Where cancers spread to depends on cellular ‘soil prep’

As challenges go, understanding how cancers spread around the body is a biggy.

We know the locations tumour cells end up in isn’t random – breast cancer cells tend to head for the lungs, liver, bones or brain, for example.

But how they do this has remained a bit of a mystery.

In 1889, London doctor Stephen Paget planted the idea of ‘seed and soil’. He believed that tumour cells find the body’s ‘fertile ground’, seeding their secondary roots in the tissues that are most welcoming.

It’s a compelling idea, yet many believe it’s too simple a view of the problem.

But a new US study – published in the journal Nature – digs deeper into this theory, finessing the idea with some convincing data to back it up.

It turns out that instead of finding already fertile soil, cancer cells might actually be ploughing their own furrow in advance of spreading there. And, crucially, the discovery could one day help make predictions about whether a tumour might spread.

We asked our experts what they thought of the new findings.

Explaining where not why

Tumour cells tend to end up in their ‘favourite’ places in the body, even when their route via the bloodstream takes them everywhere. This has led to some head scratching, explains Professor Robert Insall, whose team at the Cancer Research UK Beatson Institute in Glasgow is also tackling how cancers spread – a process called metastasis.

Instead of spreading everywhere, certain cancers seem to settle where they know best.

The seeds of a spreading cancer – so-called circulating tumour cells – can be found at high levels in the bloodstream, even in people with no signs of any secondary tumours.

And, according to Insall, there are two probable reasons for this. The key players are the sticky ‘hooks’ that poke out from cells, called adhesion molecules. These anchor the cell where it meets a complementary protein – a bit like cellular Velcro.

“First, cells only stick down in places that have the correct adhesion molecules,” says Insall.

“Second, healthy cells often need a signal when they stick to the correct place to survive. If they don’t get that they may commit a particular form of suicide, called anoikis.”

This is the crux of the seed and soil theory: the right cell will survive in the right place.

But for a team of scientists at New York’s Weill Cornell Medical College and Memorial Sloan Kettering Cancer Center, just focussing on the cells and where they land doesn’t give the full picture.

‘It’s an amazing thing to think about’

Over the last decade the three teams – led by Professors Héctor Peinado, David Lyden and Dr Jaqueline Bromberg – have been building on Paget’s 126 year old idea, revealing that molecules released by cancer cells into the bloodstream might also be helping them spread.

And their latest discovery focuses on microscopic bubbles called exosomes.

“Cancer cells can release these little bubbles of membrane into the bloodstream,” says Professor Jim Norman, a Cancer Research UK expert in adhesion molecules and metastasis, also based at the Beatson Institute.

These tumour exosomes carry a cocktail of molecules, including proteins and DNA. And when they come into contact with a cell they can fuse with it, delivering their contents and changing how the cell behaves.

The sheer complexity of it is really an amazing thing to think about

– Professor Robert Insall

Working with experimental lab models, the US teams found that the membrane bubbles released by breast cancer cells move to particular organs in mice. “And this seems to lay the groundwork for the subsequent colonisation of that organ by the tumour cells,” explains Norman.

“The tumour cells prepare their favourite sites to spread to,” adds Insall. “The sheer complexity of it is really an amazing thing to think about.”

To test how powerful this effect was the researchers collected exosomes from different types of breast cancer cells that are known to prefer to spread to particular organs or tissues. Next, they treated mice with these different exosomes to see whether it would affect where the tumour cells went.

Fascinatingly, treatment with lung-targeting exosomes redirected breast cancer cells that would normally spread to bone, causing them to spread to the lungs instead.

“If the cells in other tissues take up exosomes they go from non-friendly places where tumour cells can’t flourish, to places that have everything a tumour needs to stop, survive and grow,” Insall says.

So how does this targeting work?

‘It’s staggering’

The researchers collected exosomes from cancer cells that prefer to spread to the brain, lung or liver, and carried out some molecular fingerprinting to see which proteins were most abundant in the different exosomes.

Here they landed on a group of sticky adhesion molecules called integrins, which play a crucial role in how cells move.

There are several different types of integrin molecules, which pair up on the surface of cells and stick to different proteins around the cells.

But the US team found that exosomes also carry integrins. And the different exosomes were equipped with specific combinations of integrin molecules on their surface, which Professor Norman – whose lab also works on integrins – explains was the key to how the exosomes find their preferred location.

The key point in this paper is that the precise components of the exosomes determine where a tumour can go. It’s staggering

– Professor Robert Insall

“The integrins on the surface of the exosomes help them stick to their favourite tissue,” he says.

“A breast tumour can release exosomes that are coated with an integrin that sticks to lung tissue. When released into the blood, those integrin-coated exosomes will lodge in the lung.

“Once in the lung, these exosomes ‘plough the furrow’, making it more likely that secondary tumours will seed there.”

It’s a really important discovery and, according to Insall, offers a “clear description” of how the seed and soil theory might actually work.

“The key point in this paper is that the precise components of the exosomes determine where a tumour can go. It’s staggering,” he says.

“Exosomes that are taken up by the liver allow the cancer to spread to the liver. If they’re taken up by the lungs, the mice get secondary lung tumours.”

But what about in people?

Predicting cancer spread

It’s now possible to extract exosomes from patient blood samples, which the US teams did with samples from breast cancer and pancreatic cancer. The samples were taken before there were any signs the disease had spread, and the researchers used these samples to search for integrins.

Crucially, exosomes fished out of blood samples from patients whose cancer later went on to spread carried increased levels of the same integrins the team had identified in the mice. And the specific type of integrins they found correctly matched, and therefore predicted, where the cancer cells later spread to.

So far this has only been shown with samples from two breast cancer patients and 13 pancreatic cancer patients, but the US teams hope to expand their analysis further.

“Our work suggests that a high level of certain integrins in the plasma of patients with breast and pancreas cancer seems to predict the organ where the metastasis will occur,” says Professor Peinado.

“But these data will have to be validated in larger studies,” he adds.

According to Norman, the potential to develop tests that could detect these integrins is particularly exciting.

“If the findings can be confirmed in larger studies this discovery could make it possible to develop tests to predict which tissues might be susceptible to cancer spreading there,” he says, adding that this could also be important for selecting treatments and monitoring these patients in the future.

And of course, it doesn’t unearth the wider mystery of metastasis: “The key part of this study is explaining where tumours spread to,” says Insall. “But it doesn’t explain why they start to spread.”

Over a century ago, Stephen Paget asked: “What is it that decides what organs shall suffer in a case of disseminated cancer?” This study offers one part of what will inevitably be a very complex answer to how cancers spread.

But perhaps, most importantly, it sows the seeds for what will ultimately find new ways to stop it.

Nick