively, this models the situation seen in cancer, with the instigator cells representing the aggressive primary tumour, and the responders mimicking cancer cells with the potential to form secondary tumours.

After a few weeks, the team found that the responder cells were actively growing into ‘secondary’ tumours in all of the mice that were injected with both types. But among mice that were injected solely with responder cells, only one in five developed tumours.

Further experiments showed that the secondary tumours in the mice injected with both types of cells weren’t due to migration of cancer cells from the primary ‘instigator’ tumour. So the responder cells must be growing in reply to some kind of message sent out by the instigator cells. But what is it?

Hunting the messenger

An obvious candidate for the mystery signal would be molecules produced by the instigator tumour that travel in the bloodstream, ‘feeding’ the responder cells and making them grow. But tests of the nutrient broth used to grow the instigator cells in the lab proved negative – they couldn’t encourage the responder cells to multiply.

Finally the mystery was solved, by referring back to experiments done in 2006 showing that cells from the bone marrow can get incorporated into tumours. Could these bone marrow cells be the messengers that tell the responder cells to grow?

After some clever experiments tracking fluorescent bone marrow cells around the body, Weinberg and his team found that it was true. Bone marrow cells become ‘mobilised’ by the primary instigator tumour, then travel through the body to encourage the responder cells to grow into secondary tumours. To return to our analogy, it’s a bit like a bully from a bad school being transferred to a good school and wreaking havoc there.

The osteopontin connection
But how do bone marrow cells get recruited by the primary tumours? The researchers found that the aggressive initiator cells in the primary tumour were producing a molecule called osteopontin – a sugary protein that’s involved in inflammation, the growth of blood vessels and tumour spread.

The scientists found that osteopontin was causing changes in the bone marrow, causing bone marrow cells to move into the tumour. At the moment, it’s not clear exactly how this happens, but the finding raises a host of possibilities. For example, could blocking osteopontin be an effective way to stop cancers from spreading, by hindering the growth of secondary tumours?

Intriguingly, the researchers also found that instigator breast cancer cells could not only encourage the growth of breast tumours, but also led to secondary tumours forming from bowel cancer cells. The fact that this activation works across different cancers seems to suggest that there might be a fundamental process at work, applicable to many tumour types.

As is often the case, it’s still early days, and these experiments have only been carried out in mice. But they challenge our current understanding of how secondary tumours form, and could point to new ways to treat cancer that has spread, or even prevent the growth of secondaries in the first place.

Kat

Image courtesy of the Cancer Research UK LRI EM Unit.

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